British Society of Gastroenterology Best Practice Guidance: outpatient management of cirrhosis - part 3: special circumstances.

The prevalence of cirrhosis has risen significantly over recent decades and is predicted to rise further. Widespread use of non-invasive testing means cirrhosis is increasingly diagnosed at an earlier stage. Despite this, there are significant variations in outcomes in patients with cirrhosis across the UK, and patients in areas with higher levels of deprivation are more likely to die from their liver disease. This three-part best practice guidance aims to address outpatient management of cirrhosis, in order to standardise care and to reduce the risk of progression, decompensation and mortality from liver disease. Part 1 addresses outpatient management of compensated cirrhosis: screening for hepatocellular cancer, varices and osteoporosis, vaccination and lifestyle measures. Part 2 concentrates on outpatient management of decompensated disease including management of ascites, encephalopathy, varices, nutrition as well as liver transplantation and palliative care. In this, the third part of the guidance, we focus on special circumstances encountered in managing people with cirrhosis, namely surgery, pregnancy, travel, managing bleeding risk for invasive procedures and portal vein thrombosis.

British Society of Gastroenterology Best Practice Guidance: outpatient management of cirrhosis - part 1: compensated cirrhosis.

The prevalence of cirrhosis has risen significantly over recent decades and is predicted to rise further. Widespread use of non-invasive testing means cirrhosis is increasingly diagnosed at an earlier stage. Despite this, there are significant variations in outcomes in patients with cirrhosis across the UK, and patients in areas with higher levels of deprivation are more likely to die from their liver disease. This three-part best practice guidance aims to address outpatient management of cirrhosis, in order to standardise care and to reduce the risk of progression, decompensation and mortality from liver disease. Here, in part one, we focus on outpatient management of compensated cirrhosis, encompassing hepatocellular cancer surveillance, screening for varices and osteoporosis, vaccination and lifestyle measures. We also introduce a compensated cirrhosis care bundle for use in the outpatient setting. Part two concentrates on outpatient management of decompensated disease including management of ascites, encephalopathy, varices, nutrition as well as liver transplantation and palliative care. The third part of the guidance covers special circumstances encountered in managing people with cirrhosis: surgery, pregnancy, travel, managing bleeding risk for invasive procedures and portal vein thrombosis.

British Society of Gastroenterology Best Practice Guidance: outpatient management of cirrhosis - part 2: decompensated cirrhosis.

There are two distinct phases in the natural history of cirrhosis: compensated disease (corresponding to Child Pugh A and early Child Pugh B disease), where the patient may be largely asymptomatic, progressing with increasing portal hypertension and liver dysfunction to decompensated disease (corresponding to Child Pugh late B-C), characterised by the development of overt clinical signs, including jaundice, hepatic encephalopathy (HE), ascites, renal dysfunction and variceal bleeding. The transition from compensated cirrhosis to decompensated cirrhosis (DC) heralds a watershed in the nature and prognosis of the disease. DC is a systemic disease, characterised by multiorgan/system dysfunction, including haemodynamic and immune dysfunction. In this second part of our three-part series on the outpatient management of cirrhosis, we address outpatient management of DC, including management of varices, ascites, HE, nutrition, liver transplantation and palliative care. We also introduce an outpatient DC care bundle. For recommendations on screening for osteoporosis, hepatocellular carcinoma surveillance and vaccination see part one of the guidance. Part 3 of the guidance focusses on special circumstances encountered in patients with cirrhosis, including surgery, pregnancy, travel, management of bleeding risk for invasive procedures and portal vein thrombosis.

Guidance document: risk assessment of patients with cirrhosis prior to elective non-hepatic surgery.

As a result of the increasing incidence of cirrhosis in the UK, more patients with chronic liver disease are being considered for elective non-hepatic surgery. A historical reluctance to offer surgery to such patients stems from general perceptions of poor postoperative outcomes. While this is true for those with decompensated cirrhosis, selected patients with compensated early-stage cirrhosis can have good outcomes after careful risk assessment. Well-recognised risks include those of general anaesthesia, bleeding, infections, impaired wound healing, acute kidney injury and cardiovascular compromise. Intra-abdominal or cardiothoracic surgery are particularly high-risk interventions. Clinical assessment supplemented by blood tests, imaging, liver stiffness measurement, endoscopy and assessment of portal pressure (derived from the hepatic venous pressure gradient) can facilitate risk stratification. Traditional prognostic scoring systems including the Child-Turcotte-Pugh and Model for End-stage Liver Disease are helpful but may overestimate surgical risk. Specific prognostic scores like Mayo Risk Score, VOCAL-Penn and ADOPT-LC can add precision to risk assessment. Measures to mitigate risk include careful management of varices, nutritional optimisation and where possible addressing any ongoing aetiological drivers such as alcohol consumption. The role of portal decompression such as transjugular intrahepatic portosystemic shunting can be considered in selected high-risk patients, but further prospective study of this approach is required. It is of paramount importance that patients are discussed in a multidisciplinary forum, and that patients are carefully counselled about potential risks and benefits.

