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Autoimmune hepatitis (AIH) is a rare, chronic disease that affects both adults and children, including infants. The disease is probably triggered by environmental factors in genetically predisposed individuals. The clinical presentation ranges from asymptomatic patients or patients with non-specific symptoms, such as fatigue, to fulminant liver failure, many children presenting with symptoms indistinguishable from those of acute hepatitis. Raised transaminase and immunoglobulin G (IgG) levels, in association with circulating autoantibodies, guide towards the diagnosis. The histological hallmark is interface hepatitis, which however is non-specific and may be absent. There are no bile duct changes on cholangiography. Presence of anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA) is characteristic for type 1 AIH, whereas presence of anti-liver kidney microsomal type 1 (LKM1) antibody and/or anti-liver cytosol type 1 (LC1) antibody defines type 2 AIH. The latter accounts for about one third of the juvenile AIH cases, presents more acutely than type 1 AIH and is very rare in adults. Immunosuppressive therapy, based on steroids and azathioprine, is required, and in the vast majority of patients leads to clinical and biochemical remission, defined as absence of symptoms, normal transaminase and IgG levels, and negative or low-titer autoantibodies. In patients intolerant or non-responder to standard therapy, a number of second line drugs have been employed with variable results. For the rare cases who progress to end-stage liver disease, liver transplantation is life-saving, but recurrence of the disease is possible. A better understanding of the underlying pathogenic mechanisms will help to develop new, more effective and less toxic therapies, and to tailor treatment regimens to the individual patient., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Liver transplantation (LT) is an effective treatment for patients with end-stage autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Indications for LT for these diseases do not differ substantially from those used for other acute or chronic liver diseases. Despite the good outcomes reported, the recurrence of autoimmune liver disease is relatively common in the allograft. In addition, it has become apparent that autoimmunity and autoimmune liver disease can arise de novo after transplantation for nonautoimmune liver disorders. An awareness of the existence of recurrent autoimmune liver diseases and de novo autoimmune hepatitis after LT has important clinical implications because their management differs from the standard antirejection treatment and is similar to the management of classic autoimmune liver diseases in the native liver., (Copyright © 2013 American Association for the Study of Liver Diseases.)

We have investigated the inflammatory infiltrate in post-transplant dn-AIH, a form of late insidious graft rejection, focusing on transcription factors defining effector and T-regs, using an antigen retrieval immunohistochemical method on archived liver tissue, and compared it with ACR and classical AIH. Paraffin-embedded liver biopsies from pediatric patients with dn-AIH (n = 10), ACR (n = 10), and AIH (n = 13) were selected randomly and stained using antibodies directed to CD4, CD8, T-bet (marker of Th1 polarization), GATA-3 (marker of Th2 polarization), FOXP3 (marker for T regulatory cells), IL-17, CD56 (NK cells), and perforin. Portal and lobular lymphocytic infiltrate was assessed semi-quantitatively. Prominent CD4, CD8, and T-bet positivity were present in both the lobular and portal infiltrate of all three conditions. Overall T-bet score of lobular inflammation in the dn-AIH group was lower than in the ACR and AIH groups (p = 0.02). In contrast, most samples showed absent or minimal GATA-3 positivity. FOXP3, CD56, IL-17, and perforin staining of mild to moderate severity were present in all three groups in both the portal and lobular infiltrate. A Th1 polarization of the inflammatory infiltrate characterizes dn-AIH, but also ACR and AIH., (© 2012 John Wiley & Sons A/S.)

