Antibodies to gp210 and understanding risk in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: A variety of auto-antibody assays are available as part of the clinical care of patients with liver disease. We sought to better understand the clinical utility of immune serological testing in patients with primary biliary cholangitis (PBC). METHODS: We retrospectively analysed data from 2846 patients investigated for liver disease at a UK liver centre between 2001 and 2017. A total of 499 patients with PBC were identified. Immune serology results were examined for their diagnostic utility and prognostic significance to predict transplant-free survival. RESULTS: Antimitochondrial antibodies (AMAs) were specific (94.5%) and sensitive (85.6%) for PBC; antinuclear antibodies (ANAs) against glycoprotein 210 (gp210) and sp100 were specific (>98%) but not sensitive (<25%). The disease-specific ANAs were detectable in 29.6% of AMA-negative patients. Anti-gp210 auto-antibodies were significantly associated with elevated serum aminotransferase activity, bilirubin and liver stiffness at presentation (P < .010). Anti-gp210 auto-antibodies predicted non-response to ursodeoxycholic acid (UDCA) by GLOBE criteria (39.3% vs 16.7%, P = .005). Moreover, anti-gp210 was independently associated with death or liver transplantation (HR 3.22, 95% CI 1.49-6.96; P = .003), after accounting for other significant baseline determinants of outcome. Serologic finding of anti-gp210 antibodies conferred an independent risk of death or transplantation (HR 4.13, 95% CI 1.85-9.22; P = .001) after accounting for treatment response. CONCLUSION: In our single-centre cohort of patients with PBC, the presence of anti-gp210 was associated with an adverse presenting phenotype, predicted treatment non-response and independently predicted reduced transplant-free survival.

Nicotinamide Adenine Dinucleotide Metabolome Is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-Related Liver Disease.

Nicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Although hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+ metabolome in alcohol-related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+ metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham National Health Service Foundation Trust. The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests and histology. NAD-targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography-tandem mass spectrometry. Seventy-two human liver specimens were analyzed, including 43 with ArLD. The NAD+ metabolome differed significantly between different types of liver disease (two-way analysis of variance [ANOVA], P = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+ (432 µM vs. 616 µM in normal liver) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+ metabolome between ArLD samples with and without steatohepatitis (two-way ANOVA, P = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+ (mean, 462 µM vs. 322 µM; P < 0.01 in nonsevere vs. severe alcoholic steatohepatitis, respectively). NAD+ concentration was inversely related to serum bilirubin concentration (r 2 = -0.127; P = 0.04) and positively correlated with myeloperoxidase activity (r 2 = 0.31; P = 0.003). The concentration of NAD+ and its precursor molecules are significantly reduced in ArLD and are associated with disease activity. Conclusion: Liver samples from people with ArLD show depressed NAD+ and precursor levels as well as depressed myeloperoxidase activity.

What did the European Liver Transplant Registry bring to liver transplantation?

Since its foundation in 1985, the European Liver Transplant Registry has evolved to become an important tool to monitor the liver transplantation activity in Europe. The vast amount of data collected on 169 473 liver transplantations performed in 153 238 recipients has also resulted in scientific publications. Without doubt, several of these have influenced the daily practice of liver transplantation. This paper gives an overview of the development, the functioning, and the scientific activity of the European Liver Transplant Registry during more than three decades. Indeed, it can be said that the registry helped to advance the practice of liver transplantation not only in Europe but also worldwide.

