Racial and socioeconomic disparities in pediatric and young adult liver transplant outcomes.

Racial and socioeconomic disparities exist in liver transplantation (LT) outcomes among adults, but little research exists for pediatric LT populations. We examined racial differences in graft survival and mortality within a retrospective cohort of pediatric and young adult LT recipients at a large children's transplant center in the Southeast between 1998 and 2011. The association between race/ethnicity and rates of graft failure and mortality was examined with Cox proportional hazards models that were adjusted for demographic and clinical factors as well as individual-level and census tract-level socioeconomic status (SES). Among the 208 LT recipients, 51.0% were white, 34.6% were black, and 14.4% were other race/ethnicity. Graft survival and patient survival were higher for whites versus minorities 1, 3, 5, and 10 years after transplantation. The 10-year graft survival rates were 84% [95% confidence interval (CI) = 76%-91%] for white patients, 60% (95% CI = 46%-74%) for black patients, and 49% (95% CI = 23%-77%) for other race/ethnicity patients. The 10-year patient survival rates were 92% (95% CI = 84%-96%), 65% (95% CI = 52%-79%), and 76% (95% CI = 54%-97%) for the white, black, and other race/ethnicity groups, respectively. In analyses adjusted for demographic, clinical, and socioeconomic characteristics, the rates of graft failure [black: hazard ratio (HR) = 2.59, 95% CI = 1.29-5.45; other: HR = 3.01, 95% CI = 1.23-7.35] and mortality (black: HR = 4.24, 95% CI = 1.54-11.69; other: HR = 3.09, 95% CI = 0.78-12.19) were higher for minority groups versus whites. In conclusion, at a large pediatric transplant center in the Southeastern United States, racial/ethnic disparities exist in pediatric and young adult LT outcomes that are not fully explained by measured SES and clinical factors.

A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C.

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.

Parenchyma-wise technique for the harvest and implantation of hepatic segment 2-3 grafts: Anatomic basis and surgical steps.

We propose a technique for pediatric liver transplantation that does not waste the donor's parenchyma. Organ shortage has extended criteria for donor acceptance, such that even individuals with livers of suboptimal volume can donate their segment 2-3. By incorporating wise use of parenchyma, our proposed technique for harvesting segment 2-3 for implantation in a pediatric recipient benefits these and other donors, and it might increase donations. This is especially important in countries in which procurement of organs from the deceased is not allowed. Our technique also aims to solve the problem of the large-for-size syndrome for neonates and extremely small infants and to allow for primary closure of the abdomen. This technique enables harvest of the following four grafts: (1) complete segment 2-3; (2) reduced segment 2-3; (3) complete segment 3; and (4) reduced segment 3. The surgeon will select the type that has suitable graft-to-recipient weight ratio and that suits the donor's liver anatomy and volume. These four types benefit the donor by preserving the parenchyma of segment 4 and the left part of the caudate lobe. The three graft types other than the complete segment 2-3 graft will also preserve varying fractions of the parenchyma of segment 2-3. The technique for complete segment 2-3 graft can be put into practice immediately; the techniques for the other three grafts need an imaging modality to preoperatively delineate the donor's fourth-order bile ducts. We expect to correct this deficiency in the near future by developing the requisite imaging technique.

Aberrant bile ducts, 'remnant surface bile ducts,' and peribiliary glands: descriptive anatomy, historical nomenclature, and surgical implications.

The term "aberrant bile ducts" has been used to designate three heterogeneous groups of biliary structures: (1) bile ducts degenerating or disappearing (unknown etiology, diverse locations); (2) curious biliary structures in the transverse fissure; and (3) aberrant right bile ducts draining directly into the common hepatic duct. We report our observations on these three groups. Twenty-nine fresh human livers of stillborns and adults were injected differentially with colored latex and dissected. Adult livers showed portal venous and hepatic arterial branches, and bile ducts not associated with parenchyma, subjacent to and firmly adherent with the liver capsule: elements of ramifications of normal sheaths were present on the liver's surface. These ramifications, having lost parenchyma associated with them, then sequentially lost their portal branches, bile ducts and arterial branches. This process affected the ramifications of the sheaths in the left triangular ligament, adjacent to the inferior vena cava, in the gallbladder bed and anywhere else on the liver's surface and resulted in the presence of bile ducts accompanied by portal venous and/or hepatic arterial branches and not associated with parenchyma for a period of time. This first group represented normal bile ducts that do not meet the criteria of aberration and could be appropriately designated "remnant surface bile ducts." Such changes were not found in the transverse fissures and review of the literature revealed that the curious biliary structures are the microscopic peribiliary glands. The third group met the criteria of aberration and the anatomy of a representative duct is described.