The National Audit of Primary Biliary Cholangitis (PBC) in the United Kingdom: Defining the Audit Dataset and Data Collection System.

Primary biliary cholangitis (PBC) is a debilitating chronic liver disease that progresses to cirrhosis with attendant complications in a substantial proportion of patients. It is a major cause of liver-related morbidity and mortality in the United Kingdom (UK). The British Society of Gastroenterology (BSG) published guidelines on PBC management, which included key audit standards. Therefore, we propose the first UK-wide audit of the management of PBC, sanctioned by the BSG and the British Association for Study of the Liver (BASL), to benchmark NHS trusts and health boards against these audit standards as a guide to targeted improvement in the delivery of PBC-related health care.

Liver transplantation for alcohol-related liver disease in the UK: revised UK Liver Advisory Group recommendations for referral.

Liver disease, of which liver cirrhosis is the most advanced stage, constitutes the fourth most common cause of life-years lost in men and women younger than 75 years in England, where mortality rates from liver disease have increased by 25% in the past decade. Alcohol consumption is the most common modifiable risk factor for disease progression in these individuals, but within the UK, there is substantial variation in the distribution, prevalence, and outcome of alcohol-related liver disease, and no equity of access to tertiary transplantation services. These revised recommendations were agreed by an expert panel convened by the UK Liver Advisory Group, with the purpose of providing consensus on referral for transplant assessment in patients with alcohol-related disease, and clarifying the terminology and definitions of alcohol use in liver injury. By standardising clinical management in these patients, it is hoped that there will be an improvement in the quality of care and better access to liver transplant assessment for patients with alcohol-related liver disease in the UK.

Guidelines on the management of ascites in cirrhosis.

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the 'Grading of Recommendations Assessment, Development and Evaluation (GRADE)' system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years' time.

A stepwise thrombolysis regimen in the management of acute portal vein thrombosis in patients with evidence of intestinal ischaemia.

BACKGROUND: Anticoagulation alone in acute, extensive portomesenteric vein thrombosis (PVT) does not always result in spontaneous clot lysis, and leaves the patient at risk of complications including intestinal infarction and portal hypertension. AIM: To develop a new standard of care for patients with acute PVT and evidence of intestinal ischaemia. METHODS: We present a case series of patients with acute PVT and evidence of intestinal ischaemia plus ongoing symptoms despite initial systemic anticoagulation, who were treated with a thrombolysis protocol between 2014 and 2019. This stepwise protocol initially uses low-dose systemic alteplase, and in patients with ongoing abdominal pain, and no evidence of radiological improvement, is followed by local clot dissolution therapy (CDT) through a TIPSS. Outcomes and safety were assessed. RESULTS: Twenty-two patients were included. The mean age was 44.6 (standard deviation [SD] 16.0) years, and 64% had an identifiable prothrombotic risk factor. All patients had intestinal wall oedema and 77% had complete occlusion of all portomesenteric veins. Systemic thrombolysis was started 18.7 (SD 11.2) days after the onset of symptoms. 55% of patients underwent TIPSS insertion for CDT. At the end of treatment, symptoms resolved in 91% of patients and recanalisation in 86%. Only one patient required resection for intestinal ischaemia, and there were no deaths. Major complications occurred in two patients (9%). CONCLUSIONS: Our stepwise protocol is effective, resulting in good recanalisation rates. It can be commenced early while organising transfer to a centre capable of performing local CDT.

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.

Subclinical spontaneous bacterial peritonitis at the time of liver transplantation does not impact on outcomes.

OBJECTIVES: Liver transplant recipients are often screened for spontaneous bacterial peritonitis during the immediate preoperative evaluation to determine medical fitness to proceed. However, it is unknown whether subclinical spontaneous bacterial peritonitis impacts on post-transplant outcomes. Our aim was to determine whether subclinical spontaneous bacterial peritonitis detected at the preoperative evaluation influences the decision to proceed, and subsequent postoperative morbidity and mortality. METHODS: This study is a single-centre study of 1231 adults attending for possible first elective single-organ liver transplantation between January 2000 and December 2011. RESULTS: A total of 434 patients underwent ascitic fluid sampling on 460 occasions. Nineteen samples fulfilled the diagnostic criteria for spontaneous bacterial peritonitis (4.8%), including one that was culture positive (Candida spp.). Patients with spontaneous bacterial peritonitis had a higher serum bilirubin level than nonspontaneous bacterial peritonitis patients (P=0.018). Out of the 19 patients, 16 (84.2%) with a positive sample proceeded to transplantation on that occasion; the ascitic microscopy result did not influence the decision to proceed in any clinically stable patient. The 30-day post-transplant survival was 93.8% for spontaneous bacterial peritonitis patients and 96.2% for nonspontaneous bacterial peritonitis patients (P=0.478). After adjusting for recipient age, UK Score for Patients with End-Stage Liver Disease (UKELD) and donor risk index, there was no association between a positive tap and death within 30 days (P=0.649). CONCLUSION: Subclinical spontaneous bacterial peritonitis is rare in patients admitted for elective liver transplantation, does not influence the decision to proceed and is not associated with increased post-transplant mortality. Our findings suggest that routine preoperative ascitic fluid sampling is not indicated in clinically stable potential transplant recipients.

