Pediatric acute liver failure: Etiology,outcomes, and the role of serial pediatric end‐stage liver disease scores

To describe etiology, short‐term outcomes and prognostic accuracy of serial PELD scores in PALF. Retrospective analysis of children aged ≤16 yr, admitted with PALF under the QLTS, Brisbane, Australia, between 1991 and 2011. PELD‐MELD scores were ascertained at three time points (i) admission (ii), meeting PALF criteria, and (iii) peak value. Fifty‐four children met criteria for PALF, median age 17 months (1 day–15.6 yr) and median weight 10.2 kg (1.9–57 kg). Etiology was known in 69%: 26% metabolic, 15% infective, 13% drug‐induced, 6% autoimmune, and 9% hemophagocytic lymphohistiocytosis. Age <3 months and weight <4.7 kg predicted poor survival in non‐transplanted children. Significant independent predictors of poor outcome (death or LT) were peak bilirubin > 220 μm /L and peak INR > 4. Serial PELD‐MELD scores were higher in the 17 (32%) transplant recipients (mean: [i] 26.8, [ii] 31.8, [iii] 42.6); highest in the 12 (22%) non‐transplanted non‐survivors (mean: [i] 31.6, [ii] 37.2, [iii] 45.7) compared with the 25 (46%) transplant‐free survivors (mean: [i] 25.3, [ii] 26.0, [iii] 30.3). PELD‐MELD thresholds of ≥27 and ≥42 at (ii) meeting PALF criteria and (iii) peak predicted poor outcome (p < 0.001). High peak bilirubin and peak INR predict poor outcome and serial PELD‐MELD is superior to single admission PELD‐MELD score for predicting poor outcome.     

Improved outcomes in pediatric liver transplantation for acute liver failure

Miloh T, Kerkar N, Parkar S, Emre S, Annunziato R, Mendez C, Arnon R, Suchy F, Rodriguez‐Laiz G, Del Rio Martin J, Sturdevant M, Iyer K. Improved outcomes in pediatric liver transplantation for acute liver failure.
Pediatr Transplantation 2010: 14:863–869. © 2010 John Wiley & Sons A/S. Abstract: OLT is a life‐saving option for ALF. Aim: To evaluate our outcomes in pediatric OLT for ALF. Methods: Retrospective review of our data between 1992 and 2007. Results: Of 142 children with ALF, 126 were listed, of which 40 spontaneously improved, nine died, and 77 underwent OLT (median waiting time four days). Fifty‐three children received deceased donor grafts (34 whole and 19 split grafts), and there were 24 living donor grafts. The one‐ and five‐yr patient survival was 87% and 80%, and graft survival 83% and 79%, respectively. Thirteen patients died after OLT, and there were nine retransplants in seven patients. Patient weight, length of stay, creatinine, and infection were significantly associated with death; increased weight and black ethnicity were associated with graft loss on univariate analysis, but not on multivariate analysis. There were no significant differences in patient survival (one and five yr), graft loss, or other complications between the groups. Conclusion: We report the largest single‐center study of OLT in pediatric ALF, demonstrating no difference in outcomes between different graft types. Our liberal use of segmental grafts may allow earlier OLT in this high‐risk cohort and contribute to our excellent outcomes.     

Basiliximab treatment for steroid‐resistant rejection in pediatric patients following liver transplantation for acute liver failure

An IL‐2 receptor antagonist, basiliximab, decreases the frequency of ACR in liver transplant (LT) recipients as induction therapy. The aim of this study was to evaluate the effectiveness of basiliximab against SRR as rescue therapy in pediatric LT patients with ALF. Forty pediatric ALF patients underwent LT between November 2005 and July 2013. Among them, seven patients suffering from SRR were enrolled in this study. The median age at LT was 10 months (6–12 months). SRR was defined as the occurrence of refractory rejection after more than two courses of steroid pulse therapy. Basiliximab was administered to all patients. The withdrawal of steroids without deterioration of the liver function was achieved in six patients treated with basiliximab therapy without patient mortality, although one patient developed graft loss and required retransplantation for veno‐occlusive disease. The pathological examinations of liver biopsies in the patients suffering from SRR revealed severe centrilobular injuries, particularly fibrosis within one month after LT. We demonstrated the effectiveness and safety of rescue therapy consisting of basiliximab for SRR in pediatric LT recipients with ALF.     

