Epidemiology and outcomes of surgical site infections among pediatric liver transplant recipients.

INTRODUCTION: Surgical site infections (SSI) are a significant cause of morbidity in liver transplant recipients, and the current data in the pediatric population are limited. The goal of this study was to identify the incidence, classification, risk factors, and outcomes of SSIs among children undergoing liver transplantation (LT). METHODS: A single-center, retrospective descriptive analysis was performed of patients age ≤18 years undergoing LT between September 2007 and April 2017. SSI identified within the first 30 days were analyzed. Primary endpoints included incidence, classification, risk factors, and outcomes associated with SSIs. RESULTS: We included 86 patients, eight patients (9.3%) developed SSIs. Among segmental grafts (SG) recipients, 7/61 (11.4%) developed SSI. Among whole grafts recipients, 1/25 (4%) developed SSI. SSIs were associated with the presence of biliary complications (35% vs. 3%, p < .01; odds ratios 24, 95% CI: 3.41-487.37, p<.01). There were no differences in long term graft or patient survival associated with SSI. Patients who developed SSI were more likely to undergo reoperation (50% vs. 16.7%, p = .045) and had an increased total number of hospital days in the first 60 days post-transplant (30.5 vs. 12.5 days, p = .001). CONCLUSIONS: SSIs after pediatric LT was less frequent than what has been previously reported in literature. SSIs were associated with the presence of biliary complications without an increase in mortality. SG had an increased rate of biliary complications without an association to SSIs but, considering its positive impact on organ shortage barriers, should not be a deterrent to the utilization of SGs.

The feasibility of a group stress management Liver SMART intervention for patients with end-stage liver disease: A pilot study.

OBJECTIVE: Structured, empirically supported psychological interventions are lacking for patients who require organ transplantation. This stage IA psychotherapy development project developed and tested the feasibility, acceptability, tolerability, and preliminary efficacy of an 8-week group cognitive behavioral stress management intervention adapted for patients with end-stage liver disease awaiting liver transplantation. METHOD: Twenty-nine English-speaking United Network for Organ Sharing-registered patients with end-stage liver disease from a single transplantation center enrolled in 8-week, group cognitive-behavioral liver stress management and relaxation training intervention adapted for patients with end-stage liver disease. Patients completed pre- and postintervention surveys that included the Beck Depression Inventory II and the Beck Anxiety Inventory. Feasibility, acceptability, tolerability, and preliminary efficacy were assessed.ResultAttendance rate was 69.40%. The intervention was rated as "good" to "excellent" by 100% of participants who completed the postintervention survey in teaching them new skills to relax and to cope with stress, and by 94.12% of participants in helping them feel supported while waiting for a liver transplant. No adverse events were recorded over the course of treatment. Attrition was 13.79%. Anxious and depressive symptoms were not statistically different after the intervention.Significance of resultsThe liver stress management and relaxation training intervention is feasible, acceptable, and tolerable to end-stage liver disease patients within a transplant clinic setting. Anxious and depressive symptoms remained stable postintervention. Randomized controlled trials are needed to study the intervention's effectiveness in this population.

Biliary drainage as treatment for allograft steatosis following liver transplantation for PFIC-1 disease: A single-center experience.

Development of macrovesicular steatosis post-LT in patients with PFIC-1 is increasingly being observed, with the etiology not fully understood. We highlight successful and effective EBD for reversal of allograft steatosis in 2 patients with PFIC-1 disease and discuss our experience with internal biliary diversion in this patient population.

In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis.

BACKGROUND: The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify (13)C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations. METHODS: (13)C-labeled sodium acetate was applied orally in a single dose to 47 subjects (10 healthy subjects, 28 symptomatic patients, 9 asymptomatic carriers). RESULTS: The oral (13)C-ureagenesis assay is a safe method. While healthy subjects and asymptomatic carriers did not differ with regards to kinetic variables for urea cycle flux, symptomatic patients had lower (13)C-plasma urea levels. Although the (13)C-ureagenesis assay revealed no significant differences between individual urea cycle enzyme defects, it reflected the heterogeneity between different clinical subgroups, including male neonatal onset ornithine carbamoyltransferase deficiency. Applying the (13)C-urea area under the curve can differentiate between severe from more mildly affected neonates. Late onset patients differ significantly from neonates, carriers and healthy subjects. CONCLUSION: This study evaluated the oral (13)C-ureagenesis assay as a sensitive in-vivo measure for ureagenesis capacity. The assay has the potential to become a reliable tool to differentiate UCD patient subgroups, follow changes in ureagenesis capacity and could be helpful in monitoring novel therapies of UCD.

