Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE trial).

INTRODUCTION: Liver cirrhosis is the fifth largest cause of adult deaths, and a major complication, variceal bleeding is associated with a 1-year mortality of 40%. There is uncertainty on the first-line therapy for prevention of variceal bleeding owing to a lack of adequately powered trials comparing non-selective beta blockers, in particular carvedilol, with variceal band ligation. METHODS AND ANALYSIS: CALIBRE is a multicentre, pragmatic, randomised controlled, open-label trial with an internal pilot. The two interventions are carvedilol 12.5 mg od or variceal band ligation (VBL). Patients with liver cirrhosis and medium to large oesophageal varices that have never bled are eligible for inclusion. The primary outcome is any variceal bleeding within 1 year of randomisation. Secondary endpoints include time to variceal bleed, mortality, transplant-free survival, adverse events, complications of cirrhosis, health-related quality of life, use of healthcare resources, patient preference and use of alternative or crossover therapies. The sample size is 2630 patients over a 4-year recruitment period, across 66 hospitals in the UK. ETHICS AND DISSEMINATION: The study has been approved by a National Health Service (NHS) Research Ethics Committee (REC) (reference number 18/NE/0296). The results of this trial will be submitted for publication in a peer reviewed journal. Participants will be informed via a link to a preview of the publication. A lay summary will also be provided via email or posted to participants prior to publication (ISRCTN reference number: 73887615).

Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: a systematic review and dose-response meta-analysis.

OBJECTIVES: To examine the association between coffee, including caffeinated and decaffeinated coffee, with hepatocellular carcinoma (HCC) and assess the influence of HCC aetiology and pre-existing liver disease. DESIGN: We performed a systematic review and meta-analysis. We calculated relative risks (RRs) of HCC according to caffeinated and decaffeinated coffee consumption using a random-effects dose-response meta-analysis. We tested for modification of the effect estimate by HCC aetiology and pre-existing liver disease. We judged the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. RESULTS: We found 18 cohorts, involving 2 272 642 participants and 2905 cases, and 8 case-control studies, involving 1825 cases and 4652 controls. An extra two cups per day of coffee was associated with a 35% reduction in the risk of HCC (RR 0.65, 95% CI 0.59 to 0.72). The inverse association was weaker for cohorts (RR 0.71, 95% CI 0.65 to 0.77), which were generally of higher quality than case-control studies (RR 0.53, 95% CI 0.41 to 0.69). There was evidence that the association was not significantly altered by stage of liver disease or the presence/absence of high alcohol consumption, high body mass index, type 2 diabetes mellitus, smoking, or hepatitis B and C viruses. An extra two cups of caffeinated and decaffeinated coffee (2 and 3 cohort studies, respectively) were associated with reductions of 27% (RR 0.73, 95% CI 0.63 to 0.85) and 14% (RR 0.86, 95% CI 0.74 to 1.00) in the risk of HCC. However, due to a lack of randomised controlled trials, potential publication bias and there being no accepted definition of coffee, the quality of evidence under the GRADE criteria was 'very low'. CONCLUSIONS: Increased consumption of caffeinated coffee and, to a lesser extent, decaffeinated coffee are associated with reduced risk of HCC, including in pre-existing liver disease. These findings are important given the increasing incidence of HCC globally and its poor prognosis.

(1)H nuclear magnetic resonance spectroscopy-based metabonomic study in patients with cirrhosis and hepatic encephalopathy.