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

OBJECTIVE: Recent data have suggested that non-selective ß-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.

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

BACKGROUND & AIMS: 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. METHODS: A single centre study of 570 patients listed for first elective single-organ liver transplantation January 2007-June 2011. RESULTS: The median listing neutrophil-to-lymphocyte ratio was 2.9 (IQR 1.9-4.7). Neutrophil-to-lymphocyte ratio demonstrated a positive correlation with listing serum bilirubin (P < 0.001), negative correlation with serum sodium (P < 0.001), and positive correlation with the MELD score (P < 0.001). Neutrophil-to-lymphocyte ratio increased with increasing severity of ascites (P < 0.001). A higher neutrophil count (P < 0.001) and lower lymphocyte count (P = 0.001) were predictors of wait-list death. In a multivariate competing risk Cox model, neutrophil-to-lymphocyte ratio remained independently associated with mortality (HR 1.10; 95% CI 1.05-1.15, P < 0.001). The proportion of patients with a neutrophil-to-lymphocyte ratio <2, 2-4.9, and ≥5 who had died by 3 months of listing was 3%, 13.8% and 37.3% respectively (P < 0.001). After adjusting for MELD, increasing increments of neutrophil-to-lymphocyte ratio were predictive of death by 3 months (P = 0.043). CONCLUSIONS: The blood neutrophil-to-lymphocyte ratio, a simple and readily available marker of systemic inflammation, is an independent predictor of mortality in patients with liver failure 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.

Split liver transplant recipients do not have an increased frequency of acute kidney injury.

Small series have suggested that split liver transplantation (SLT) has an increased frequency of peri-operative acute kidney injury (AKI). However, the optimal donor selection in this setting could have a favourable impact on renal outcomes. This was a retrospective single-centre study of 76 adults who underwent SLT (right extended lobe) and 301 adults who underwent elective full-size donation after brain death liver transplantation (FSLT). SLT recipients were less likely than unmatched FSLT recipients to develop AKI (≥stage 1 KDIGO criteria) (40.3% vs. 56.1%, P = 0.016) and had a reduced frequency of renal replacement therapy (11.8% vs. 21.9%, P = 0.049). In 72 pairs of SLT patients and propensity risk score-matched FSLT controls the incidence of AKI was not significantly different (40.3% vs. 47.2%, P = 0.473). However, SLT patients were less likely to require renal replacement therapy (11.1% vs. 23.6%, P = 0.078; adjusted OR 0.32; 95% CI 0.11-0.87, P = 0.026). There was no association between SLT and the development of chronic kidney disease (eGFR<60 ml/min/1.73 m(2) , log rank P = 0.534). In conclusion, SLT is not associated with an increased frequency of AKI. These observations support the postulation that the optimal donor status of SLT may result in less graft injury with renal sparing effects.

Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding.

BACKGROUND & AIMS: Rebleeding after an initial oesophageal variceal haemorrhage remains a significant problem despite therapy with band ligation, non-selective ß-blockers or a combination of these. Carvedilol is a vasodilating non-selective ß-blocker with alpha-1 receptor and calcium channel antagonism. A recent study has suggested it is effective in the prevention of a first variceal bleed. Our aim was to compare oral carvedilol with variceal band ligation (VBL) in the prevention of rebleeding following a first variceal bleed. METHODS: Patients who were stable 5 days after presentation with a first oesophageal variceal haemorrhage and had not been taking ß-blockers were randomised to oral carvedilol or VBL. Patients were followed-up after one week, monthly, then every 3 months. The primary end point was variceal rebleeding on intention-to-treat analysis. RESULTS: 64 patients were randomised, 33 to carvedilol and 31 to VBL. 58 (90.6%) patients had alcohol related liver disease. Age and Child-Pugh score were similar in both groups at baseline. Median follow-up was 26.3 (interquartile range [IQR] 10.2-46.6)months. Compliance was 68% and 65% for carvedilol and VBL respectively (p=0.993) and serious adverse events between the two groups were similar (p=0.968). Variceal rebleeding occurred during follow-up in 12 (36.4%) and 11 (35.5%) patients in the carvedilol and VBL groups, respectively (p=0.857), with 9 (27.3%) and 16 (51.6%) deaths in each group, respectively (p=0.110). CONCLUSIONS: Carvedilol is not superior to VBL in the prevention of variceal rebleeding. The trend to a survival benefit for patients taking this drug compared with those undergoing banding requires further exploration.

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.