Resolution of non-alcoholic steatohepatitis after growth hormone replacement in a pediatric liver transplant patient with panhypopituitarism.

NAFLD is a common condition linked to obesity, type 2 diabetes, and metabolic syndrome. Simple hepatic steatosis is a risk factor for inflammatory reactions in the liver (NASH), which may lead to cirrhosis. While the mechanism is unclear, NAFLD and NASH are associated with panhypopituitarism, which in the pediatric population often results from craniopharyngioma or pituitary adenoma and the sequelae of treatment, causing hypothyroidism, adrenal insufficiency, hypogonadotropic hypogonadism, and GH deficiency. Refractory NAFLD in panhypopituitarism may be amenable to GH replacement. Here, we report a pediatric case of NASH secondary to panhypopituitarism from craniopharyngioma, which recurred by 11 months after LDLT. Despite low-dose GH replacement, the patient remained GH deficient. Pubertal dosed GH therapy led to rapid and complete resolution of hepatic steatosis, which we tracked using serial 1 H MRS. Pediatric patients with NASH cirrhosis secondary to panhypopituitarism can be good candidates for liver transplantation, but hormone deficiencies predispose to recurrence after transplant. High-dose GH replacement should be considered in pediatric patients with GH deficiency and recurrent disease. A multidisciplinary team approach is essential for successful outcomes.

New method of stent-facilitated arterial reconstruction for orthotopic mouse liver transplantation.

BACKGROUND: Arterialized orthotopic liver transplantation (OLT) in the mouse mimics human liver transplantation physiologically and clinically. The present method of sutured anastomosis for reconstruction of the hepatic artery is complex and is associated with high incidence of complications and failure. This makes the endpoint assessment of using this complex model difficult because of the many variables of the technical aspect. METHODS: A total of 14 pairs of donors and recipients from syngeneic male mice were used for arterialized OLT. The grafts were stored in University of Wisconsin solution at 4°C for less than 4 h, and the recipients underwent OLT using a two-cuff technique. The arterial reconstruction was facilitated by the use of a single stent connecting the donor liver artery segment to the recipient common hepatic artery. RESULTS: All 14 recipients survived with the time for arterial reconstruction ranging from 4-10 min. Patency of the artery was confirmed by transecting the artery near the graft 2 and 14 d after transplantation. At day 2, five of the six arteries transected were patent and at day 14, seven of the remaining eight were patent for an overall patency rate of 85.7%. CONCLUSIONS: The stent-facilitated arterial reconstruction can be done quickly with a high patency rate. This model expands the translational research efforts to address marginal livers such as steatotic livers.

Radiographic features of potential donor livers that precluded donation.

OBJECTIVE: The objective of our study was to catalog the anatomic features shown on preoperative CT that precluded living-donor liver donation. MATERIALS AND METHODS: We retrospectively reviewed the records of 159 consecutive candidates who were evaluated for potential right or left lobe liver donation from November 2007 to January 2012 using MDCT angiography and cholangiography. For the potential donors who were excluded secondary to findings depicted on preoperative imaging, we determined which findings precluded donation. RESULTS: In two (1%) patients who had no prohibitive preoperative imaging findings, anatomic abnormalities were detected intraoperatively that precluded transplantation. Sixty-one (38%) candidates were excluded from liver donation on the basis of imaging findings. Of these patients, 40 (66%) had inadequate liver volume, 14 (23%) had vascular or biliary variants, five (8%) had steatosis, and two (3%) were found to have renal cell carcinoma. Arterial and biliary variants were the most common reason for exclusion based on anatomic findings. CONCLUSION: Inadequate liver volume was the most common reason for exclusion based on preoperative imaging. Arterial and biliary anatomic variants precluded both right and left lobe transplantation in a number of cases.

Metastatic gastrinoma in a pediatric patient with Zollinger-Ellison syndrome.

Metastatic neuroendocrine tumors of childhood are extremely rare, and as such present diagnostic and therapeutic challenges. Here, we report a case of gastrinoma with extensive hepatic metastases in a pediatric patient with Zollinger-Ellison Syndrome who underwent orthotopic liver transplant followed by cytotoxic chemotherapy, somatostatin analog therapy, and immune modulation.

Impact of estimated liver volume and liver weight on gender disparity in liver transplantation.

