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.

Assessment and Interventions for Vascular Injuries Associated With Fractures.

Vascular injuries associated with fractures are limb-threatening injuries with notable morbidity. The prompt and thorough evaluation of these patients is imperative to diagnose vascular injuries, and coordinated multidisciplinary care is needed to provide optimal outcomes. The initial assessment includes a detailed physical examination assessing for hard and soft signs of arterial injury, and the arterial pressure index can be used to reliably identify vascular compromise and the need for additional assessment or intervention. Advanced imaging in the form of CT angiography is highly sensitive in additional characterization of the potential injury and can be obtained in an expedient manner. The optimal treatment of fractures with vascular injuries includes providing skeletal stability and confirming or reestablishing adequate distal perfusion as soon as possible. Options for vascular intervention include observation, ligation, direct arterial repair, vascular bypass grafting, endovascular intervention, and staged temporary shunting, followed by bypass grafting. Although the optimal sequence of surgical intervention remains an incompletely answered question, the orthopaedic role in the care of patients with these injuries is to provide mechanical stability to the injured limb to protect the vascular repair and surrounding soft-tissue envelope.

Economic evaluation of covered stents for transjugular intrahepatic portosystemic stent shunt in patients with variceal bleeding and refractory ascites secondary to cirrhosis.

OBJECTIVES: Transjugular intrahepatic portosystemic stent shunt (TIPSS) is clinically effective in variceal bleeding and refractory ascites; however, the cost-effectiveness of TIPSS has yet to be evaluated in the UK. This study aimed to establish the cost-effectiveness of (i) pre-emptive TIPSS versus endoscopic band ligation (EBL) in populations with variceal bleeding and (ii) TIPSS versus large volume paracentesis (LVP) in refractory ascites. METHODS: A cost-utility analysis was conducted with the perspective including healthcare costs and quality-adjusted life years (QALYs). A Markov model was constructed with a 2-year time horizon, health states for mortality and survival and probabilities for the development of variceal bleeding, ascites and hepatic encephalopathy. A survival analysis was conducted to extrapolate 12-month to 24-month mortality for the refractory ascites indication. Uncertainty was analysed in deterministic and probabilistic sensitivity analyses. RESULTS: TIPSS was cost-effective (dominant) and cost saving for both indications. For variceal bleeding, pre-emptive TIPSS resulted in 0.209 additional QALYs, and saved £600 per patient compared with EBL. TIPSS had a very high probability of being cost-effective (95%) but was not cost saving in scenario analyses driven by rates of variceal rebleeding. For refractory ascites, TIPSS resulted in 0.526 additional QALYs and saved £17 983 per patient and had a 100% probability of being cost-effective and cost saving when compared with LVP. CONCLUSIONS: TIPSS is a cost-effective intervention for variceal bleeding and refractory ascites. TIPSS is highly cost-saving for refractory ascites. Robust randomised trial data are required to confirm whether pre-emptive TIPSS is cost saving for variceal bleeding.

Decompensated cirrhosis is the commonest presentation for NAFLD patients undergoing liver transplant assessment.

Non-alcoholic fatty liver disease (NAFLD) accounts for 10-15% of orthotopic liver transplants (OLTs) in the UK. Index presentations with cirrhotic decompensation represent missed opportunities for preventive treatment leaving OLT or palliation as the only options.We retrospectively reviewed patient records for all NAFLD patients undergoing assessment for OLT between January 2003 and December 2017.Data were available for 81 patients with NAFLD as the primary diagnosis. Fifty-two patients had decompensated cirrhosis at first presentation; 91.7% presented to secondary care compared to 52.7% referred from primary care (p=0.001). Cirrhosis was not suspected at the time of referral to hospital in 24.7% of patients subsequently assessed for OLT. Most patients undergoing assessment for OLT for NAFLD had decompensated cirrhosis at their first diagnosis of chronic liver disease. These data highlight the plight of patients with NAFLD cirrhosis in whom chronic liver disease is diagnosed late.

The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial.