Predictive factors for 28-day mortality in acute-on-chronic liver failure patients admitted to the intensive care unit.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is an entity comprising an acute deterioration of liver function in cirrhotic patients, associated with organ failure(s) and high short-term mortality. We aimed to identify predictive factors for short-term mortality in patients admitted with ACLF that may benefit most from liver transplantation. METHODS: Retrospective analysis of patients admitted in ACLF to a tertiary intensive care unit between 2013 and 2017 was performed. The EASL-CLIF acute-on-chronic liver failure in cirrhosis (CANONIC) criteria were used to define ACLF grade. Multivariable analysis using 28-day mortality as an end-point was performed, including severity-of-disease scores and clinical parameters. RESULTS: Seventy-seven patients were admitted in ACLF over the study period. The commonest aetiology of liver disease was alcohol related 52/77(68%) and the commonest precipitant of ACLF was variceal haemorrhage 38/77(49%). Overall 28-day mortality was 42/77(55%) [ACLF-(grade)1:3/42(7%); ACLF-2:10/42(24%); and, ACLF-3:29/42(69%);p = 0.002]. On multivariable analysis MELD ≥ 26 [odds ratio(OR) = 11.559; 95% confidence interval(CI):2.820-47.382;p = 0.001], ACLF-3 (OR = 3.287; 95%CI:1.047-10.325;p = 0.042) at admission and requirement for renal replacement therapy (OR = 5.348; 95%CI:1.385-20.645;p = 0.015) were independently associated with 28-day mortality. CONCLUSION: Patients admitted with ACLF to intensive care have a high mortality rate. Defined early thresholds at admission can identify patients at the highest risk that may benefit most from liver transplantation.

Normothermic Machine Perfusion Enhances Intraoperative Hepatocellular Synthetic Capacity: A Propensity Score-matched Analysis.

BACKGROUND: Normothermic machine perfusion (NMP) of liver grafts is increasingly being incorporated in clinical practice. Current evidence has shown NMP plays a role in reconditioning the synthetic and energy capabilities of grafts. Intraoperative coagulation profile is a surrogate of graft quality and preservation status; however, to date this aspect has not been documented. METHODS: The liver transplantation recipients who received NMP liver grafts in the QEHB between 2013 and 2016 were compared in terms of intraoperative thromboelastography characteristics (R time, K time, α-angle, maximum amplitude, G value, and LY30) to a propensity score-matched control group, where the grafts were preserved by traditional static cold storage (SCS). RESULTS: After propensity matching, none of the thromboelastography characteristics were found to differ significantly between the 72 pairs of SCS and NMP organs when measured preimplantation. However, postimplantation, NMP organs had significantly shorter K time (median: 2.8 vs 3.6 min, P = 0.010) and R + K time (11.4 vs 13.7 min, P = 0.016), as well as significantly larger α-angle (55.9° vs 44.8°, P = 0.002), maximum amplitude (53.5 vs 49.6 mm, P = 0.044), and G values (5.8 vs 4.9k dynes/cm, P = 0.043) than SCS organs. Hyperfibrinolysis after implantation was also mitigated by NMP, with fewer patients requiring aggressive factor correction during surgery (LY30 = 0, NMP vs SCS: 83% vs 60%, P = 0.004). Consequently, NMP organs required significantly fewer platelet units to be transfused during the transplant procedure (median: 0 vs 5, P = 0.001). CONCLUSIONS: In this study, we have shown that NMP liver grafts return better coagulation profiles intraoperatively, which could be attributed to the preservation of liver grafts under physiological conditions.

Incidence and outcome of colorectal cancer in liver transplant recipients: A national, multicentre analysis on 8115 patients.

BACKGROUND & AIMS: De novo malignancies after liver transplantation represent one of the leading causes of death in the long-term. It remains unclear whether liver transplant recipients have an increased risk of colorectal cancer and whether this negatively impacts on survival, particularly in those patients affected by primary sclerosing cholangitis and ulcerative colitis. METHODS: In this national multicentre cohort retrospective study, the incidence of colorectal cancer in 8115 evaluable adult patients undergoing a liver transplantation between 1 January 1990 and 31 December 2010 was compared to the incidence in the general population through standardised incidence ratios. RESULTS: Fifty-two (0.6%) cases of colorectal cancer were identified at a median of 5.6 years postliver transplantation, predominantly grade 2 (76.9%) and stage T3 (50%) at diagnosis. The incidence rate of colorectal cancer in the whole liver transplant population was similar to the general UK population (SIR: 0.92), but significantly higher (SIR: 7.0) in the group of patients affected by primary sclerosing cholangitis/ulcerative colitis. One-, five- and ten-year survival rates from colorectal cancer diagnosis were 71%, 48% and 31%, respectively, and the majority of colorectal cancer patients died of cancer-specific causes. CONCLUSIONS: Liver transplantation alone is not associated with an increased risk of colorectal cancer development. The primary sclerosing cholangitis/ulcerative colitis liver transplant population showed a significantly higher risk of colorectal cancer development than the general population, with a high proportion of advanced stage at diagnosis and a reduced patient survival.