Liver transplantation is an effective treatment for patients with end-stage acute and chronic autoimmune hepatitis. However, despite the good outcomes reported, disease recurrence is relatively common in the allograft. In addition, autoimmunity and autoimmune liver disease can arise de novo after transplantation for non-autoimmune liver disorders. Little is known about the mechanisms by which autoimmune diseases develop after liver transplantation, but genetic factors, molecular mimicry, impaired regulatory T-cell responses, and exposures to new alloantigens might be involved. Regardless of the pathogenic mechanisms, it is important to remain aware of the existence of recurrent and de novo autoimmune hepatitis after liver transplantation; these disorders are similar to classic autoimmune hepatitis and are therefore not treated with standard antirejection strategies., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The clinical impact of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections in the early post-transplantation period are poorly documented. We investigated the prevalence and timing of EBV and CMV infections during the first 21 d post-transplantation in relation to graft function and acute cellular rejection in a large cohort of pediatric liver transplantation recipients., Patients and Methods: Clinical, biochemical, virological, and histopathological data of 62 consecutive children who received a liver transplant were reviewed retrospectively., Results: Seventeen patients (27%) developed EBV and 11 (18%) CMV viremia (mean interval from surgery: 7.6 d, SD 3.6 and 8.7 d, SD 6.4, respectively). EBV and CMV viremia were more common as a consequence of reactivation than of primary infection. EBV viremic recipients had more often abnormal bilirubin levels [p = 0.01; OR 5.8: 95% CI 1.3-25.5]. Acute rejection was diagnosed in 20 recipients (32.3%). No correlation was found between rejection and EBV and CMV serology before transplantation and viremia after transplantation (mean interval between the diagnosis of rejection and the detection of EBV DNA and CMV DNA: one d, SD 4.4 and five d, SD 9.2, respectively)., Conclusion: EBV and CMV viremia occur at a very early-stage post-transplantation and do not appear to affect the short-term outcome of the transplant., (© 2011 John Wiley & Sons A/S.)

CNI have improved the outcome of LT. However, their inherent potential to nephrotoxic and sometimes-inadequate immunosuppressive effect has lead to the usage of newer drugs like SRL. Aim of this study was to review children who received SRL. Thirty-seven (20 women) children post-LT, median age 10.4 yr (0.8-17.4) with a minimum follow-up of six months comprised the study group. Indications for SRL were biopsy-proven resistant acute allograft rejection (n = 12), early CR (n = 12), and CNI-induced nephropathy with MMF intolerance (n = 11). In two patients, the indication was the recurrence of BSEP disease in the allograft. In patients with acute rejection, AST normalized in 10/12 patients. In patients with CR, AST normalized in 6/12 patients. Those with renal impairment showed improvement in their creatinine levels from a mean baseline of 99-56.7 μm (p = 0.03) and their mean cystatin C was 1.02 after SRL. Side effects leading to discontinuation of SRL were seen in three patients. SRL was effective in rescuing patients with acute and chronic allograft rejection and improving renal function in CNI-induced nephropathy group., (© 2011 John Wiley & Sons A/S.)

Propionic acidemia (PA) is a rare inherited disorder of branched chain amino acid metabolism; despite improvements in conventional medical management, the long-term outcome remains disappointing. Liver transplantation (LT) has been proposed to minimize the risk of further metabolic decompensations and to improve the quality of life. We performed a retrospective review of all children with PA who underwent LT between 1987 and 2008. Five children were identified with a median age of 1.2 years (range = 0.7-4.1 years) at referral. Four of the children presented clinically at 3 weeks of age or less, and 1 child was diagnosed prenatally. All had metabolic acidosis and hyperammonemia. Two had seizures and required intensive care; this care included inotropic support and continuous venovenous hemofiltration in 1 child. The children were considered for elective LT for the following reasons: frequent metabolic decompensations (2), previous sibling death (2), and elective management (1). One child underwent auxiliary LT, and 4 children received orthotopic grafts (1 living related graft). The median age at LT was 1.5 years (range = 0.8-7.0 years). There was 1 retransplant 3 months after LT due to hepatic artery thrombosis. One year after LT, 1 patient suffered a metabolic stroke with minimal residual neurology. After a median follow-up of 7.3 years (range = 2.2-15.0 years), all the children had normal graft function and a good quality of life with a protein-unrestricted diet and no further metabolic decompensations. In conclusion, LT has a role in the management of PA: it reduces the risk of metabolic decompensation and improves the quality of life. The potential for the development of metabolic sequelae is not completely eliminated., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Many centers are now performing DCD adult LT. There has been a reluctance to transplant pediatric recipients with DCD livers due to concern over the medium to long-term outcome. We describe the outcome of 14 children (median age seven yr, 8 months-16 yr) that underwent LT with DCD grafts from July 2001 to December 2007. Donors had a median age of 23 yr (10-64), intensive care stay of five d (2-14) and bilirubin of 9 mmol/L (6-60). Median warm and cold ischemic time was 16 min (11-29) and seven h (5.5-8.4). Livers were transplanted as a whole organ (4), reduced graft (8), formal split (1) or auxiliary transplant (1). Compared to DBD recipients AST was significantly higher on the first three post-operative days and there was no difference in the INR, bilirubin or GGT out to 12 months. There were no biliary or vascular complications and patient and graft survival is 100% at a median follow-up of 41.8 months (1.7-74 months). LT with DCD grafts in pediatric recipients can be performed with low morbidity and excellent short-to-medium term patient and graft outcome.