BACKGROUND: Alcoholic hepatitis (AH) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods, which is characterised by jaundice and liver failure. Severe disease is associated with high short-term mortality. Prednisolone and pentoxifylline (PTX) are recommended in guidelines for treatment of severe AH, but trials supporting their use have given heterogeneous results and controversy persists about their benefit. OBJECTIVES: The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX. DESIGN: The trial was a randomised, double-blind, 2 × 2 factorial, multicentre design. SETTING: Sixty-five gastroenterology and hepatology inpatient units across the UK. PARTICIPANTS: Patients with a clinical diagnosis of AH who had a Maddrey's discriminant function value of ≥ 32 were randomised into four arms: A, placebo/placebo; B, placebo/prednisolone; C, PTX/placebo; and D, PTX/prednisolone. Of the 5234 patients screened for the trial, 1103 were randomised and after withdrawals, 1053 were available for primary end-point analysis. INTERVENTIONS: Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days. OUTCOMES: The primary outcome measure was mortality at 28 days. Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year. Rates of recidivism among survivors and the impact of recidivism on mortality were assessed. RESULTS: At 28 days, in arm A, 45 of 269 (16.7%) patients died; in arm B, 38 of 266 (14.3%) died; in arm C, 50 of 258 (19.4%) died; and in arm D, 35 of 260 (13.5%) died. For PTX, the odds ratio for 28-day mortality was 1.07 [95% confidence interval (CI) 0.77 to 1.40; p = 0.686)] and for prednisolone the odds ratio was 0.72 (95% CI 0.52 to 1.01; p = 0.056). In the logistic regression analysis, accounting for indices of disease severity and prognosis, the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 (95% CI 0.41 to 0.91; p = 0.015). At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups. Serious infections occurred in 13% of patients treated with prednisolone compared with 7% of controls (p = 0.002). At the 90-day follow-up, 45% of patients reported being completely abstinent, 9% reported drinking within safety limits and 33% had an unknown level of alcohol consumption. At 1 year, 37% of patients reported being completely abstinent, 10% reported drinking within safety limits and 39% had an unknown level of alcohol consumption. Only 22% of patients had attended alcohol rehabilitation treatment at 90 days and 1 year. CONCLUSIONS: We conclude that prednisolone reduces the risk of mortality at 28 days, but this benefit is not sustained beyond 28 days. PTX had no impact on survival. Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection. TRIAL REGISTRATION: This trial is registered as EudraCT 2009-013897-42 and Current Controlled Trials ISRCTN88782125. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 102. See the NIHR Journals Library website for further project information. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding.

Prednisolone or pentoxifylline for alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

Digital image analysis of collagen assessment of progression of fibrosis in recurrent HCV after liver transplantation.

BACKGROUND & AIMS: Histological assessment of fibrosis progression is currently performed by staging systems which are not continuous quantitative measurements. We aimed at assessing a quantitative measurement of fibrosis collagen proportionate area (CPA), to evaluate fibrosis progression and compare it to Ishak stage progression. METHODS: We studied a consecutive cohort of 155 patients with recurrent HCV hepatitis after liver transplantation (LT), who had liver biopsies at one year and were subsequently evaluated for progression of fibrosis using CPA and Ishak staging, and correlated with clinical decompensation. The upper quartile of distribution of fibrosis rates (difference in CPA or Ishak stage between paired biopsies) defined fast fibrosers. RESULTS: Patients had 610 biopsies and a median follow-up of 116 (18-252) months. Decompensation occurred in 29 (18%) patients. Median Ishak stage progression rate was 0.42 units/year: (24 (15%) fast fibrosers). Median CPA fibrosis progression rate was 0.71%/year (36 (23%) fast fibrosers). Clinical decompensation was independently associated by Cox regression only with CPA (p=0.007), with AUROCs of 0.81 (95% CI 0.71-0.91) compared to 0.68 (95% CI 0.56-0.81) for Ishak stage. Fast fibrosis defined by CPA progression was independently associated with histological de novo hepatitis (OR: 3.77), older donor age (OR: 1.03) and non-use/discontinuation of azathioprine before 1 year post-LT (OR: 3.85), whereas when defined by Ishak progression, fast fibrosers was only associated with histological de novo hepatitis. CONCLUSIONS: CPA fibrosis progression rate is a better predictor of clinical outcome than progression by Ishak stage. Histological de novo hepatitis, older donor age and non-use/discontinuation of azathioprine are associated with rapid fibrosis progression in recurrent HCV chronic hepatitis after liver transplantation.

