Time Of Liver Transplantation Research Articles

PNPLA3 rs738409 G allele carriers with genotype 1b HCV cirrhosis have lower viral load but develop liver failure at younger age.

BackgroundPNPLA3 rs738409 minor allele c.444G represents a risk factor for liver steatosis and fibrosis progression also in chronic hepatitis C (HCV). We investigated its impact on the timing of liver transplantation (LT) in patients with genotype 1b HCV cirrhosis.MethodsWe genotyped and evaluated 172 LT candidates with liver cirrhosis owing to chronic HCV infection, genotype 1b. One hundred patients needed LT for chronic liver failure (CLF) and 72 for a small hepatocellular carcinoma (HCC) in the cirrhotic liver without CLF. Population controls (n = 647) were selected from the Czech cross-sectional study MONICA.ResultsThe CLF patients were younger (53.5 ± 7.2 vs. 59.6 ± 6.6, P < 0.001) with more advanced liver disease than HCC patients (Child-Pugh’s score 9.1 ± 1.8 vs. 7.1 ± 1.9, P < 0.001, MELD 14.1 ± 3.9 vs. 11.1 ± 3.7, P < 0.001). PNPLA3 G allele increased the risk of LT for CLF in both allelic and recessive models (CG + GG vs. CC: OR, 1.90; 95% CI, 1.017–3.472, P = 0.045 and GG vs. CC + CG: OR, 2.94; 95% CI, 1.032–7.513, P = 0.042). Multivariate analysis identified younger age (P < 0.001) and the G allele (P < 0.05) as risk factors for CLF. The genotype frequencies between the CLF group and MONICA study significantly differed in both, allelic and recessive model (P = 0.004, OR 1.87, 95% CI 1.222–2.875; P < 0.001, OR 3.33, 95% CI 1.824–6.084, respectively). The OR values almost doubled in the recessive model compared with the allelic model suggesting the additive effect of allele G. In contrast, genotype frequencies in the HCC group were similar to the MONICA study in both models. Pretransplant viral load was significantly lower in GG than in CC + CG genotypes (median, IQR; 162,500 (61,550–319,000) IU/ml vs. 570,000 (172,000–1,595,000) IU/ml, P < 0.0009).ConclusionsOur results suggest that PNPLA3 rs738409 G allele carriage may be associated with a faster progression of HCV cirrhosis to chronic liver failure.

463 – Significantly Worse Functional Status At Time of Liver Transplant (LT) Waitlist Registration Among Patients with Alcoholic Liver Disease May Reflect Delays in Timely Referral for Lt Evaluation

463 – Significantly Worse Functional Status At Time of Liver Transplant (LT) Waitlist Registration Among Patients with Alcoholic Liver Disease May Reflect Delays in Timely Referral for Lt Evaluation

Sa1573 – Worse Functional Status and Older Age At Time of Liver Transplantation (LT) Have the Greatest Negative Impact of Post-Lt Survival in Patients with Nonalcoholic Steatohepatitis and Alcoholic Liver Disease

Sa1573 – Worse Functional Status and Older Age At Time of Liver Transplantation (LT) Have the Greatest Negative Impact of Post-Lt Survival in Patients with Nonalcoholic Steatohepatitis and Alcoholic Liver Disease

Intraoperative anesthetic management of the liver transplant recipient with portopulmonary hypertension.

Liver transplantation in patients with portopulmonary hypertension (POPH) is associated with increased perioperative risk. Important recent advances in the management of liver transplantation recipients with POPH are discussed. The presence of POPH at the time of liver transplantation should not be a contraindication for liver transplantation, as POPH is common and may be related to volume overload and/or high cardiac output (CO). Available data suggest that patients with mild POPH (25-35 mmHg) can safely undergo liver transplantation surgery. In more severe cases, treatment of POPH with a combination of vasoactive drugs may lead to successful liver transplantation with normalization of POPH. The key to successful intraoperative anesthetic management is maintaining the right ventricular preload and avoiding right ventricular dysfunction. Techniques include diuresis, intraoperative hemodialysis, venovenous bypass, or extracorporeal membrane oxygenation. Apart from the surgical and anesthetic techniques used, factors that contribute to increased pulmonary vascular resistance have to be avoided and the continuation of the vasodilators into the intraoperative and postoperative periods is crucial. The current article provides a review of the current challenges and advances in the management of liver transplantation recipients with POPH from the anesthetic point of view.