Giant and complicated variants of cystic bile duct hamartomas of the liver: MRI findings and pathological correlations.

PURPOSE: To describe a new category of liver cyst we propose calling "giant bile duct hamartoma (giant-BDH)" and to provide a more complete record of the magnetic resonance imaging (MRI) features of BDHs with potential for clinical impact. MATERIALS AND METHODS: This study was Institutional Review Board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPPA)-compliant. Fifteen patients were identified with surgical liver pathology in keeping with complicated BDH and MRI findings of giant cysts. RESULTS: In all, 14/15 patients presented with pain that resolved in 14/14 with surgery. Imaging features common to pretreatment cysts included sharply defined, lobulated margins with thin, smooth rim-enhancement. Treated symptomatic cysts measured 9.8 cm on average and 21.6 cm maximum. The 14/15 patients had coexistent <2.0 cm BDH. Elevated T1 signal corresponded with hemorrhagic cyst content (10/15 patients); cyst-wall rim-enhancement corresponded with histological findings of inflammation (15/15), fibrocystic changes (12/15), and smaller BDH in the adjacent liver (13/15). Histology of giant-BDH cyst walls corresponded with complicated BDH in 15/15. The incidence of symptomatic-treated BDH at our institution was 0.4%. CONCLUSION: BDH is a benign hepatic cystic lesion that may undergo cystic enlargement, internal hemorrhage, and clinically present with abdominal pain treatable by minimally invasive laparoscopic fenestration. Complicated giant-BDH coexists with smaller BDH and the MRI features of giant-BDH are characteristic.

Liver retransplantation in children: the Atlanta experience.

Liver retransplantation is routinely offered at our institution. Previous reports document that patient and graft survival is significantly less after pediatric rLT compared to primary LT. This has engendered intense debate regarding optimal allocation of organs. Here, we examine our program's approach to pediatric hepatic retransplantation related to patient factors affecting outcomes. Between 1997 and 2009, 272 LTs were performed in 234 patients (mean survival 1994 +/- 1367 days) at our center. Thirty-four patients required rLT including 10 who received their primary transplant elsewhere and four who required two retransplantations. Patient survival did not differ significantly between rLT and LT at one and three yr (p = 0.56). Graft survival between rLT and LT was also similar (p = 0.606) at one and three yr. No significant difference in graft or patient survival was noted between: Patients retransplanted <30 days after LT vs. those >30 days (p = 0.152); patients transplanted with technical variants vs. whole grafts (p = 0.966); technical variants utilized for LT vs. rLT (p = 0.713); rLT recipient age (< or >5 yr; p = 0.298); or ABOI for rLT and LT (p = 0.650). Retransplantation should be offered to optimize pediatric recipient survival after LT and offers similar survival as primary transplant.

Incidence, impact, and treatment of portal and hepatic venous complications following pediatric liver transplantation: a single-center 12 year experience.