Comparison of the sequential organ failure assessment score with the King's College Hospital criteria and the model for end-stage liver disease score for the prognosis of acetaminophen-induced acute liver failure.

Acetaminophen-induced acute liver failure (ALF) is a complex multiorgan illness. An assessment of the prognosis is essential for the accurate identification of patients for whom survival without liver transplantation (LT) is unlikely. The aims of this study were the comparison of prognostic models [King's College Hospital (KCH), Model for End-Stage Liver Disease, Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II)] and the identification of independent prognostic indicators of outcome. We evaluated consecutive patients with severe acetaminophen-induced ALF who were admitted to the intensive care unit. At admission, demographic, clinical, and laboratory parameters were recorded. The discriminative ability of each prognostic score at the baseline was evaluated with the area under the receiver operating characteristic curve (AUC). In addition, using a multiple logistic regression, we assessed independent factors associated with outcome. In all, 125 consecutive patients with acetaminophen-induced ALF were evaluated: 67 patients (54%) survived with conservative medical management (group 1), and 58 patients (46%) either died without LT (28%) or underwent LT (18%; group 2). Group 1 patients had significantly lower median APACHE II (10 versus 14) and SOFA scores (9 versus 12) than group 2 patients (P < 0.001). The independent indicators associated with death or LT were a longer prothrombin time (P = 0.007), the inspiratory oxygen concentration (P = 0.005), and the lactate level at 12 hours (P < 0.001). The KCH criteria had the highest specificity (83%) but the lowest sensitivity (47%), and the SOFA score had the best discriminative ability (AUC = 0.79). In conclusion, for patients with acetaminophen-induced ALF, the SOFA score performed better than the other prognostic scores, and this reflected the presence of multiorgan dysfunction. A further evaluation of SOFA with the KCH criteria is warranted.

Assessment of reproducibility of creatinine measurement and MELD scoring in four liver transplant units in the UK.

UNLABELLED: The Model for End-Stage Liver Disease (MELD) or similar scoring system is proposed in the UK for prioritization for liver transplantation. We evaluated the reproducibility of creatinine measurements and therefore MELD scores in four liver transplant units in the UK. METHODS: All transplant units were invited to participate; four agreed to do so, contributing 36 patients awaiting liver transplantation. Blood was collected from these 36 and divided into aliquots then sent to the four participating centres. Every centre measured creatinine and bilirubin for every patient. The results were analysed for the degree of agreement between centres for creatinine and MELD scores using the Bland-Altman method and Wilcoxon rank test. RESULTS: The mean creatinine value varied from 101 mumol/l in centre C to 110 micromol/l for the same sample in centre A, with significant differences between the four centres (P < 0.05, Wilcoxon signed-rank test). The MELD scores were significantly different between centre C and all other centres (P < 0.05). CONCLUSION: This study demonstrates lack of agreement in measurement of serum creatinine and MELD scoring between four UK transplant centres. A difference in two MELD points can have a significant impact on patient outcome, and these factors will have to be addressed if a UK-wide transplant list is to be initiated.

RIFLE classification as predictive factor of mortality in patients with cirrhosis admitted to intensive care unit.

BACKGROUND AND AIM: To evaluate the association of the Risk, Injury, Failure, Loss and End-stage renal failure (RIFLE) score on mortality in patients with decompensated cirrhosis admitted to intensive care unit (ICU). METHODS: A cohort of 412 patients with cirrhosis consecutively admitted to ICU was classified according to the RIFLE score. Multivariable logistic regression analysis was used to evaluate the factors associated with mortality. Liver-specific, Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA) and RIFLE scores on admission, were compared by receiver-operator characteristic curves. RESULTS: The overall mortality during ICU stay or within 6 weeks after discharge from ICU was 61.2%, but decreased over time (76% during first interval, 1989-1992 vs 50% during the last, 2005-2006, P < 0.001). Multivariate analysis showed that RIFLE score (odds ratio: 2.1, P < 0.001) was an independent factor significantly associated with mortality. Although SOFA had the best discrimination (area under receiver-operator characteristic curve = 0.84), and the APACHE II had the best calibration, the RIFLE score had the best sensitivity (90%) to predict death in patients during follow up. CONCLUSIONS: RIFLE score was significantly associated with mortality, confirming the importance of renal failure in this large cohort of patients with cirrhosis admitted to ICU, but it is less useful than other scores.