Activation of the Alternate Renin-Angiotensin System Correlates with the Clinical Status in Human Cirrhosis and Corrects Post Liver Transplantation.

Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.

Karnofsky Performance Status Following Liver Transplantation in Patients With Multiple Organ Failures and Probable Acute-on-Chronic Liver Failure

Little is known about outcomes of patients who underwent liver transplantation for acute on chronic liver failure (ACLF) and multiple organ failures. We compared Karnofsky Performance Status (KPS) before and after liver transplantation among patients with different numbers of organ failures and probable ACLF. We performed a retrospective cohort study of adults who underwent liver transplantation within 30 days of listing with the United Network for Organ Sharing (UNOS) network from January 1, 2006, through September 30, 2016. We determined the prevalence of organ failures using a modified version of the Chronic Liver Failure-Sequential Organ Failure Assessment scale and collected KPS scores at the time of transplantation and at intervals of 3 to 12 months after liver transplantation. Multivariate analyses were performed to adjust for confounders including UNOS region. At the time of liver transplantation, 2838 patients had no organ failure, 2944 had 1 to 2 organ failures, and 1342 patients had 3 or more organ failures. KPS scores following liver transplantation improved significantly in all groups; scores ranged from 81 in patients with no organ failure to 72 in patients with 5 to 6 organ failures. Excellent performance status (KPS score, ≥80) by 1 year after transplantation was achieved by 60% of patients with 5 to 6 organ failures, 64% to 66% of patients with 3 to 4 organ failures, and 70% to 71% of patients with 1 to 2 organ failures, compared with 72.5% of patients without organ failure. Patients with 1 to 4 organ failure were more likely to achieve KPS scores of 80 or more than patients without organ failure, after we adjusted for other covariates and UNOS region. In addition, black patients were less likely, and patients with alcoholic cirrhosis were more likely, to have KPS scores of 80 or more after liver transplantation. In a retrospective cohort study of patients with probable ACLF who underwent liver transplantation within 30 days of listing with the UNOS network, 60% to 66% of patients with 3 or more organ failures achieved excellent performance 3 to 12 months later.

No need to discontinue hepatitis C virus therapy at the time of liver transplantation.

ObjectivesDirect antiviral agents (DAA) has dramatically improved the therapy outcome of hepatitis C-virus (HCV) infection, both on the waiting-list and post liver transplantation (LT). DAA are generally well-tolerated in patients with mild to moderate liver and kidney failure, but some DAAs are contraindicated in patients with severe dysfunction of these organs. Today there are few studies of peri-LT DAA use and treatment is commonly discontinued at the time of LT. We report here our experience of DAA therapy given continuously in the perioperative LT period in a real-life setting in Sweden.MaterialIn total 10 patients with HCV-cirrhosis, with or without hepatocellular carcinoma, and a median age of 60.5 years (range, 52–65) were treated with DAAs on the waiting list for LT, and continued in the early postoperative period without any interruption, on the basis of not having reached a full treatment course at the time of LT. Sofosbuvir and a NS5A inhibitor with or without ribavirin, or sofosbuvir and ribavirin only, were given. The distribution of genotypes was genotype 1 and 3, in 4 and 6 patients, respectively. Six of the 10 patients had previously been treated with IFN-based therapy.ResultsThere were no adverse events leading to premature DAA discontinuation. All recipients achieved a sustained viral response 12 weeks after end-of-treatment (SVR12). At the time of LT the median MELD-score was 16.5 (range 7–21), CTP-score 9.0 (range 5–10), creatinine 82.5 μmol/L (range 56–135, reference 60–105), bilirubin 33 μmol/L (range 16–79, reference 5–25) and PK-INR 1.5 (range 1.1–1.8). The median duration of DAA therapy was 60 days (range 18–132) pre-LT, 54 days post-LT (range 8–111 days) and in total 15.5 weeks (range 12–30 weeks).ConclusionInterferon-free DAA therapy of HCV-infection given in the immediate pre- and post-operative LT period is safe, well-tolerated and yields high SVR rates.