High urgency liver transplantation in ornithine transcarbamylase deficiency presenting with acute liver failure

OTCD can present with ALF at any age. Under adequate therapy symptoms resolve quickly. We report a three-yr-old girl with the manifestation of an OTCD as ALF. Despite adequate pharmacotherapy and protein restriction, the patient deteriorated and developed hepatic encephalopathy. A high urgency liver transplantation was performed and the patient recovered completely. We conclude that in patients with ALF urea cycle defects in general and OTCD in particular should be considered as differential diagnosis. Patients should be managed in a center that has the capacity for an emergency liver transplantation.     

Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience

Heffron TG, Pillen T, Smallwood G, Rodriguez J, Sekar S, Henry S, Vos M, Casper K, Gupta NA, Fasola CG, Romero R. Pediatric liver transplantation for acute liver failure at a single center: A 10‐yr experience.
Pediatr Transplantation 2010:14:228–232. © 2009 John Wiley & Sons A/S. Abstract: 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.     

Mortality of biliary atresia in children not undergoing liver transplantation in the Netherlands

In order to further improve the outcome of BA, we characterized the mortality of BA patients who did not undergo OLT in the Netherlands, and compared our results with international data. For this purpose, we analyzed the causes of mortality of non-transplanted BA patients before the age of five yr, using the NeSBAR database. To evaluate trends in mortality, we compared the cohort 1987-1996 (n=99) with 1997-2008 (n=111). We compared clinical condition at OLT assessment with available international data, using the PELD-score. Mortality of non-transplanted BA children was 26% (26/99) in 1987-1996 and 16% (18/111) in 1997-2008 (p=0.09). Sepsis was the prevailing direct cause of death (30%; 13/44). PELD-scores at the time of assessment were higher in non-transplanted BA patients (median 20.5; range 13-40) compared with international data (mean/median between 11.7 and 13.3). Based on our national data, we conclude that pretransplant mortality of BA patients is still considerable, and that sepsis is a predominant contributor. Our results strongly indicate that the prognosis of patients with BA in the Netherlands can be improved by earlier listing of patients for OLT and by improving pretransplant care.     

Orthotopic liver transplantation for children with Alagille syndrome

Arnon R, Annunziato R, Miloh T, Suchy F, Sakworawich A, Hiroshi S, Kishore I, Kerkar N. Orthotopic liver transplantation for children with Alagille syndrome.
Pediatr Transplantation 2010: 14:622–628. © 2010 John Wiley & Sons A/S. Abstract: AGS is an inherited disorder involving the liver, heart, eyes, face, and skeleton. Aim: To determine the outcome of LT in children with AGS compared to those with BA. Methods: Children with AGS and BA who had a LT between 10/1987 and 5/2008 were identified from the UNOS database. Results: Of 11 467 children who received a liver transplant, 461 (4.0%) had AGS and 3056 (26.7%) had BA. One‐ and five‐yr patient survival was significantly lower in patients with AGS in comparison with patients with BA (AGS; 82.9%, 78.4%, BA; 89.9%, 84%, respectively). Early death (<30 days from transplant) was significantly higher in AGS than in BA. One‐ and five‐yr graft survival was significantly lower in AGS than in BA (AGS; 74.7%, 61.5%, BA; 81.6%, 70.0%, respectively). Death from graft failure, neurological, and cardiac complications was significantly higher in patients with AGS than in patients with BA. Serum creatinine at transplant, prior LT, and cold ischemic time >12 h were identified as risk factors for death. Conclusion: Children with AGS were older at the time of LT and their one‐ and five‐yr patient and graft survival were significantly lower compared to BA. Risk factors for poor outcome in AGS after LT were identified.     