Although lower Model for End-Stage Liver Disease (MELD) scores due to lower levels of serum creatinine in women might account for some of the gender disparity in liver transplantation (LT) rates, even within MELD scores, women undergo transplantation at lower rates than men. It is unclear what causes this disparity, but transplant candidate/donor liver size mismatch may be a factor. We analyzed Organ Procurement and Transplantation Network data for patients with end-stage liver disease on the waiting list. A pooled conditional logistic regression analysis was used to assess the association between gender and LT and to determine the degree to which this association was explained by lower MELD scores or liver size. In all, 28,866 patients and 424,001 person-months were included in the analysis. The median estimated liver volume (eLV) and the median estimated liver weight (eLW) were significantly lower for women versus men on the LT waiting list (P < 0.001). When we controlled for the region and the blood type, women were 25% less likely to undergo LT in a given month in comparison with men (P < 0.001). When the MELD score was included in the model, the odds ratio (OR) for gender increased to 0.84, and this suggested that 9 percentage points of the 25% gender disparity were due to the MELD score. When eLV was added to the model, there was an additional 3% increase in the OR for gender, and this suggested that transplant candidate/donor liver size mismatch was an underlying factor for the lower LT rates in women versus men (OR = 0.87, P < 0.001). In conclusion, lower LT rates among women on the waiting list can be explained in part by lower MELD scores, eLVs, and eLWs in comparison with men. However, at least half of the gender disparity still remains unexplained.

Comparison of multidetector computed tomography angiography and cholangiography performed at 80 and 120 kVp in live liver donors.

OBJECTIVE: The objective of this study was to compare the radiation exposure and image quality of contrast-enhanced multidetector computed tomography angiography (CTA) and computed tomography cholangiography (CTC) performed for living liver donor evaluation using 80 and 120 kVp. METHODS: Ninety-three potential liver donors who underwent preoperative contrast-enhanced 64 multidetector CTA and CTC were retrospectively divided into 2 groups: at 80 and at 120 kVp. An institutional review board waiver was obtained. Signal-to-noise ratio and contrast-to-noise ratio of the hepatic artery and common bile duct were obtained. The dose-length product was recorded. Image quality and visibility of hepatic artery and biliary tract anatomy were evaluated. Mann-Whitney U test was used for statistical evaluation. RESULTS: Mean hepatic artery/common bile duct signal-to-noise ratio was 28.9/28.6 (SD, 14.2/10.0) at 80 kVp and 27.6/25.8 (SD, 8.0/6.2) at 120 kVp (P = 0.61/0.099). Mean hepatic artery/common bile duct contrast-to-noise ratio was 24.8/23.3 (SD, 12.9/8.6) at 80 kVp and 22.2/19.3 (SD, 7.7/5.0) at 120 kVp (P = 0.76/0.005). Mean CTA/CTC dose-length product was 279/281 (SD, 42/52) mGy-cm at 80 kVp and 407/451 (SD, 208/243) mGy-cm at 120 kVp (P = 0.026/0.002). Computed tomography cholangiography image quality and visibility of biliary tract anatomy were not significantly different at 80 versus 120 kVp (all P > 0.13). Computed tomography angiography image quality was significantly lower (P < 0.01), and the noise scores significantly higher (P < 0.01) at 80 versus 120 kVp, but diagnostic. CONCLUSIONS: Contrast-enhanced CTA and CTC performed at 80 kVp result in comparable image quality and anatomical evaluation with reduced radiation exposure when compared with 120 kVp.

Portal hypertension in children: expert pediatric opinion on the report of the Baveno v Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.

Complications of portal hypertension in children lead to significant morbidity and are a leading indication for consideration of liver transplantation. Approaches to the management of sequelae of portal hypertension are well described for adults and evidence-based approaches have been summarized in numerous meta-analyses and conferences. In contrast, there is a paucity of data to guide the management of complications of portal hypertension in children. An international panel of experts was convened on April 8, 2011 at The Children's Hospital of Pittsburgh of UPMC to review and adapt the recent report of the Baveno V Consensus Workshop on the Methodology of Diagnosis and Therapy in Portal Hypertension to the care of children. The opinions of that expert panel are reported.

Emergency ABO-incompatible liver transplant secondary to fulminant hepatic failure: outcome, role of TPE and review of the literature.

The increasing demand for solid organ transplants has brought to light the need to utilize organs in critical situations despite ABO-incompatibility. However, these transplantations are complicated by pre-existing ABO antibodies which may be potentially dangerous and makes the transplantation prone to failure due to rejection with resulting necrosis or intrahepatic biliary complications. We report the clinical outcome of an emergency ABO-incompatible liver transplant (due to fulminant hepatic failure with sudden and rapidly deteriorating mental status) using a modified therapeutic plasma exchange (TPE) protocol. The recipient was O-positive with an initial anti-B titer of 64 and the cadaveric organ was from a B-positive donor. The patient underwent initial TPE during the peri-operative period, followed by a series of postoperative daily TPE, and later a third series of TPE for presumptive antibody-mediated rejection. The latter two were performed in conjunction with the use of IVIg and rituximab. The recipient's anti-B titer was reduced and maintained at 8 or less 8 months post-op. However, an elevation of transaminases 3 months post-transplant triggered a biopsy which was consistent with cellular rejection and with weak C4d positive staining suggestive of antibody mediated rejection. Additional plasma exchange procedures were performed. The patient improved rapidly after modification of her immunosuppression regimen and treatment with plasma exchange. This case illustrates that prompt and aggressive plasma exchange, in conjunction with immunosuppression, is a viable approach to prevent and treat antibody mediated transplant rejection in emergency ABO-incompatible liver transplant.