Staging of liver fibrosis in biliary atresia : Comparison of Chevallier and Ishak score as well as automated evaluation

Biliary atresia (BA) is arare disease of the newborn, resulting in liver cirrhosis due to obliterative cholangiopathy. Liver biopsies are commonly performed in order to confirm the diagnosis and in order to stage fibrosis. The present study intended to analyze two established scores for evaluating liver fibrosis focusing on the interobserver variability as well as the prognostic reliability towards the time of liver transplantation. Liver biopsies of BA patients between 2012 and 2015 were evaluated retrospectively by two pathologists at the Hannover Medical School (MHH) and the RWTH Aachen University Hospital. Fibrosis was measured using Ishak and Chevallier scores. Furthermore, acomputerized automatically algorithm-based analyzation (ABAA) was performed. Results were evaluated towards the time point of liver transplantation and hepatoportoenterostomy (HPE). Overall, 34liver biopsies were analyzed. The Ishak score showed aremarkable interobserver variability (ΚW = 0.68) while the Chevallier score was proven to have apoor interobserver variability (Fleiss' Κappa = -0.01). However, both scores were correlated positively, as was the ABAA (p < 0.001). Regarding prognostic reliability, ROC analyses of the Ishak score revealed the best validity towards an early liver transplantation within 12months (AUC 0.813, p = 0.011). In addition, an increased Ishak score ≥4 reduced the survival time with the native liver (hazard ratio6.6 [95% CI1.9-23.3]). The Ishak score was revealed to have the best interobserver variability as well as prognostic validity towards an early liver transplantation in BA patients. Due to its easy applicability, the Ishak score was proven superior in comparison to the Chevallier score and ABAA. Therefore, use of the Ishak score is recommended in daily clinical routine for analyzing liver biopsies in BA patients.

Patients with hepatorenal syndrome may have better renal outcome after living donor liver transplantation comparing with patients with chronic kidney disease

Introduction: Hepatorenal syndrome (HRS) is one of the most severe complications of liver cirrhosis. Liver transplantation (LT), the ultimate curative treatment for end-stage liver disease, is needed to completely reverse HRS. However, risk of renal function deterioration after LT has been associated with pre-LT renal dysfunction. Several studies have reported outcome comparisons between patients with or without HRS. Here we compare the outcomes between LT patients with HRS or with chronic kidney disease (CKD). Method: Medical records of adult patients receiving living donor liver transplantation (LDLT) at Kaohsiung Chang Gung Memorial Hospital from July 2008 to September 2017 were reviewed. Patients with renal function impairment were enrolled. According to the diagnostic criteria of HRS, 12 patients were type 1, 19 patients were type 2, and 44 patients were CKD, respectively. And 67 patients with normal renal function were chosen for comparison. Result: The serum creatinine levels of the 3 groups with renal dysfunction at initial presentation had no significant differences. At the time of liver transplantation, the serum creatinine level of HRS type 2 group was better than CKD group (1.46mg/dL vs 2.32mg/dL, p = 0.002). There were no significant differences in creatinine level between HRS type 1 and 2, neither between HRS type 1 and CKD group. However, model for end-stage liver disease (MELD) score in HRS type 1 group was significantly higher than in CKD group. Two years later after LDLT, patients in CKD group had the highest serum creatinine level than in HRS type 1 and type 2 group (2.30mg/dL vs. 1.95mg/dL and 1.49mg/dL, p = 0.152 and 0.084, respectively). Conclusion: Despite higher pre-LT disease severity, patients with HRS still had slightly better renal outcome at two years after LDLT than patients with CKD.

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

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). 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). 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. 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.

Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.