Hepatocellular carcinoma in children and effect of living-donor liver transplantation on outcome

Hepatocellular carcinoma (HCC) is primarily observed in the older children and in most cases it develops in association with liver cirrhosis. Liver transplantation offers a good chance for long-term cure. To evaluate the outcome of children with HCC and the impact of living-donor orthotopic liver transplantation (OLT) on survival a retrospective review of radiographic, laboratory, pathologic, and therapeutic data in 13 children (six female and seven male) with chronic liver disease accompanied with HCC were studied. The patients were divided into two groups according to therapeutic modality: transplanted and non-transplanted patients. Kaplan-Meier survival curves in various therapeutic groups were plotted. The mean age of patients was 6.4 +/- 4.8 yr. Pediatric end-stage liver disease score was adapted to model for end-stage liver disease score for HCC and ranged between 1-44 and 18-44, respectively. The underlying liver diseases were tyrosinemia type 1 (n = 6), chronic hepatitis B infection (n = 6), glycogen storage disease type 1 (n = 1). Alfa-feto protein levels were elevated in all patients except one. Median number of tumor nodules was three (1-10), median maximal diameter of tumor nodules was 3.4 cm (0.5-8). Eleven patients were eligible for OLT whereas two patients were not eligible. Seven of the 11 patients considered for transplantation underwent living-donor OLT. Remaining four patients died while waiting on cadaveric transplant list. Overall 1 and 4-yr survival rates for all patients were 53.3 and 26.6%, respectively, and were found significantly higher in transplanted children than non-transplanted children (72%, 72% vs. 33% and 16.6%). No patient had tumor recurrence at median of 36-month follow-up after OLT. OLT is a life-saving procedure for children with chronic liver disease accompanying with HCC. Living-donor OLT avoids the risk of tumor progression and transplant ineligibility in these children.     

Lifesaving liver transplantation for multi‐organ failure caused by Bacillus cereus food poisoning

Bacillus cereus is a spore‐forming, gram‐positive bacterium that causes food poisoning presenting with either emesis or diarrhea. Diarrhea is caused by proteinaceous enterotoxin complexes, mainly hemolysin BL, non‐hemolytic enterotoxin (NHE), and cytotoxin K. In contrast, emesis is caused by the ingestion of the depsipeptide toxin cereulide, which is produced in B. cereus contaminated food, particularly in pasta or rice. In general, the illness is mild and self‐limiting. However, due to cereulide intoxication, nine severe cases with rhabdomyolysis and/or liver failure, five of them lethal, are reported in literature. Here we report the first case of life‐threatening liver failure and severe rhabdomyolysis in this context that could not be survived without emergency hepatectomy and consecutive liver transplantation.     

Autoimmune hepatitis in a child presenting with hepatopulmonary syndrome (HPS)

HPS has been described in 9–20% of children with end‐stage liver disease. We present a case of a previously, asymptomatic nine‐yr‐old incidentally found to have low oxygen saturation. Physical exam was remarkable for digital clubbing, splenomegaly and orthodeoxia. Laboratory evaluation revealed a low platelet count, hyperammonemia, and prolonged coagulation studies. Sonography showed evidence of splenomegaly and portal venous hypertension. High resolution CT thorax and CTA were normal. HPS was confirmed by agitated saline contrast enhanced echocardiography and Tc‐99m MAA scan with evidence of intrapulmonary vascular dilatations. Liver biopsy was performed and consistent with autoimmune hepatitis. A high clinical index of suspicion should be maintained for HPS in pediatric patients who have unexplained hypoxemia as typical signs and symptoms of severe liver disease are often absent. In this report, we discuss a case of HPS complicated AIH in a pediatric patient and review the relevant literature.     

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??The causes of acute liver failure ??ALF?? in children differ from those observed in adults. They can be schematically grouped into six categories?? metabolic?? infective?? toxic?? autoimmune?? vascular and malignancy-induced ALF. Although the mechanisms of liver injury contributing to ALF vary due to different causes and are incompletely understood?? they can be summarized into two categories?? direct damage and immune-mediated liver injury. Cellular necrosis and apoptosis are the final changes of pathology. This article will review the current knowledge of the epidemiology and mechanisms of ALF in children.     