Outcomes of Pregnancy in Recipients of Liver Transplants.

BACKGROUND & AIMS: Despite increasing reports of pregnancy in women who received liver transplants, it is not clear how transplantation and immunosuppression affect pregnancy. We collected data from liver transplant recipients who became pregnant on immunosuppression regimens, pregnancy management, graft morbidity, and outcomes of mothers and neonates. METHODS: We searched the liver transplant database in Birmingham, United Kingdom, for women who reported pregnancy after liver transplantation from August 1986 through May 2016. We collected information on morbidities and outcomes of 139 pregnancies in 83 women (median age at conception, 27 y; range, 15-46 y). Fisher exact tests were used to compare categoric variables and Mann-Whitney U and Kruskal-Wallis tests were used to compare continuous variables. The primary outcome was the live birth rate in the entire cohort. Additional outcomes analyzed included differences in immunotherapy regimens, and outcomes associated with exposure to cyclosporine and tacrolimus, time to transplantation (<12 vs >12 mo), and time period of pregnancy (1986-2000 vs 2001-2016). RESULTS: Of the pregnancies, 69% resulted in live births, 19% resulted in miscarriages or still births, and 9% were terminated. A higher proportion of patients who conceived more than 1 year after liver transplantation had live births than of women who conceived before this time (98% vs 80%; P = .006). Tacrolimus exposure was associated with higher risks of premature delivery (P = .045) and caesarian section (P = .031) than cyclosporine exposure. Compared with the period from 1986 to 2000, women who conceived from 2001 to 2016 had a significantly shorter time between transplantation and conception (median, 3 vs 7 y; P = .027), frequent use of tacrolimus vs cyclosporine (84% vs 26%; P = .001), and a higher incidence of cesarean section (44% vs 32%; P = .025). CONCLUSIONS: Almost 70% of women who conceive after liver transplantation have live births, although this rate is lower than that of women in the overall population. These cases require involvement of hepatologists and obstetricians.

Revascularization Time in Liver Transplantation: Independent Prediction of Inferior Short- and Long-term Outcomes by Prolonged Graft Implantation.

BACKGROUND: Strategies for successful transplantation are much needed in the era of organ shortage, and there has been a resurgence of interest on the impact of revascularization time (RT) on outcomes in liver transplantation (LT). METHODS: All primary LT performed in Birmingham between 2009 and 2014 (n = 678) with portal reperfusion first were stratified according to RT (<44 minutes vs ≥44 minutes) and graft quality (standard liver graft [SLG], Donor Risk Index < 2.3 vs marginal liver graft [MLG], Donor Risk Index ≥ 2.3). RESULTS: Revascularization time of 44 minutes or longer resulted in significantly greater incidence of early allograft dysfunction (EAD) (29% vs 47%, P < 0.001), posttransplant acute kidney injury (AKI) (39% vs 60%, P < 0.001), and new-onset AKI (37% vs 56%, P < 0.001), along with poor long-term outcome (3-year graft survival 92% vs 83%, P = 0.001; 3-year patient survival 87% vs 79%, P = 0.004). On multivariable analysis, RT ≥ 44 was a significant independent predictor of EAD, renal dysfunction, and overall graft survival, but not patient survival. The cumulative effect of prolonged revascularization in marginal grafts (MLG) resulted in the worst transplant outcome compared with all other groups, which could be mitigated by rapid revascularization (SLG, SLG, MLG vs MLG; EAD 24%, 39%, 39% vs 69%; AKI 32%, 46%, 51% vs 70%; 3-year graft survival 94%, 87%, 88% vs 70%, respectively; each P < 0.001). Factors associated with lack of abdominal space, larger grafts, and surgical skills were predictive of RT ≥ 44. CONCLUSIONS: Shorter graft revascularization is a protective factor in LT, particularly in the setting of graft marginality. Careful graft-recipient matching and emphasis on surgical expertise may aid in achieving better outcomes in LT.

Severe Unresolved Cholestasis Due to Unknown Etiology Leading to Early Allograft Failure Within the First 3 Months of Liver Transplantation.