HLA, Non-HLA Antibodies, and Eplet Mismatches in Pediatric Liver Transplantation: Observations From a Small, Single-Center Cohort.

OBJECTIVES: To identify the risk of developing acute rejection, allograft fibrosis, and antibody-mediated rejection, a retrospective review of pediatric patients who underwent liver transplant between July 31, 1998 and February 29, 2016 and had donor-specific antibodies measured at time of liver biopsy was undertaken. MATERIALS AND METHODS: HLAMatchmaker Software (http://www.hlamatchmaker.net) was used to define epitope mismatches between donors and recipients and to predict de novo donor-specific antibody risk. Epitope mismatches were evaluated for their immunogenicity. RESULTS: In our group of 42 recipients, 20 (48%) had donor-specific antibodies. Having an antibody against HLA-DQB1*02 was associated with acute rejection (66.6% vs 36%; P = .024). We found that DQ epitope mismatch load was greater in recipients with class II donor-specific antibodies (9.7 vs 3.6; P = .001). HLA-DQ (7.4 vs 3.6; P = .04) and HLA-DR (8.8 vs 3.8; P = .04) epitope mismatch loads were higher in recipients with DQ + DR donor-specific antibodies. A high portal fibrosis score was associated with higher mismatch load at the DQ locus (P = .005) and DQ + DR loci (P = .03). Having > 5 or > 6 epitope mismatch loads at the DQ locus identified a threshold above which development of DQ donor-specific antibodies would occur (area under the curve = 0.878). Mismatches for eplet 4Q, 45GE, 52PQ, and 52PL, thought to be immunodominant epitopes, were observed for several recipients. CONCLUSIONS: Knowledge of epitope mismatches between recipients and donors may aid transplant physicians in devising immunosuppression strategies.

Psychiatric Comorbidity, Health-Related Quality of Life, and Mental Health Service Utilization Among Patients Awaiting Liver Transplant.

CONTEXT: The prevalence of psychiatric disorders and mental health service utilization among patients with end-stage liver disease awaiting transplant remains understudied. OBJECTIVES: This study assessed the prevalence of psychological disorders and symptoms with the use of a structured diagnostic interview and self-report measures, and examined patient-reported mental health service utilization and barriers to care. METHODS: Waitlisted liver transplant candidates (N = 120) completed assessments during routine clinic appointments at a single time point. RESULTS: Participants endorsed moderate-to-severe levels of depression (19.2%), anxiety (26.7%), and Post Traumatic Stress Disorder (PTSD) (23.3%). Forty-three percent had received some form of mental health treatment in the recent past, and a range of barriers to accessing mental health services were endorsed. In a subset of 39 participants who received a structure diagnostic assessment, there was a high prevalence of current (51.3%) and past (82.1%) psychiatric disorders. Elevated scores on depression, anxiety, and PTSD measures were associated with significant decrements in health-related quality of life, but were not differentially associated with mental health service utilization. CONCLUSION: There are a significant number of end-stage liver disease patients who could benefit from intervention who are not currently connected to treatment. Many patients do not see the need for accessing services, perhaps because of a lack of insight or knowledge about the benefits of mental health treatment. Future research should determine optimal treatment and service delivery methods for this vulnerable population.

De-novo hepatocellular carcinoma after pediatric living donor liver transplantation.

De-novo malignancies carry an incidence ranging between 3%-26% after transplant and account for the second highest cause of post-transplant mortality behind cardiovascular disease. While the majority of de-novo malignancies after transplant usually consist of skin cancers, there has been an increasing rate of solid tumor cancers over the last 15 years. Although, recurrence of hepatocellular carcinoma (HCC) is well understood among patients transplanted for HCC, there are increasing reports of de-novo HCC in those transplanted for a non-HCC indication. The proposed pathophysiology for these cases has been mainly connected to the presence of advanced graft fibrosis or cirrhosis and always associated with the presence of hepatitis B or C virus. We report the first known case of de-novo HCC in a recipient, 14 years after a pediatric living related donor liver transplantation for end-stage liver disease due to biliary atresia without the presence of hepatitis B or C virus before and after transplant. We present this case report to increase the awareness of this phenomenon and address on the utility for screening and surveillance of hepatocellular carcinoma among these individuals. One recommendation is to use similar guidelines for screening, diagnosis, and treatment for HCC as those used for primary HCC in the pre-transplant patient, focusing on those recipients who have advanced fibrosis in the allograft, regardless of etiology.