AIM: To identify plasma metabolites used as biomarkers in order to distinguish cirrhotics from controls and encephalopathics. METHODS: A clinical study involving stable cirrhotic patients with and without overt hepatic encephalopathy was designed. A control group of healthy volunteers was used. Plasma from those patients was analysed using (1)H - nuclear magnetic resonance spectroscopy. We used the Carr Purcell Meiboom Gill sequence to process the sample spectra at ambient probe temperature. We used a gated secondary irradiation field for water signal suppression. Samples were calibrated and referenced using the sodium trimethyl silyl propionate peak at 0.00 ppm. For each sample 128 transients (FID's) were acquired into 32 K complex data points over a spectral width of 6 KHz. 30 degree pulses were applied with an acquisition time of 4.0 s in order to achieve better resolution, followed by a recovery delay of 12 s, to allow for complete relaxation and recovery of the magnetisation. A metabolic profile was created for stable cirrhotic patients without signs of overt hepatic encephalopathy and encephalopathic patients as well as healthy controls. Stepwise discriminant analysis was then used and discriminant factors were created to differentiate between the three groups. RESULTS: Eighteen stabled cirrhotic patients, eighteen patients with overt hepatic encephalopathy and seventeen healthy volunteers were recruited. Patients with cirrhosis had significantly impaired ketone body metabolism, urea synthesis and gluconeogenesis. This was demonstrated by higher concentrations of acetoacetate (0.23 ± 0.02 vs 0.05 ± 0.00, P < 0.01), and b-hydroxybutarate (0.58 ± 0.14 vs 0.08 ± 0.00, P < 0.01), lower concentrations of glutamine (0.44 ± 0.08 vs 0.63 ± 0.03, P < 0.05), histidine (0.16 ± 0.01 vs 0.36 ± 0.04, P < 0.01) and arginine (0.08 ± 0.01 vs 0.14 ± 0.02, P < 0.03) and higher concentrations of glutamate (1.36 ± 0.25 vs 0.58 ± 0.04, P < 0.01), lactate (1.53 ± 0.11 vs 0.42 ± 0.05, P < 0.01), pyruvate (0.11 ± 0.02 vs 0.03 ± 0.00, P < 0.01) threonine (0.39 ± 0.02 vs 0.08 ± 0.01, P < 0.01) and aspartate (0.37 ± 0.03 vs 0.03 ± 0.01). A five metabolite signature by stepwise discriminant analysis could separate between controls and cirrhotic patients with an accuracy of 98%. In patients with encephalopathy we observed further derangement of ketone body metabolism, impaired production of glycerol and myoinositol, reversal of Fischer's ratio and impaired glutamine production as demonstrated by lower b-hydroxybutyrate (0.58 ± 0.14 vs 0.16 ± 0.02, P < 0.0002), higher acetoacetate (0.23 ± 0.02 vs 0.41 ± 0.16, P < 0.05), leucine (0.33 ± 0.02 vs 0.49 ± 0.05, P < 0.005) and isoleucine (0.12 ± 0.02 vs 0.27 ± 0.02, P < 0.0004) and lower glutamine (0.44 ± 0.08 vs 0.36 ± 0.04, P < 0.013), glycerol (0.53 ± 0.03 vs 0.19 ± 0.02, P < 0.000) and myoinositol (0.36 ± 0.04 vs 0.18 ± 0.02, P < 0.010) concentrations. A four metabolite signature by stepwise discriminant analysis could separate between encephalopathic and cirrhotic patients with an accuracy of 87%. CONCLUSION: Patients with cirrhosis and patients with hepatic encephalopathy exhibit distinct metabolic abnormalities and the use of metabonomics can select biomarkers for these diseases.

Elevated levels of the long pentraxin 3 in paracetamol-induced human acute liver injury.