The Macrophage Activation Marker Soluble CD163 is Associated With Early Allograft Dysfunction After Liver Transplantation

Soluble CD163 (sCD163), a macrophage activation marker, is upregulated in conditions of macrophage proliferation and activation. Elevated sCD163 levels have been associated with liver disease severity and progression. During liver transplantation, the implanted liver is exposed to ischaemia and reperfusion injury, resulting in an acute inflammatory response and macrophage activation. The relationship between sCD163 levels during liver transplantation and the development of early allograft dysfunction (EAD) has not been investigated. We included 27 cirrhosis patients (age 55 [range 32-72] years, 23 men) on the waiting list for liver transplantation. Alcohol consumption and viral hepatitis were the most frequent causes for cirrhosis. Patients were characterised by standard biochemical analysis and based on clinical disease severity scores. Information about donor, graftand course of the liver transplantation was recorded. sCD163 levels were measured at the time of liver transplantation before surgery, 2h after reperfusion, and then at 24h after transplantation. We observed above-normal sCD163 levels at baseline (5.9mg/L [4.7-8.8]). Two hours after reperfusion, sCD163 levels increased significantly from baseline (8.4mg/L [7.4-10.9]; P<0.01). Twenty-four hours after transplantation, sCD163 levels were significantly reduced compared with baseline (3.7mg/L [2.9-5.5]; P<0.01). However, in patients with EAD (n=16), sCD163 levels were increased compared with patients without EAD (4.1 [3.2-7.4] vs. 3.1 [2.8-3.8] mg/L; P=0.03). We observed elevated sCD163 levels in patients with EAD after liver transplantation, confirming macrophage activation to play a role in EAD. Thus, sCD163 may be used as an early marker for EAD after liver transplantation, but larger studies are warranted to validate these findings.

Worse Performance Status at Time of Liver Transplant Is Associated With Significantly Lower Survival Following Liver Transplantation

Worse Performance Status at Time of Liver Transplant Is Associated With Significantly Lower Survival Following Liver Transplantation

Among U.S. Adults Undergoing Liver Transplantation, African Americans and Hispanics Have Significantly Worse Functional Status at Time of Liver Transplant

Introduction: While poor functional status correlates with worse post-liver transplantation (LT) outcomes, it is unclear if certain groups have disparately worse functional status at time of LT. We aim to evaluate sex-, age-, and ethnicity-specific differences in functional status at LT and its impact on post-LT survival. Methods: Based on 2005-2016 United Network for Organ Sharing data, functional status at LT, determined using Karnofsky Performance Status score (KPSS 1: functional status 80-100%, KPSS 2: 60-70%, KPSS 3: 40-50%, KPSS 4: 10-30%), was compared by sex, age, and ethnicity using chi-square testing. The interactions of sex, age, ethnicity, and KPSS on post-LT survival were evaluated with Kaplan Meier methods and multivariate logistic regression models (adjusted for age, sex, race/ethnicity, liver disease etiology, MELD score, insurance, transplant year, and hepatocellular carcinoma (HCC). Results: Among 66,397 LT recipients, 68% were male, 72% non-Hispanic white, 22% had concurrent HCC. Compared to men, women were more likely to have worse KPSS at LT (KPSS 4: 28.0% vs. 22.8% (males), p> 70), 21.9% (age 60-69), 23.7% (age 50-59) vs. 29.9% (age<50), p<0.01 for all). Compared to Caucasians, significantly worse KPSS at LT was seen in Hispanics (KPSS 4: 31.7% vs. 23.0%, p<0.001) and African Americans (AA) (KPSS 4: 25.4% vs. 23.0%, p<0.01). Worse KPSS at LT was associated with lower 5-year post-LT survival in males (69.8% (KPSS 4) vs. 78.7% (KPSS 1)) and females (71.2% (KPSS 4) vs. 80.4% (KPSS 1)), p<0.01 for both. Similar trends were seen in all age and race/ethnic groups (5-year survival: Caucasians, 70.3% (KPSS 4) vs. 79.8% (KPSS 1); African Americans, 65.8% (KPSS 4) vs. 70.4% (KPSS 1); Hispanics, 72.1% (KPSS 4) vs. 78.8% (KPSS 1); Asians, 75.0% (KPSS 4) vs. 84.1% (KPSS 1), p<0.01 for all). On multivariate regression, compared to Caucasians, post-LT mortality was higher in AA (HR 1.31; 95% CI 1.23-1.39) and lower in Hispanics (HR 0.87; 95% CI 0.82-0.93), p<0.001 for both. Compared to patients age <50, increasing age at LT correlated with higher post-LT mortality. Conclusion: Among U.S. adults undergoing LT, African Americans and Hispanics had significantly worse KPSS at time of LT compared to Caucasians. Women and younger adults also had worse KPSS. These findings are concerning given that worse functional status correlates with lower post-LT survival.1018 Figure 1 No Caption available.