Novel application and serial evaluation of tissue-engineered portal vein grafts in a murine model.

AIM: Surgical management of pediatric extrahepatic portal vein obstruction requires meso-Rex bypass using autologous or synthetic grafts. Tissue-engineered vascular grafts (TEVGs) provide an alternative, but no validated animal models using portal TEVGs exist. Herein, we preclinically assess TEVGs as portal vein bypass grafts. MATERIALS & METHODS: TEVGs were implanted as portal vein interposition conduits in SCID-beige mice, monitored by ultrasound and micro-computed tomography, and histologically assessed postmortem at 12 months. RESULTS: TEVGs remained patent for 12 months. Histologic analysis demonstrated formation of neovessels that resembled native portal veins, with similar content of smooth muscle cells, collagen type III and elastin. CONCLUSION: TEVGs are feasible portal vein conduits in a murine model. Further preclinical evaluation of TEVGs may facilitate pediatric clinical translation.

Host factors are dominant in the development of post-liver transplant non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is a recognized problem in patients after orthotopic liver transplantation and may lead to recurrent graft injury. As the increased demand for liver allografts fail to match the available supply of donor organs, split liver transplantation (SLT) has emerged as an important technique to increase the supply of liver grafts. SLT allows two transplants to occur from one donor organ, and provides a unique model for observing the pathogenesis of NAFLD with respect to the role of recipient environmental and genetic factors. Here we report on two recipients of a SLT from the same deceased donor where only one developed non-alcoholic steatohepatitis (NASH), suggesting that host factors are critical for the development of NASH.

Biliary complications in 96 consecutive right lobe living donor transplant recipients.

BACKGROUND: Biliary reconstruction represents one of the most challenging parts of right lobe (RL) living donor liver transplantations (LDLTs). Different causes, surgical techniques, and treatments have been suggested but are incompletely defined. METHODS: Between June 1999 and January 2002, 96 RL LDLTs were performed in our center. We reviewed the incidence of biliary complications in all the recipients. RESULTS: Roux-en-Y reconstruction was performed in 53 cases (55.2%) and duct-to-duct was performed in 39 cases (40.6%). Both procedures were performed in 4 cases (4.2%). Multiple ducts (> or =2) were found in 58 grafts (60.4%). Thirty-nine recipients (40.6%) had 43 biliary complications: 21 had bile leaks, 22 had biliary strictures, and 4 had both complications. Patients with multiple ducts had a higher incidence of bile leaks than those patients with a single duct (P=0.049). No significant differences in complications were found between Roux-en-Y or duct-to-duct reconstructions. Freedom from biliary complications was 59% at 1 year and 55% at 2 years. The overall 1-year and 2-year survival rates for patients were 86% and 81%, respectively. The overall 1-year and 2-year survival rates for grafts were 80% and 77%, respectively. Occurrence of bile leaks affected patient and graft survival (76% and 65% 2-year patient and graft survival, respectively, vs. 89% and 85% for those without biliary leaks, P=0.07). CONCLUSIONS: Despite technical modifications and application of various surgical techniques, biliary complications remain frequent after RL LDLT. Patients with multiple biliary reconstructions had a higher incidence of bile leaks. Patients who developed leaks had lower patient and graft survival rates.

Emphysematous Cholecystitis Resulting in Secondary Biliary Cirrhosis: A Rare Complication of Endoscopic Retrograde Cholangiopancreatography.

A 48-year-old female developed acute emphysematous cholecystitis after an endoscopic retrograde cholangiopancreatography (ERCP) for evaluation of sphincter of Oddi dysfunction. Cholecystectomy was performed 2 days later. Cultures grew Clostridium perfringens. The patient received broad-spectrum antibiotics but developed recurrent cholangitic abscesses and intra- and extra-hepatic biliary necrosis. She was managed by percutaneous transhepatic biliary drains. For next 3 years, patient had recurrent episodes of biliary obstruction, cholangitis, and sepsis, resulting in secondary biliary cirrhosis requiring a liver transplantation. Emphysematous cholecystitis is a rare complication of ERCP. Prompt diagnosis and surgical management can prevent further spread of infection to biliary tree.