Liver transplantation for acute liver failure due to toxic agent ingestion in children

Abstract: ALF is characterized by sudden onset, impaired liver function, jaundice and encephalopathy, without previous liver disease. We analyzed the patients who underwent LT due to toxic agent induced ALF to raise community awareness about preventing the toxic agent induced ALF. Five children (three boys, two girls) underwent LT due to toxic agent ingestion. Toxic agents were mushroom poisoning (n = 2), Datura stramonium (n = 1), yellow phosphorous (n = 1) and INH (n = 1). On admission, one patient had stage IV, two had stage III and two had stage II hepatic encephalopathy but worsened during the follow‐up. One patient had renal failure, and three patients required mechanical ventilation. Three patients underwent LRLT and others from a DD. Post‐operative complications were managed by supportive managements successfully, and overall all the patients are alive (100% survival) without any organ sequelae. Although outcome of these patients are excellent, ALF may be prevented in these cases by educating the public about consuming mushrooms and toxic effects of wild plants, prohibiting fireworks and serial liver enzyme measurements after initiating INH.     

Successful recovery of aplastic anemia following orthotopic liver transplantation for non-A-E acute liver failure

This report describes a teenager who developed aplastic anemia (AA) because of non-A-E acute liver failure (ALF) requiring orthotopic liver transplantation (OLT). His AA did not recover spontaneously and he required treatment with ATG 9 months post-OLT. Bone marrow recovery occurred 4 months after immunotherapy and coincided with further intensification of immunusuppression required to treat early chronic rejection of the liver graft. Three years post-OLT he remains well with good bone marrow and liver function. Intensification of immunosuppression can lead to successful resolution of AA associated with non-A-E ALF.     

Approaches to acute liver failure in children

Acute liver failure (ALF) is a rare but often fatal disorder in childhood. Its aetiology includes infections, toxins, metabolic disorders, infiltrative diseases, autoimmune hepatitis, ischaemia, irradiation damage, but in a high proportion of cases it remains unknown. In contrast to adults, in children with ALF hepatic encephalopathy can be a late event, and may not develop at all, despite a lethal outcome, particularly in infants. Children with ALF should be managed in experienced centres with facilities for liver transplantation. Transplantation should be offered only if the underlying disease is treatable by liver replacement and if the prognosis of transplant is better than that of the underlying disease, as in many cases of ALF the liver has the potential to recover with supportive treatment, if the child is kept alive and stable long enough. Universally accepted criteria for listing for transplantation have not been defined as yet. In our centre, maximum INR, bilirubin level, and white cell count, together with age have proven to be reliable predictors of outcome. Future efforts in the management of ALF should concentrate on designing efficient supportive therapy and specific treatments to provide effective non-transplant therapeutic options.     

Outcomes in pediatric hepatitis C transplant recipients: Analysis of the UNOS database

HCV may lead to the development of ESLD in late childhood and, consequently, contributes to the need for liver transplantation. The aim of this study was to examine post‐transplant outcomes in HCV‐positive pediatric patients with ESLD from any cause and to determine the impact of the PELD scoring system, introduced in February 2002, on post‐transplant patient and graft survival. A retrospective analysis of the UNOS database from 1994 to 2010 was performed to assess graft and patient survival in pediatric HCV‐seropositive liver transplant recipients. Graft survival and patient survival comparing subjects in the pre‐PELD era and post‐PELD era were analyzed using Kaplan–Meier statistics. Factors associated with survival were identified using Cox regression analysis. Of 120 pediatric HCV transplant recipients, 80 were transplanted in the pre‐PELD era and 40 were transplanted post‐PELD. Median serum total bilirubin, INR, and creatinine were 4.8 mg/dL, 1.6, and 0.7 mg/dL in the pre‐PELD era vs. 5.5 mg/dL, 1.7, and 0.6 mg/mL, respectively, in the post‐PELD era (p NS). One‐yr graft survival in the pre‐PELD vs. post‐PELD era was 65.0% and 89.7%, respectively (p < 0.01); corresponding three‐yr graft survival was 57.3% vs. 76.2% (p = 0.04). One‐yr patient survival in the pre‐PELD vs. post‐PELD era was 79.0% and 97.5%, respectively (p < 0.01); corresponding three‐yr survival was 79.0% vs. 89.4% (p = 0.17). Twenty‐eight patients (23.3%) were retransplanted: 24 (30%) in the pre‐PELD era (median time to retransplant 272 days) and four (10%) in the post‐PELD era (median time to retransplant 586 days). Early follow‐up demonstrates a trend toward improved pediatric HCV liver transplant graft and patient survival in the post‐PELD era. Superior outcomes may be attributed to pretransplant factors, improved surgical technique and better treatment options for HCV infection.     