BACKGROUND: Causes of severe cholestasis after liver transplantation (LT) are multi-factorial. Although the etiology is predictable in some, others culminate in graft/patient loss without a definitive cause identified. Severe cholestasis is usually associated with overlapped histological findings of rejection and biliary features, and diagnostic interpretation may pose a challenge. METHODS: This is 10-year retrospective analysis of patients with unexplained severe cholestasis resulting in death/graft loss within 90 days of LT. Of 1 583 LT during the study period, 90-day graft failure occurred in 129 (8%) cases; a total of 45 (3%) patients had unresolving severe cholestasis (bilirubin, >100 µmol/L; alkaline phosphatase, >400 UI/L after 15 days from LT), excluding those due to primary nonfunction/sepsis/vascular causes (n = 84). Demographics, allograft biopsies, radiological investigations, and clinical outcome were analyzed. RESULTS: All patients had persistent abnormal liver biochemistry. Doppler ultrasound scan was normal in all cases. Thirty-five (78%) recipients had at least 1 allograft biopsy (2 [1-9]). On the first biopsy, 22 (63%) patients had acute rejection, 4 (18%) early-chronic rejection, 12 (34%) antibody-mediated rejection. In subsequent biopsies chronic rejection was evident in 5 (14%) cases. Donor-specific antibodies were detected in all patients tested. Biliary anatomy was studied in detail in 9 (20%) patients, all presenting biliary strictures. The majority (n = 39; 87%) died within 32 (10-91) days, only survivors were from retransplantation (n = 3;6.5%) and biliary intervention (n = 3;6.5%). CONCLUSIONS: Unresolving severe cholestasis after LT is a key parameter predicting patient/allograft outcome. Histologically, rejection seems to overlap with biliary strictures; hence, allograft biopsy with signs of rejection should not be a reason to overlook biliary problems, in particular when biliary features are present. Only extensive radiological investigation/intervention or retransplantation prevents patient/allograft loss.

Retransplantation in Late Hepatic Artery Thrombosis: Graft Access and Transplant Outcome.

BACKGROUND: Definitive treatment for late hepatic artery thrombosis (L-HAT) is retransplantation (re-LT); however, the L-HAT-associated disease burden is poorly represented in allocation models. METHODS: Graft access and transplant outcome of the re-LT experience between 2005 and 2016 was reviewed with specific focus on the L-HAT cohort in this single-center retrospective study. RESULTS: Ninety-nine (5.7%) of 1725 liver transplantations were re-LT with HAT as the main indication (n = 43; 43%) distributed into early (n = 25) and late (n = 18) episodes. Model for end-stage liver disease as well as United Kingdom model for end-stage liver disease did not accurately reflect high disease burden of graft failure associated infections such as hepatic abscesses and biliary sepsis in L-HAT. Hence, re-LT candidates with L-HAT received low prioritization and waited longest until the allocation of an acceptable graft (median, 103 days; interquartile range, 28-291 days), allowing for progression of biliary sepsis. Balance of risk score and 3-month mortality score prognosticated good transplant outcome in L-HAT but, contrary to the prediction, the factual 1-year patient survival after re-LT was significantly inferior in L-HAT compared to early HAT, early non-HAT and late non-HAT (65% vs 82%, 92% and 95%) which was mainly caused by sepsis and multiorgan failure driving 3-month mortality (28% vs 11%, 16% and 0%). Access to a second graft after a median waitlist time of 6 weeks achieved the best short- and long-term outcome in re-LT for L-HAT (3-month mortality, 13%; 1-year survival, 77%). CONCLUSIONS: Inequity in graft access and peritransplant sepsis are fundamental obstacles for successful re-LT in L-HAT. Offering a graft for those in need at the best window of opportunity could facilitate earlier engrafting with improved outcomes.

Clinical outcomes of donation after circulatory death liver transplantation in primary sclerosing cholangitis.