PVT or PVS and HVOO are known causes of graft and patient loss after pediatric liver transplantation. Increased incidences of these complications have been reported in partial livers including DDSLT or LDLT. From 1997 to 2008, 241 consecutive pediatric patients received 271 hepatic grafts at a single center. Median follow-up is 1856 days. Surgical technique, demographics, lab values, and radiologic imaging procedures were obtained utilizing OTTR to evaluate the relationship of portal and hepatic complications with risk factors, patient and graft survival. Grafts were composed of 115/271 (42.4%) partial livers of which 90 (33.2%) were DDSLT and 25 (9.2%) LDLT. Of 271 patients, 156 (57.6%) received whole-sized grafts. There were six PVC in five patients with one patient requiring retransplantation (0.34%) and no patient deaths. Utilizing all three hepatic vein orifices on the recipient hepatic vena cava and the donor hepatic vein cut short enables a wide hepatic outflow tract unlikely to twist. None of the 241 patients developed early or late complications of the hepatic vein. None of the last 128 consecutive patients who received 144 grafts over seven and a half yr have developed either early or late complications of the hepatic or portal vein. Partial-graft actuarial survival was similar to whole-graft survival (87.2% vs. 85.3% at one yr; 76.6% vs. 80.2 at three yr; p = 0.488). Likewise, patient survival was similar between partial grafts and whole grafts (93.8% vs. 93.1% at one yr; 89.8% vs. 87.2% at three yr; p = 0.688) with median follow-up of 1822 (+/-1334) days. Patients receiving partial livers were significantly younger and smaller than patients receiving whole livers (p < 0.001). Portal and hepatic venous complications may have negative effects on patient or graft survival after pediatric liver transplantation. In our series, there was one graft and no patient loss related to portal or hepatic venous complications after pediatric liver transplantation over 12 yr.

Pediatric liver transplantation for acute liver failure at a single center: a 10-yr experience.

Children transplanted for ALF urgently require an optimal graft and have lower post-transplant survival compared with children transplanted for chronic liver disease. Over 10 yr, 33 consecutive children transplanted for ALF were followed. Demographics, encephalopathy, intubation, dialysis, laboratory values, graft type ABOI, XL (GRWR > 5%), DDSLT, LDLT and WLT were evaluated. Complications and survival were determined. ALF accounted for 33/201 (16.4%) of transplants during this period. Twelve of 33 received ABOI, five XL grafts, 18 DDSLT, and three LDLT. Waiting time pretransplant was 2.1 days. One- and three-yr patient survival in the ALF group was 93.4% and 88.9%, and graft survivals were 86.4% and 77.7%. Median follow-up was 1452 days. ABOI one- and three yr patient and graft survival in the ALF was 91.6% and 78.6%. No difference in graft or patient survival was noted in the ALF and chronic liver disease group or the ABOI and the ABO compatible group. A combination of ABO incompatible donor livers, XL grafts, DDSLT, LDLT and WLT led to a short wait time and subsequent graft and patient survival comparable to patients with non-acute disease.

Successful outcome after early combined liver and en bloc-kidney transplant in an infant with primary hyperoxaluria type 1: a case report.

PH1 is a metabolic disorder characterized by urolithiasis and the accumulation of oxalate crystals in the kidneys and other organs. Although patients often first present with renal failure, PH1 results from a deficiency of the hepatic peroxisomal enzyme AGT. Ultimately only liver transplantation will cure the underlying metabolic defect. Herein, we report the case of a three-month-old male infant diagnosed with PH and treated using a combined liver and en bloc-kidney transplant from a single donor. At the time of transplant, the patient was 11 months old and weighed 7.9 kg. He received a full size liver graft and en bloc kidneys from a two-yr-old donor. At 36 months post-transplant, the patient is steadily growing with normal renal and hepatic function. This is one of the first reports of successful liver and en bloc-kidney transplantation with abdominal compartment expansion by PTFE for the infantile form of PH1 in a high risk child before one yr of age. Prompt diagnosis and early referral to a specialized center for liver and kidney replacement offer the best chance for survival for infants with this otherwise fatal disease.

A refined long RT-PCR technique to amplify complete viral RNA genome sequences from clinical samples: application to a novel hepatitis C virus variant of genotype 6.

The goal of this study was to adapt a long RT-PCR technique to amplify large PCR fragments from the genome of hepatitis C virus (HCV) isolates using clinical samples. This was done by using a reverse transcriptase devoid of RNase H activity and a mixture of two antibody-bound thermostable polymerases to combine the high processivity of Taq and the high fidelity of Pwo with its 3'-->5' exonuclease activity. Other modifications included gentle handling during RNA extraction, the absence of tRNA and random primers, a two-step reverse transcription procedure to optimize cDNA synthesis, and increasing the annealing temperature for primers. With this approach, the HCV-1 genome (nucleotides 35-9282) was amplified consistently as two overlapping fragments of 5344 and 4675 bp from a pooled chimpanzee plasma sample containing approximately 10(6) genome copies of HCV RNA/ml. Using the conditions that we identified, 96% of the complete genomic sequence of a distinct HCV genotype 6 variant (km45) was determined from less than 300 microl of serum. This method should prove useful for molecular, epidemiological and clinical studies of hepatitis C where samples are limited but complete virus sequence is required, for example, identifying mutational hot spots of HCV under specific clinical conditions.