Hodgkin disease relapse discovered at the time of liver transplant for acute liver failure

Lymphoma is a recognized cause of liver damage and in rare instances presents as ALF. In such cases, the underlying malignancy is often difficult to detect. Historically, the prognosis has been poor. Cure has occasionally been achieved with chemotherapy alone. LT in this setting is controversial, but has contributed to successful outcomes, as in the case of the five-yr-old girl reported here.     

CPAP by helmet for treatment of acute respiratory failure after pediatric liver transplantation

ARF after pediatric liver transplantation accounts for high rate of morbidity and mortality associated with this procedure. The role of CPAP in postoperative period is still unknown. The aim of the study was to describe current practice and risk factors associated with the application of helmet CPAP. In this retrospective observational cohort study, 119 recipients were divided into two groups based on indication to CPAP after extubation. Perioperative variables were studied, and determinants of CPAP application were analyzed in a multivariate logistic model. Sixty patients (60/114) developed ARF and were included in the CPAP group. No differences were found between the two groups for primary disease, graft type, and blood product transfused. At multivariate analysis, weight <11 kg (OR = 2.9; 95% CI = 1.1‐7.3; P = .026), PaO₂/FiO₂ <380 before extubation (OR = 5.4; 95% CI = 2.1‐13.6; P < .001), need of vasopressors (OR = 2.6; 95% CI = 1.1‐6.4; P = .038), and positive fluid balance >148 mL/kg (OR = 4.0; 95% CI = 1.6‐10.1; P = .004) were the main determinants of CPAP application. In the CPAP group, five patients (8.4%) needed reintubation. Pediatric liver recipients with lower weight, higher need of inotropes/vasopressors, higher positive fluid balance after surgery, and lower PaO₂/FiO₂ before extubation were at higher odds of developing ARF needing CPAP application.     

Outcome of pediatric liver transplant recipients in Turkey: single center experience

To summarize the evolution of the pediatric liver transplant program in a developing country. Between April 1997, and September 2003, 32 cadaveric (CD) and 35 living donor (LD) liver transplantations were performed on 61 children (median age 3.8 yr, range 0.5-16) at Ege University Organ Transplantation and Research Center. The patient's charts were reviewed retrospectively. The outcome of patient and graft survival was analyzed and the incidence of graft loss, complications and rejections was calculated. Indications for liver transplantation were metabolic liver disease (n = 17), biliary atresia (n = 14), viral hepatitis (n = 4), autoimmune hepatitis (n = 6), cryptogenic cirrhosis (n = 11), fulminant liver failure (n = 5) and others (n = 5). Seven of 61 children with chronic liver disease had hepatocellular carcinoma concomitantly. Median pediatric end-stage liver disease score was 23 (range 1-54). Seven children (11.4%) were UNOS status I, 44 (72%) were UNOS status II and 10 (16.6%) were UNOS status III. The median follow-up of the study population was 3.6 yr (range 0.5-6). Actuarial patient survival rates at 1, 2, 3 and 4 yr were 86, 86, 71.3 and 65% in the CD group vs. 80, 76, 67 and 67% in the LR group, respectively (p = NS). Patients listed as UNOS status 1 had lower survival rates than patients listed as UNOS status 2 and 3 (p < 0.05). The mortality rate was 26.2%. Graft survival rates were 81, 81, 75 and 64% at 1, 2, 3 and 4-yr respectively. Six patients (9%) underwent retransplantation. The main complications were infections (64.7%) and surgical complications (43.2%) (including biliary complication, vascular problems, postoperative bleeding, small for size and large for size). The incidence of acute cellular rejection was 39.3%, whereas chronic rejection was 7.4%. The result of liver transplantation in Turkish children was slightly inferior to those reported for North American and European children. However, an important characteristic of these patients that distinguishes them from Europe and North America is that most were UNOS status IIa and UNOS status I (44%). Despite technical and medical progress, infectious and biliary problems have continued to be an important cause of mortality in these patients.