BACKGROUND & AIM: Primary sclerosing cholangitis (PSC) is a progressive fibro-inflammatory cholangiopathy for which liver transplantation is the only life-extending intervention. These patients may benefit from accepting liver donation after circulatory death (DCD), however their subsequent outcome is unknown. The aim of this study was to determine the clinical impact of using DCD liver grafts in patients specifically undergoing transplantation for PSC. METHODS: Clinical outcomes were prospectively evaluated in PSC patients undergoing transplantation from 2006 to 2016 stratified by donor type (DCD, n=35 vs. donation after brainstem death [DBD], n=108). RESULTS: In liver transplantation for PSC; operating time, days requiring critical care support, total ventilator days, incidence of acute kidney injury, need for renal replacement therapy (RRT) or total days requiring RRT were not significantly different between DCD vs. DBD recipients. Although the incidence of ischaemic-type biliary lesions was greater in the DCD group (incidence rate [IR]: 4.4 vs. 0 cases/100-patient-years; p<0.001) there was no increased risk of post-transplant biliary strictures overall (hazard ratio [HR]: 1.20, 0.58-2.46; p=0.624), or in sub-analysis specific to anastomotic strictures or recurrent PSC, between donor types. Graft loss and mortality rates were not significantly different following transplantation with DCD vs. DBD livers (IR: 3.6 vs. 3.1 cases/100-patient-years, p=0.34; and 3.9 vs. 4.7, p=0.6; respectively). DCD liver transplantation in PSC did not impart a heightened risk of graft loss (HR: 1.69, 0.58-4.95, p=0.341) or patient mortality (0.75, 0.25-2.21, p=0.598). CONCLUSION: Transplantation with DCD (vs. DBD) livers in PSC patients does not impact graft loss or patient survival. In an era of organ shortage, DCD grafts represent a viable therapeutic option for liver transplantation in PSC patients. Lay summary: This study examines the impact of liver transplantation in primary sclerosing cholangitis (PSC) with organs donated after circulatory death (DCD), compared to donation after brainstem death (DBD). We show that in appropriately selected patients, the outcomes for DCD transplantation mirror those using DBD livers, with no significant differences in complication rate, patient survival or transplanted liver survival. In an era of organ shortage and increasing wait-list times, DCD livers represent a potential treatment option for transplantation in PSC.

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.

Acute kidney injury and post-reperfusion syndrome in liver transplantation.

In the past decades liver transplantation (LT) has become the treatment of choice for patients with end stage liver disease (ESLD). The chronic shortage of cadaveric organs for transplantation led to the utilization of a greater number of marginal donors such as older donors or donors after circulatory death (DCD). The improved survival of transplanted patients has increased the frequency of long-term complications, in particular chronic kidney disease (CKD). Acute kidney injury (AKI) post-LT has been recently recognized as an important risk factor for the occurrence of de novo CKD in the long-term outcome. The onset of AKI post-LT is multifactorial, with pre-LT risk factors involved, including higher Model for End-stage Liver Disease score, more sever ESLD and pre-existing renal dysfunction, either with intra-operative conditions, in particular ischaemia reperfusion injury responsible for post-reperfusion syndrome (PRS) that can influence recipient's morbidity and mortality. Post-reperfusion syndrome-induced AKI is an important complication post-LT that characterizes kidney involvement caused by PRS with mechanisms not clearly understood and implication on graft and patient survival. Since pre-LT risk factors may influence intra-operative events responsible for PRS-induced AKI, we aim to consider all the relevant aspects involved in PRS-induced AKI in the setting of LT and to identify all studies that better clarified the specific mechanisms linking PRS and AKI. A PubMed search was conducted using the terms liver transplantation AND acute kidney injury; liver transplantation AND post-reperfusion syndrome; acute kidney injury AND post-reperfusion syndrome; acute kidney injury AND DCD AND liver transplantation. Five hundred seventy four articles were retrieved on PubMed search. Results were limited to title/abstract of English-language articles published between 2000 and 2015. Twenty-three studies were identified that specifically evaluated incidence, risk factors and outcome for patients developing PRS-induced AKI in liver transplantation. In order to identify intra-operative risk factors/mechanisms specifically involved in PRS-induced AKI, avoiding confounding factors, we have limited our study to "acute kidney injury AND DCD AND liver transplantation". Accordingly, three out of five studies were selected for our purpose.

