Organ offers in liver transplantation are high-risk medical decisions with a low certainty of whether a better liver offer will come along before death. We hypothesized that decision support could improve the decision to accept or decline. With data from the Scientific Registry of Transplant Recipients, survival models were constructed for 42,857 waiting-list patients and 28,653 posttransplant patients from 2002 to 2008. Daily covariate-adjusted survival probabilities from these 2 models were combined into a 5-year area under the curve to create an individualized prediction of whether an organ offer should be accepted for a given patient. Among 650,832 organ offers from 2008 to 2013, patient survival was compared by whether the clinical decision was concordant or discordant with model predictions. The acceptance benefit (AB)--the predicted gain or loss of life by accepting a given organ versus waiting for the next organ--ranged from 3 to -22 years (harm) and varied geographically; for example, the average benefit of accepting a donation after cardiac death organ ranged from 0.47 to -0.71 years by donation service area. Among organ offers, even when AB was >1 year, the offer was only accepted 10% of the time. Patient survival from the time of the organ offer was better if the model recommendations and the clinical decision were concordant: for offers with AB > 0, the 3-year survival was 80% if the offer was accepted and 66% if it was declined (P < 0.001). In conclusion, augmenting clinical judgment with decision support may improve patient survival in liver transplantation.

Adult recipients of living donor liver transplantation (LDLT) have a higher incidence of biliary complications than recipients of deceased donor liver transplantation (DDLT). Our objective was to define the intensity of the interventions and the time to resolution after the diagnosis of biliary complications after liver transplantation. We analyzed the management and resolution of posttransplant biliary complications and investigated the comparative effectiveness of interventions in LDLT and DDLT recipients. For the analysis of biliary complications (leaks or strictures), we used a retrospective cohort of patients who underwent liver transplantation at 8 centers between 1998 and 2006 (median follow-up from onset=4.7 years). The numbers, procedure types, and times to resolution were compared for LDLT and DDLT recipients. Posttransplant biliary complications occurred in 47 of the 189 DDLT recipients (25%) and in 141 of the 356 LDLT recipients (40%). Biliary leaks constituted 38% of the post-DDLT biliary complications (n=18) and 65% of the post-LDLT biliary complications (n=91). The median times to first biliary complications were similar for DDLT and LDLT (11 versus 14 days for leaks, P=0.63; 69 versus 107 days for strictures, P=0.34). Overall, 1225 diagnostic and therapeutic procedures, including reoperation and retransplantation, were performed (6.5±5.4 per recipient; 5.5±3.6 for DDLT versus 6.8±5.8 for LDLT, P=0.52). The median number of months to the resolution of a biliary complication (i.e., a tube-, stent-, and drain-free status) did not significantly differ between the DDLT and LDLT groups for leaks (2.3 versus 1.3 months, P=0.29) or strictures (4.9 versus 2.3 months, P=0.61). Although the incidence of biliary complications is higher after LDLT versus DDLT, the treatment requirements and the time to resolution after the development of a biliary complication are similar for LDLT and DDLT recipients.

We quantified the rates of hepatic regeneration and functional recovery for 6 months after right hepatic lobectomy in living donors for liver transplantation. Twelve donors were studied pre-donation (baseline); 8 were retested at a mean ± SD of 11±3 days after donation (T1), 10 were retested at a mean of 91±9 days after donation (T2), and 10 were retested at a mean of 185±17 days after donation (T3). Liver and spleen volumes were measured with computed tomography (CT) and single-photon emission computed tomography (SPECT). Hepatic metabolism was assessed with caffeine and erythromycin, and hepatic blood flow (HBF) was assessed with cholates, galactose, and the perfused hepatic mass (PHM) by SPECT. The regeneration rates (mL kg(-1) of body weight day(-1)) by CT were 0.60±0.22 mL from the baseline to T1, 0.05±0.02 mL from T1 to T2, and 0.01±0.01 from T2 to T3; by SPECT they were 0.54±0.20, 0.04±0.01, and 0.01±0.02, respectively. At T3, the liver volumes were 84%±7% of the baseline according to CT and 92%±13% of the baseline according to SPECT. Changes in the hepatic metabolism did not achieve statistical significance. At T1, the unadjusted clearance ratios with respect to the baseline were 0.75±0.07 for intravenous cholate (P<0.001), 0.88±0.15 for galactose (P=0.07), 0.84±0.08 for PHM (P=0.002), and 0.83±0.19 for the estimated HBF (P=0.06). At T1, these ratios adjusted per liter of liver were up to 50% greater than the baseline values, suggesting recruitment of HBF by the regenerating liver. Increased cholate shunt, increased spleen volume, and decreased platelet count, were consistent with an altered portal circulation. In conclusion, initial hepatic regeneration is rapid, accounts for nearly two-thirds of total regeneration, and is associated with increases in HBF and cholate uptake. Right lobe donation alters the portal circulation of living donors, but the long-term clinical consequences, if there are any, are unknown.