Pediatric liver transplantation with daclizumab induction.

BACKGROUND: A new class of monoclonal antibodies (non-T-cell depleting) has gained favor for induction therapy after transplantation. This study evaluated the non-T-cell depleting antibody to the CD25 cell, daclizumab, as a single-dose induction agent immediately after pediatric liver transplantation to spare the use of the calcineurin inhibitor, tacrolimus, for 7 days in respect to both efficacy and renal function. METHODS: From January 1998 to November 2001, 81 pediatric orthotopic liver transplant recipients receiving 89 liver grafts were evaluated. The treatment arm (n=61) received daclizumab 1 mg/kg immediately after liver transplantation along with mycophenolate, steroids, and, on postoperative day 7, tacrolimus. The control group did not receive induction therapy, whereas tacrolimus, mycophenolate, and steroids were started immediately after surgery. RESULTS: The induction group had fewer patients with rejection within the first 30 days after liver transplantation (9 [14.8%] vs. 10 [50%]; P=0.003). The mean time to first rejection was similar between groups (12.1 [+/-7.8] days vs. 18.5 [+/-8.1] days; P=not significant). There was a 3.39 increase in relative risk to develop rejection within the first 30 days after orthotopic liver transplantation if the patient did not receive induction therapy (relative risk=3.39; 95% confidence interval [1.61, 7.14]). Two-year actuarial survival for the induction group was 93.2% compared with 85% in the control; graft survival was also similar between groups (87.8% vs. 72.7%) at 2 years. CONCLUSION: Daclizumab 1 mg/kg given immediately after pediatric liver transplantation and withholding tacrolimus, is safe, efficacious, and reduces rejections within the first 30 days after surgery.

Does interferon use prior to liver transplant influence hepatitis C outcomes following transplantation?

BACKGROUND: The most frequent reason for orthotopic liver transplantation (OLT) in the United States is due to complications of hepatitis C (HCV). Recent reports have shown decreased survival for HCV after OLT. Of note, the use of interferon (IFN) products has become wide spread with the majority of HCV patients being treated before transplant. AIM: To review the outcomes of HCV patients who have received IFN products before liver transplant compared with HCV patients those who have never received IFN. METHOD: Single-center, retrospective review of patients transplanted for HCV since December 1998 (n=131). Primary endpoint is the effect of IFN exposure before transplant on posttransplant outcomes. RESULTS: Patients receiving before transplant (pre-IFN group; n=45) had a more aggressive recurrence of HCV with earlier recurrence (181.1+/-236 days vs. 303.4+/- 327 days; P=0.031), frequency of recurrence [41/45 (91.1%) vs. 62/86 (72.1%); P=0.013], and 1-year recurrence free survival [20% (+/-0.06) vs. 48.2% (+/-0.05); P=0.005]. Survival difference was noted in the pre-IFN group at 1 year and 3 years [79.7% (+/-0.06) vs. 90.5% (+/-0.03); 65.7 (+/-0.08) vs. 75.9% (+/-0.05); P=0.05] when compared with patients not receiving IFN (n=86) before transplant. CONCLUSIONS: Based on this study, interferon use before transplant for the HCV patient indicates poor outcomes After OLT. Because of the increasing numbers of HCV patients coming to transplant, validation of these results should be of utmost importance.

Corticosteroid-free immunosuppression with daclizumab in HCV(+) liver transplant recipients: 1-year interim results of the HCV-3 study.

This work is a 1-yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid-free immunosuppression on hepatitis C virus-positive (HCV(+)) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 +/- 6.2%, 60.1 +/- 6.1%, and 67.0 +/- 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 +/- 2.2% vs. 81.9 +/- 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid-free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV(+) liver transplant recipients.

A novel three-dose regimen of daclizumab in liver transplant recipients with hepatitis C: a pharmacokinetic and pharmacodynamic study.