Length of Variable Numbers of Tandem Repeats in the Carboxyl Ester Lipase (CEL) Gene May Confer Susceptibility to Alcoholic Liver Cirrhosis but Not Alcoholic Chronic Pancreatitis.

BACKGROUND: Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP. METHODS: Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups. RESULTS: Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16-16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC. CONCLUSIONS: We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.

Preoperative Thromboelastography as a Sensitive Tool Predicting Those at Risk of Developing Early Hepatic Artery Thrombosis After Adult Liver Transplantation.

BACKGROUND: Whilst causes of hepatic artery thrombosis (HAT) after liver transplantation (LT) are multifactorial, early HAT (E-HAT) remains pertinent complication impacting on graft and patient survival. Currently there is no screening tool that would identify patients with increased risk of developing E-HAT. METHODS: We analyzed the native procoagulant state of LT recipients, identified through pretransplant thromboelastographic (TEG) data among other known risk factors, to identify risk factors for E-HAT. RESULTS: The outcomes of 828 adult patients undergoing LT between 2008 and 2013 were analyzed. Overall, 79 (9.5%) patients experienced HAT, E-HAT was diagnosed in 23, and in the remainder this was "late" HAT. The maximum amplitude (MA) on preoperative TEG was significantly higher in patients diagnosed with E-HAT compared with those who did not (71.2 mm vs 57.9 mm; P < 0.0001). Receiver operating characteristic analysis with the cutoff value for MA of 65 mm or greater returned area under the curve of 0.750 (P < 0.001) predicting E-HAT with a sensitivity of 70%. A total of 7% of patients with an MA of 65 mm or greater went on to develop E-HAT (hazard ratio, 5.28; 95% confidence interval, 2.10-12.29; P < 0.001), whereas only 1.2% patients with an MA less than 65 mm experienced E-HAT. CONCLUSIONS: Preoperative TEG may reliably identify group of recipients at greater risk of developing E-HAT, and intense surveillance and anticoagulation prophylaxis may avoid this serious complication after LT.

Long-term follow-up after endovascular treatment of hepatic venous outflow obstruction following liver transplantation.

Hepatic venous outflow obstruction (HVOO) is a rare complication after liver transplantation (LT) associated with significant morbidity and reduced graft survival. Endovascular intervention has become the first-line treatment for HVOO, but data on long-term outcomes are lacking. We have analysed outcomes after endovascular intervention for HVOO in 905 consecutive patients who received 965 full-size LT at our unit from January 2007 to June 2014. There were 27 (3%) patients who underwent hepatic venogram for suspected HVOO, with persistent ascites being the most common symptom triggering the investigation (n = 19, 70%). Of those, only 10 patients demonstrated either stricture or pressure gradient over 10 mmHg on venogram, which represents a 1% incidence of HVOO. The endovascular interventions were balloon dilatation (n = 3), hepatic vein stenting (n = 4) and stenting with dilatation (n = 3). Two patients required restenting due to stent migration. The symptoms of HVOO completely resolved in all but one patient, with a median follow-up period of 74 (interquartile range 39-89) months. There were no procedure-related complications or mortality. In conclusion, the incidence of HVOO in patients receiving full-size LT is currently very low. Endovascular intervention is an effective and safe procedure providing symptom relief with long-lasting primary patency.

The new liver allocation score for transplantation is validated and improved transplant survival benefit in Germany but not in the United Kingdom.