OBJECTIVES: Pentraxin 3 (PTX3) is a long pentraxin with diverse humoral innate immune functions. The aims of this study were to measure levels of PTX3 and C-reactive protein (CRP), a hepatocyte-derived short pentraxin, in patients after acute liver injury. METHODS: PTX3 and CRP levels were measured in a total of 60 patients [48 paracetamol overdose (POD), 12 non-POD]. PTX3 expression was assessed by immunohistochemical analysis in explanted liver tissue. RESULTS: Admission PTX3 levels were significantly higher in POD acute liver failure (ALF) patients compared with POD non-ALF patients (P=0.0005) and non-POD patients (P=0.004). PTX3 levels in POD patients who died or required orthotopic liver transplantation (OLT, n=14) were significantly higher compared with those in spontaneous survivors (n=34, P=0.0011). The area under the receiver operator characteristic for PTX3 for death/OLT in POD patients was 0.80 (95% confidence interval 0.67-0.93). PTX3 levels were significantly higher in those POD patients who developed the systemic inflammatory response syndrome (P=0.001). Conversely, admission CRP levels were significantly lower in POD compared with non-POD patients (P=0.011), with no significant differences between survivors and nonsurvivors. After emergency OLT, PTX3 levels fell markedly; in contrast, CRP levels rapidly increased. Immunohistochemical analysis showed PTX3 expression in sinusoidal lining cells of a normal liver, infiltrating inflammatory cells in patients with ALF, and in a membranous distribution on injured hepatocytes in POD patients. CONCLUSION: Increased PTX3 levels are associated with adverse outcomes following POD, suggesting that the humoral innate immune system plays an underrecognized role in this condition.

A biochemical prognostic model of outcome in paracetamol-induced acute liver injury.

BACKGROUND: The aim of this study was to develop a prognostic model of outcome for patients with paracetamol induced acute liver injury based on admission parameters METHODS: We used a cohort of 97 patients admitted to the Scottish Liver Transplant Unit between 1997 and 1998 to identify biochemical prognostic markers of outcome and thus create a prognostic model. Blood samples were taken on admission for analysis. The model was subsequently validated by testing it on a second cohort of 86 patients admitted between 1999 and 2000. RESULTS: The following were identified as independent variables of poor prognosis (death/ transplant); phenylalanine, pyruvate, alanine, acetate, calcium, haemoglobin and lactate. A prognostic model was then constructed by stepwise forward logistic regression analysis: (400xPyruvate mmols/L)+(50xPhenylalanine (mmols/L)-(4 x Hemoglobin (g/dL). A value of <16 had an accuracy of 93% in predicting death correctly. When applied to the validation cohort this model had a positive predictive value of 91%, a negative predictive value of 94%, a sensitivity of 91%, and a specificity of 94%. On the same population overall, the positive and negative predictive value of the King's criteria were 94% and 93% respectively, whereas their sensitivity and specificity were 88% and 96% respectively. CONCLUSIONS: Using admission characteristics our model is able to identify patients who die from paracetamol overdose fulminant hepatic failure as accurately as King's College criteria, but at a much earlier stage in their condition.

Psychological outcome and quality of life following liver transplantation: a prospective, national, single-center study.

Liver transplantation is a well-established treatment for liver failure. Prolongation in survival is accepted, but long-term effects of liver transplantation on cognitive and psychological outcome are unclear. In the present study, psychological data were prospectively collected for 164 patients who were assessed for liver transplantation. Memory impairment, psychomotor slowing, anxiety, and depression were commonly observed. Severity of liver disease at assessment was significantly associated with slowing of reaction time. Memory impairment distinguished those who were not listed for transplantation because of illness severity. One year posttransplantation, follow-up data from transplant recipients showed significant improvement in most psychological domains relative to both healthy comparison participants and patients with chronic liver disease who did not undergo transplantation. Immunosuppression (cyclosporine versus tacrolimus) did not have differential effects on quality of life, fatigue, or affective status, although those administered cyclosporine showed greater improvements at 1-year follow-up on simple and choice reaction times. Elevated levels of anxiety and neuroticism at pretransplantation assessment were associated with worse psychosocial outcome at 1 year posttransplantation. Severity of liver disease was not related to psychological outcome at 1 year. Good psychological outcome at 1 year was maintained at the 3-year follow-up.

Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis.