We quantified rates of hepatic regeneration and functional recovery for 6 months after right hepatic lobectomy in living donors for liver transplantation.Twelve donors were studied at baseline; eight retested at (mean±SD) 11±3 days (T1), 10 at 91±9 days (T2), and 10 at 185±17 days (T3) after donation. Liver and spleen volumes were measured by computed tomography (CT) and single photon emission computed tomography (SPECT). Hepatic metabolism was assessed from caffeine and erythromycin, and hepatic blood flow from cholates, galactose, and perfused hepatic mass (PHM, by SPECT).Regeneration rates (mL liver per kg body weight per day) were 0.60±0.22 from baseline to T1, 0.05±0.02 from T1 to T2, 0.01±0.01 from T2 to T3 by CT, 0.54±0.20, 0.04±0.01 and 0.01±0.02 by SPECT. At T3, liver volume was 84±7% of baseline by CT and 92±13% by SPECT. Changes in hepatic metabolism did not achieve statistical significance. At T1, unadjusted clearance ratios relative to baseline were 0.75±0.07 for intravenous cholate (p=0.0001), 0.88±0.15 for galactose (p=0.0681), 0.84±0.08 (p=0.002) for PHM, and 0.83±0.19 (p=0.056) for estimated hepatic blood flow. These ratios approached 1.00 by T3. At T1, ratios adjusted per L liver were 20%-50% greater than baseline and trended toward baseline by T3. Several findings were consistent with alteration of the portal circulation: increased cholate shunt, increased spleen volume, decreased platelet count, and decreased clearance of orally-administered cholate.During the first 2 weeks after donation, hepatic regeneration is rapid and accounts for nearly two-thirds of total regeneration. Increases in hepatic blood flow and uptake of cholate characterize the early phase of regeneration. Right lobe donation alters the portal circulation of living donors, but long-term clinical consequences, if any, are unknown.

Background

Early allograft dysfunction (EAD) after living donor liver transplantation (LDLT) has often been attributed to inadequate graft size, and termed small-for-size syndrome. Early allograft dysfunction definitions include a variable constellation of findings, including hyperbilirubinemia, coagulopathy, encephalopathy, and ascites formation. Among putative causes of EAD after LDLT are excessive portal pressure and/or flow. Our objective was to evaluate patterns of EAD after LDLT.

Methods

In this study, 631 LDLT recipients were monitored for complications, EAD (defined by postoperative day 7 bilirubin >10 mg/dL or international normalized ratio >1.6), and graft failure. Approximately 200 had portal venous and arterial pressure and flow measurements before and after LDLT. Portal inflow modification (splenic artery ligation, hemiportocaval shunt, or splenectomy) was performed at the discretion of the operating surgeon. Associations between EAD and recipient, donor, and transplant factors were examined using multivariable logistic regression.

Results

Risk of EAD was associated with left lobe grafts, lower graft weight among left lobes, higher preoperative bilirubin, higher portal reperfusion pressure, higher donor age, and higher donor body mass index. The risk of graft loss within the first 90 days was 5.2 times higher for recipients with EAD versus those without EAD (P < 0.001).

Conclusions

Early allograft dysfunction can be defined using postoperative day 7 laboratory values that are highly predictive of early graft failure within 90 days. Risk factors associated with EAD after LDLT include: graft type and size, preoperative bilirubin, portal reperfusion pressure, donor age, and donor body mass index.

Objectives

To advance our understanding of monogenic forms of intrahepatic cholestasis.

Methods

Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data.

Results

Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported.

Conclusions

In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Background and aims

Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.

Approach and results

A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS.

Conclusions

Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.