Prognostic models for the prediction of 90-day mortality after transplantation with pretransplant donor and recipient variables are needed to calculate transplant benefit. Transplants in adult recipients in Germany (Hannover, n = 770; Kiel, n = 234) and the United Kingdom (Birmingham, n = 829) were used for prognostic model design and validation in separate training and validation cohorts. The survival benefit of transplantation was estimated by subtracting the observed posttransplant 90-day mortality from the expected 90-day mortality without transplantation determined by the Model for End-Stage Liver Disease (MELD) score. A prognostic model called the liver allocation score (LivAS) was derived using a randomized sample from Hannover using pretransplant donor and recipient variables. This model could be validated in the German training and validation cohorts (area under the receiver operating characteristic curve [AUROC] > 0.70) but not in the English cohort (AUROC, 0.58). Although 90-day mortality rates after transplantation were 13.7% in Hannover, 12.1% in Kiel, and 8.3% in Birmingham, the calculated 90-day survival benefits of transplantation were 6.8% in Hannover, 7.8% in Kiel, and 2.8% in Birmingham. Deployment of the LivAS for limiting allocation to donor and recipient combinations with likely 90-day survival as indicated by pretransplant LivAS values below the cutoff value would have increased the survival benefit to 12.9% in the German cohorts, whereas this would have decreased the benefit in England to 1.3%. The English and German cohorts revealed significant differences in 21 of 28 pretransplant variables. In conclusion, the LivAS could be validated in Germany and may improve German allocation policies leading to greater survival benefits, whereas validation failed in England due to profound differences in the selection criteria for liver transplantation. This study suggests the need for national prognostic models. Even though the German centers had higher rates of 90-day mortality, estimated survival benefits were greater. Liver Transplantation 22 743-756 2016 AASLD.

Longterm corticosteroid use after liver transplantation for autoimmune hepatitis is safe and associated with a lower incidence of recurrent disease.

Patients transplanted for autoimmune hepatitis (AIH) are at risk of recurrent disease. Our current practice is to maintain long-term low-dose corticosteroids with additional immunosuppressive agents. This study describes the implications on patients' outcomes, sepsis, and osteoporosis. We collected data on patients transplanted between January 1999 and October 2014 in a single center who survived for more than 6 months. AIH recurrence was diagnosed by a combination of histology, raised immunoglobulin G levels, and exclusion of other etiologies. Sepsis was defined as any infection that resulted in significant morbidity or mortality. Osteoporosis was defined as a bone densitometry T score of less than -2.0 or evidence of osteoporosis-related fractures. Outcomes were assessed using Kaplan-Meier survival analysis methods. Seventy-three AIH patients underwent liver transplantation with a median follow-up of 94 months (interquartile range, 55-144). The cohort was mainly Caucasian (78%), female (79%), with type 1 AIH (90%), and a mean age of 43 ± 15 years. Overall survival was 92%, 90%, 86%, and 73%, and regraft-free survival was 86%, 81%, 78%, and 64% at 1, 3, 5, and 10 years, respectively. Five patients developed AIH recurrence, giving recurrence rates of 0%, 4%, 6%, and 11% at 1, 3, 5, and 10 years, respectively. Pneumonia was the most common infection, but gastroenteritis and cholangitis were the most recurrent. Freedom from sepsis was 91%, 82%, 80%, and 63%, and freedom from osteoporosis was 100%, 94%, 82%, and 58% at 1, 3, 5, and 10 years, respectively. Longterm low-dose corticosteroid in combination with other immunosuppressive agents seems to reduce AIH recurrence without jeopardizing patient and graft survival. Sepsis and osteoporosis did not occur more often compared to the published literature on liver transplant recipients.

Accepting multiple simultaneous liver offers does not negatively impact transplant outcomes.

Impact of performing multiple liver transplants (LT) in a short period of time is unknown. Consecutively performed LT potentially increase complication rates through team fatigue and overutilization of resources and increase ischemia time. We analyzed the impact of undertaking consecutive LT (Consecutive liver transplant, CLT; LT preceded by another transplant performed not more than 12 h before, both transplants grouped together) on outcomes. Of 1702 LT performed, 314 (18.4%) were CLT. Outcome data was compared with solitary LT (SLT; not more than one LT in 12-h period). Recipient, donor, and graft characteristics were evenly matched between SLT and CLT; second LT of CLT group utilized younger donors grafts with longer cold ischemic times (P = 0.015). Implantation and operative time were significantly lower in CLT recipients on intergroup analysis (P = 0.0001 and 0.002, respectively). Early hepatic artery thrombosis (E-HAT) was higher in CLT versus SLT (P = 0.038), despite absolute number of E-HAT being low in all groups. Intragroup analysis demonstrated a trend toward more frequent E-HAT in first LT, compared to subsequent transplants; however, difference did not reach statistical significance (P = 0.135). In era of organ scarcity, CLT performed at high-volume center is safe and allows pragmatic utilization of organs, potentially reducing number of discarded grafts and reducing waiting list mortality.

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.