Vasopressin, or antidiuretic hormone, is a peptide hormone that is released from the posterior pituitary gland in response to changes in blood pressure and plasma osmolality. The main pathophysiological states associated with high plasma vasopressin concentrations are cirrhosis, cardiac failure and syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Pharmacological treatments for disorders of excess vasopressin secretion have been limited. However, oral bio-available selective and non-selective V(1) and V(2) receptor antagonists have recently become available for clinical use. Water retention in cirrhosis is a common problem, leading to ascites, peripheral oedema and hyponatraemia. Raised plasma vasopressin concentrations and decreased delivery of glomerular filtrate are believed to be the most important factors in the development of water retention. V(2) receptor antagonists are aquaretic agents that promote water excretion and improve hyponatraemia. Their potential role in cirrhosis has been examined in a number of recent studies that have shown increased free water clearance and serum sodium concentrations with few adverse effects. V(2) receptor antagonists represent a novel and promising new class of agent that may have major clinical utility in the treatment of patients with liver cirrhosis.

Nitric oxide mediates the reduced vasoconstrictor response to angiotensin II in patients with preascitic cirrhosis.

BACKGROUND/AIMS: Altered vascular responses to vasopressor agents contribute to the pathogenesis of the circulatory dysfunction in cirrhosis. This study aims to assess the role of endogenous nitric oxide (NO) in the reduced vascular responsiveness to angiotensin II (ANG-II) in eight patients with preascitic cirrhosis compared with eight age- and sex-matched healthy controls. METHODS: Forearm blood flow (FBF) responses to sub-systemic, locally-active intra-brachial infusions of ANG-II were measured using venous occlusion plethysmography before and during the application of an 'NO-clamp', a balanced co-infusion of L-N(G)-monomethyl-arginine (a selective NO synthase inhibitor) and sodium nitroprusside (an exogenous NO donor) to block endogenous NO production and restore normal NO-mediated basal blood flow, respectively. RESULTS: Before applying the 'NO-clamp', ANG-II caused dose-dependent reductions of FBF in both groups (P<0.001) that were significantly attenuated in the cirrhotic patients (P=0.012). In the presence of the 'NO-clamp', the ANG-II-mediated vasoconstriction was enhanced in cirrhotic patients (P<0.01), unchanged in controls, and now similar in both groups. CONCLUSIONS: This study confirms that vasoconstriction to ANG-II is reduced in patients with preascitic cirrhosis, and suggests that this is principally due to enhanced NO generation mediated by ANG-II.

Endoscopic use of human thrombin in bleeding gastric varices.

OBJECTIVE: The management of gastric variceal hemorrhage remains a clinical challenge. Bovine thrombin has been reported to be effective in two small series. We report our experience with human thrombin in the treatment of bleeding gastric varices. METHODS: We reviewed the case records of 12 patients presenting over a 2-yr period with gastric variceal bleeding requiring endoscopic injection of human thrombin. Ten were male and the mean age was 52 yr (range = 26-83). The underlying diagnoses were cirrhosis in nine, portal vein thrombosis in two, and liver metastasis in one. The majority had fundal gastric varices, and none were thought to have bled from their esophageal varices. Eight received thrombin as primary treatment, whereas four had thrombin only after failing transjugular intrahepatic portosystemic shunts. Patients received one to four sessions (mean = 1.9) of thrombin with a mean total dose of 1833 U (range = 800-4000). Mean follow-up was 17.8 months for those still alive (range = 7-33). RESULTS: Hemostasis in the acute setting was successful in nine patients all of whom received thrombin within 48 hours of the bleed. In the longer term, nine of the 12 had no further bleeding. Of these, five patients did well with thrombin alone, one died of cancer, and the other three went on electively to more definitive shunt procedures. Three patients rebled from their gastric varices of which one was successfully retreated with thrombin. Only one death was related to variceal bleeding (8%). No adverse reactions were noted. CONCLUSION: Our experience demonstrates that endoscopic therapy with thrombin appears safe and can be effective in the management of gastric variceal bleeding.