Transjugular intrahepatic portosystemic shunt in the management of ascites and hepatorenal syndrome.

Ascites is the most common complication of liver cirrhosis and when it develops mortality is 50% at 5 years, apart from liver transplantation. Large volume paracentesis has been the only option for ascites refractory to medical treatment. The role of transjugular intrahepatic portosystemic shunt in the management of diuretic-resistant ascites has been evaluated in many cohort studies and five randomized trials up to now, clearly showing improvement in natriuresis and clinical efficacy. It, however, remains unclear how transjugular intrahepatic portosystemic shunt affects survival and quality of life, because hospital admissions owing to worsening encephalopathy may counterbalance the reduced need of paracentesis. What is clear is that the patient selection is critical. About 30% of patients with ascites develop hepatorenal syndrome at 5 years, leading to high mortality in its severe and progressive form. As its main pathogenetic factor is derangement of circulatory function owing to portal hypertension, these patients may benefit from transjugular intrahepatic portosystemic shunt, but this has been shown only in small series, in which mortality remains very high, owing to the underlying poor liver function.

Update on the classification, assessment of prognosis and therapy of Budd-Chiari syndrome.

Budd-Chiari syndrome (BCS) occurs as a result of obstruction of hepatic venous outflow at any level from the small hepatic veins to the junction of the inferior vena cava with the right atrium. Diagnosis can be difficult because of the wide spectrum of presentation of the disease and the varying severity of liver damage. The traditional classification of BCS--as fulminant, acute or chronic--is not prognostically useful. This makes assessing the benefit of therapy difficult, especially as there is no evidence from randomized studies. This article highlights advances in the prognosis and therapy of BCS. Identification of the site of venous obstruction has a major effect on prognosis. Portal-vein thrombosis occurs in 20-30% of cases, and acute presentation of BCS reflects an acute or chronic syndrome in 60% of BCS cases. BCS can be diagnosed and treated on a single occasion in the setting of the radiology department, with hepatic venography, transjugular liver biopsy, retrograde CO2 portography and inferior vena cava pressure measurements performed simultaneously with therapies such as dilation or stenting of webs in the inferior vena cava or hepatic veins, and placement of transjugular intrahepatic portosystemic shunts. Disruption of a portal vein thrombus can also be done during the same session. Surgical shunts have been superseded by the use of transjugular intrahepatic portosystemic shunts. Liver transplantation is reserved for fulminant and progressive chronic forms of BCS. Anticoagulation therapy must be used routinely, before and after specific therapy, regardless of whether a thrombophilic disorder is diagnosed.

Assessment of blood coagulation in severe liver disease using thromboelastography: use of citrate storage versus native blood.

Thromboelastography evaluates the viscoelastic properties of blood coagulation. Using native blood, measurement must start soon after sampling. With normal coagulation, native and citrated blood values correlate well. No data exists from cirrhotic patients. We compared native and citrate thromboelastography parameters in 30 cirrhotic patients (20 Child-Pugh C class, two liver failure). Thromboelastography was performed within 4 min using native blood and after recalcification within 1-2 h of citrate storage. Thromboelastography variables (, alpha, ) were compared using the Mann-Whitney test, correlation investigated with the Pearson method and the degree of agreement with the Bland-Altman method. There was no significant difference between citrated and native blood for all variables. Median values for native and citrated were, respectively, 16.4 (range 2.3-22.5) and 15.1 (range 9.8-29.9); 6.3 (range 3.5-11.3) and 6.2 (range 2.8-10.9); 48.3 (range 30.7-62.9) and 46.2 (range 30.4-60.4); angle alpha 30.8 (range 18.7-46.8) and 33.2 (range 19.9-55.8). Correlation for each variable was significant ( 0.01). There was a good degree of agreement for all but two patients (both bleeding) for all variables. Citrated blood can substitute native blood using thromboelastography in cirrhotic patients, allowing more time between sampling and the thromboelastography measurement.