This study evaluated the pharmacokinetics and pharmacodynamics of a novel 3-dose regimen of daclizumab in de novo hepatitis C liver transplant recipients. In 30 of 156 recipients receiving daclizumab, mycophenolate mofetil, tacrolimus, and no steroids (Arm 3 of Hep C 3 Liver Study), daclizumab (2, 2, and 1 mg/kg, respectively) was given on days 1, 3, and 8 posttransplant, respectively, with trough, peak (C(max)), and CD25 saturation (CD(sat)) measured sequentially. Mean daclizumab C(max) was 50.3 microg/mL on day 1, and mean trough levels were 21.8, 25.7, and 9.9 microg/mL on days 3, 8, and 30, respectively. A significant decline in CD(sat) (mean, 15.7% to 4.7%) was observed on day 1 and was sustained throughout the study (2.8% on day 30). Daclizumab concentration > or = 5 microg/mL was the level where most of the effect on CD(sat) was noticed. Elevated baseline CD(sat) was observed in African Americans, patients weighing < or = 75 kg, and patients <60 years of age. After 365 days, 2 patients had experienced 3 rejections, 10 patients had recurrent hepatitis C, 4 patients died, and 2 grafts were lost. In conclusion, this novel 3-dose regimen is effective in rapidly achieving high therapeutic concentration of daclizumab and a significant decline in CD(sat) lasting over 30 days.

Low incidence of hepatic artery thrombosis after pediatric liver transplantation without the use of intraoperative microscope or parenteral anticoagulation.

The risk of hepatic artery thrombosis (HAT) after pediatric liver transplantation (PLT) has been reported to range from 0 to 25%. We report our experience focusing on the interrelationships between risk factors, surgical technique and the incidence of HAT after liver transplantation in the pediatric age group. From February 18, 1997 to December 31, 2003, 150 consecutive liver transplants were performed in 132 pediatric patients. There were similar numbers of whole grafts when compared with partial grafts, 80 (53.3%) vs. 70 (46.7%), p = 0.30. Four grafts (2.7%) developed HAT. Of the grafts with HAT, three were successfully revascularized within the first 24 h. Only one graft (0.66%) was lost to HAT. A single surgeon utilizing 3.5-6.0 magnification loupes performed all but one hepatic arterial anastomoses. All patients were followed postoperatively by a daily ultrasound protocol and with anticoagulation of aspirin and alprostadil only. Living and deceased donor left lateral segment grafts had an increased rate of HAT when compared with whole liver grafts. HAT with subsequent graft loss may be minimized in PLT with the use of surgical loupes only, anticoagulation utilizing aspirin, alprostadil, and daily ultrasounds.

Peripheral eosinophilia and eosinophilic gastroenteritis after pediatric liver transplantation.

Reports indicate peripheral eosinophilia (PE) and gastrointestinal eosinophilic inflammation can occur after pediatric liver transplantation. The incidence of these conditions, potential risk factors, and the impact of PE and gastrointestinal eosinophilic inflammation on liver transplant outcome were determined in this pediatric liver transplant program. Medical records of liver transplant recipients from 1 to 97 and from 12 to 99 were reviewed. Fifty-seven transplants on 54 patients were performed during the study period. Fifty-three patients were evaluated; all had normal pre-transplantation peripheral eosinophil counts. PE of > 10% developed in 28% of patients. Using this definition, all such identified patients had absolute eosinophil counts of > 350/mm3. History of immediate hypersensitivity did not differ between patients with or without eosinophilia. Gastrointestinal endoscopy and biopsy was performed in 23 patients with gastrointestinal complaints. Of those, six had eosinophilic gastroenteritis and all six had PE. Compared with patients without eosinophilia, those with PE were younger at the time of transplantation (p < 0.05), had more frequent rejection (p < 0.01), were more commonly managed with tacrolimus-based immunosuppression (p < 0.001), and experienced more frequent episodes of detectable EBV viral load (p < 0.04). Patients with eosinophilic gastroenteritis were more frequently retransplanted (p < 0.006). PE associated with symptomatic eosinophilic gastroenteritis is common after pediatric liver transplantation. Age at transplant, frequency of rejection episodes, tacrolimus-based immunosuppression, and EBV viral load may be associated with the development of this condition. There may be higher rates of graft loss in such patients. Whether innate immune responsiveness or an acquired immune dysregulation accounts for these findings merits further evaluation.