Summary of the Third International Workshop on Clinical Tolerance.

The Third International Workshop on Clinical Tolerance was held in Stanford, California, September 8-9, 2017. This is a summary of Workshop presentations of clinical trials designed to withdraw or minimize immunosuppressive (IS) drugs in kidney and liver transplant patients without subsequent evidence of rejection. All clinical protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. Tolerance to HLA matched and mismatched living donor kidney transplants with complete withdrawal of IS drugs without subsequent rejection for up to 14 years of observation was achieved in more than 50 patients enrolled in trials in four medical centers after the establishment of transient or persistent chimerism. Complete IS drug withdrawal without chimerism was reported in a prospective trial of liver transplantation combined with injection of regulatory T cells. IS drug minimization without rejection was reported in recipients of living donor kidney transplants enrolled in the One Study consortium after injection of recipient regulatory T cells, or injection of donor regulatory monocytes or dendritic cells. In conclusion, considerable progress has been made in achieving IS drug withdrawal after cell therapy in recipients of organ transplants.

Daytime variation in hepatitis C virus replication kinetics following liver transplant.

Background: There is a growing interest in the role of circadian regulated pathways in disease pathogenesis. Methods: In a cohort of hepatitis C virus (HCV) infected patients undergoing liver transplantation, we observed differences in early viral infection kinetics of the allograft that associated with the time of liver transplant. Results: A higher frequency of subjects transplanted in the morning showed a rebound in viral RNA levels (n=4/6) during the first week post-surgery. In contrast, no viral rebound was observed in seven subjects transplanted in the afternoon. None of the other parameters previously reported to influence viral replication in the post-transplant setting, such as donor age, cold-ischemia time and length of surgery associated with viral rebound. Conclusions: These observation highlights a role for circadian processes to regulate HCV infection of the liver and warrants further investigation.

Daytime variation in hepatitis C virus replication kinetics following liver transplant

Background: There is a growing interest in the role of circadian regulated pathways in disease pathogenesis. Methods: In a cohort of hepatitis C virus (HCV) infected patients undergoing liver transplantation, we observed differences in early viral infection kinetics of the allograft that associated with the time of liver transplant. Results: A higher frequency of subjects transplanted in the morning showed a rebound in viral RNA levels (n=4/6) during the first week post-surgery. In contrast, no viral rebound was observed in seven subjects transplanted in the afternoon. None of the other parameters previously reported to influence viral replication in the post-transplant setting, such as donor age, cold-ischemia time and length of surgery associated with viral rebound. Conclusions: These observation highlights a role for circadian processes to regulate HCV infection of the liver and warrants further investigation.

Vitamin D status and risk of infections after liver transplantation in the Swiss Transplant Cohort Study.

Increasing evidence indicates a role of vitamin D in the immune system affecting response to infections. We aimed to characterize the role of vitamin D status, i.e. deficiency [25-OH vitamin D (25-OHD) <50 nmol/l] and no deficiency (25-OHD ≥50 nmol/l) in incident infections after liver transplantation. In 135 liver transplant recipients, blood samples drawn at time of liver transplantation and 6 months afterwards were used to determine 25-OHD levels. Incident infections episodes were prospectively collected within the Swiss Transplant Cohort Study database. Poisson regression was applied to address associations between vitamin D status and incident infections. Vitamin D deficiency was common at time of transplantation and 6 months afterwards without a significant change in median 25-OHD levels. In univariable analyses, vitamin D deficiency was a risk factor for incident infections in the first 6 months post-transplant incidence rate ratio (IRR 1.52, 95% CI 1.08-2.15, P = 0.018) and for bacterial infections occurring after 6 up to 30 months post-transplant (IRR 2.29, 95% CI 1.06-4.94, P = 0.034). These associations were not detectable in multivariable analysis with adjustment for multiple confounders. Efforts to optimize vitamin D supplementation in liver transplant recipients are needed. Our data question the role of vitamin D deficiency in incident infections.

Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma.

There is limited data on the molecular mechanisms whereby hepatitis D virus (HDV) promotes liver cancer. Therefore, serum and liver specimens obtained at the time of liver transplantation from well-characterized patients with HDV-HCC (n = 5) and with non-HCC HDV cirrhosis (n = 7) were studied using an integrated genomic approach. Transcriptomic profiling was performed using laser capture-microdissected (LCM) malignant and nonmalignant hepatocytes, tumorous and nontumorous liver tissue from patients with HDV-HCC, and liver tissue from patients with non-HCC HDV cirrhosis. HDV-HCC was also compared with hepatitis B virus (HBV) HBV-HCC alone, and hepatitis C virus (HCV) HCV-HCC. HDV malignant hepatocytes were characterized by an enrichment of upregulated transcripts associated with pathways involved in cell-cycle/DNA replication, damage, and repair (Sonic Hedgehog, GADD45, DNA-damage-induced 14-3-3σ, cyclins and cell-cycle regulation, cell cycle: G2-M DNA-damage checkpoint regulation, and hereditary breast cancer). Moreover, a large network of genes identified functionally relate to DNA repair, cell cycle, mitotic apparatus, and cell division, including 4 cancer testis antigen genes, attesting to the critical role of genetic instability in this tumor. Besides being overexpressed, these genes were also strongly coregulated. Gene coregulation was high not only when compared with nonmalignant hepatocytes, but also to malignant hepatocytes from HBV-HCC alone or HCV-HCC. Activation and coregulation of genes critically associated with DNA replication, damage, and repair point to genetic instability as an important mechanism of HDV hepatocarcinogenesis. This specific HDV-HCC trait emerged also from the comparison of the molecular pathways identified for each hepatitis virus-associated HCC. Despite the dependence of HDV on HBV, these findings suggest that HDV and HBV promote carcinogenesis by distinct molecular mechanisms.Implications: This study identifies a molecular signature of HDV-associated hepatocellular carcinoma and suggests the potential for new biomarkers for early diagnostics. Mol Cancer Res; 16(9); 1406-19. ©2018 AACR.

Morbidity of liver transplantation in patients with multiorgan failure in the intensive care unit

Background: The mean MELD-Na at the time of liver transplant (LT) varies widely across the 11 regions in the United States (US), due to organ supply versus demand issues, from 22 to as high as 35. Utilizing marginal donors on very sick patients has become more commonplace in some regions of the US but it has not been determined as to which patients are “too sick” to undergo LT. The purpose of our study was to determine if the use of Methods: A retrospective review comparing LT in patients from home (n = 40) to patients from the ICU (n = 44) between 2009–2016 with a MELD-Na >25. Preoperative variables included: demographics, etiologies, MELD-Na, and ICU risk factors (mechanical ventilation, vasopressors, hemodialysis, blood transfusions, length of stay (LOS)). Intraoperative variables included: transfusions, organ ischemia, donor risk index, operative time, and complications. Postoperative outcomes included: LOS, mechanical ventilation, re-operation, biliary complications, infection, short and long term renal dysfunction, 30-day readmission, liver biopsy, graft and patient 1 year survival. Results: We found that in in patients who underwent LT from the ICU versus those from home: median MELD-Na 43 vs 36 (p < 0.05), 1 year graft survival of 86.7% vs 90% (p = 0.74), 1 year patient survival of 86.7% vs 92.5% (p = 0.49). Conclusion: LT in the ICU patient continues to face challenges, especially when considering the severe organ shortage in the US. We found that in carefully selected ICU patients, even with multiorgan dysfunction, 1 year graft and patient survival are similar to outpatients.