Unlabelled: We aim to report a single center experience of the management and long term outcome of HPS in pediatric liver transplant recipients. A retrospective review of children with HPS from 1990 to 2004., Inclusion Criteria: liver disease or portal hypertension, hypoxemia (PaO(2) < 70 mmHg or SaO(2) < 95%) and intrapulmonary shunting documented by macroaggregated albumin scan ratio of >4% (classified mild group [<20%], moderate group [20-40%] and severe group [>40%]). Resolution of HPS post-liver transplant was defined as PaO(2) > 70 mmHg or SaO(2) > 95%. Eighteen children (six male [34%], median age at diagnosis of HPS 8.6 [1-15.5] yr) had HPS: biliary atresia (n = 8), idiopathic biliary cirrhosis (n = 4), progressive intrahepatic cholestasis (n = 2), miscellaneous (n = 4). The majority had mild shunting (n = 8). Fourteen underwent transplantation with resolution of HPS in 13. Six developed complications: hepatic artery thrombosis (n = 4), biliary (n = 2). Four children died (28%), two pretransplant. There was a tendency towards shunt fraction worsening to a slower degree over time. One-yr survival rate post-transplant was 93%. Median PaO(2) was significantly lower in non-survivors compared to survivors (43 vs. 55.2 mmHg, p = 0.03). There was correlation between oxygen parameters pretransplant and time to HPS resolution post-transplant. HPS is reversible after transplant, but is associated with increasing mortality and morbidity.

Aims: The aims of this article were to report a single-center experience of pediatric liver transplantation for liver-based metabolic disorders and to compare the outcome of cirrhotic versus noncirrhotic metabolic liver disease., Methods: The medical records of 96 patients younger than 18 years undergoing transplantation for liver-based metabolic disorders from 1989 to 2005 were reviewed., Results: Hundred twelve transplants were performed in 96 patients at a median age of 59.7 months (range, 0-208 months). The cumulative 1-, 5-, and 10-year graft and patient survival rates were 83%, 77%, and 62% and 91%, 86%, and 82%, respectively. Acute liver failure at first presentation (hazard ratio [HR] 3.0; 95% confidence interval [CI] 1.1-8.1), age less than 1 year at time of transplantation (HR 4.6; 95% CI 1.7-12.4) and hospitalization (HR 3.2; 95% CI 1.1-9.3) were significant predictors of worse patient survival. For noncirrhotic disorders, the long-term patient (100% vs. 100%, 90% vs. 100%, and 90% vs. 75%, P=0.87) and graft survivals (93% vs. 100%, 70% vs. 100%, and 70 vs. 75%, P=0.12) at 1, 5, and 7 years for auxiliary versus orthotopic transplantation were not significantly different., Conclusions: Long-term patient survival after transplantation for metabolic disorders is excellent for both cirrhotic and noncirrhotic metabolic disorders. For noncirrhotic metabolic disorders, auxiliary transplantation has similar patient and graft survival compared with orthotopic transplantation, but further research is recommended.

From October 1993 to February 2007, 25 liver transplantations were performed for hepatoblastoma. Of these 25, 18 children received cadaveric grafts, and 7 received left lateral segments from living donors. Fifteen patients were at level IV in the pretreatment extent of disease staging system for hepatoblastoma (PRETEXT IV; 11 received cadaveric grafts and 4 underwent living related liver transplantation [LRLT]) and 10 were level III (PRETEXT III; 7 received cadaveric grafts and 3 underwent LRLT). Preoperative chemotherapy was given according to the risk stratification system for children with hepatoblastoma protocols of the International Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL): SIOPEL I in the first 3 patients, SIOPEL II in 6, SIOPEL III in 10, and SIOPEL IV in 3 patients. Patient and graft survival after cadaveric transplantation was 91%, 77.6%, and 77.6%, at 1, 5, and 10 years, respectively, with no retransplantations. Patient and graft survival for children undergoing LRLT was 100%, 83.3%, and 83.3%, at 1, 5, and 10 years, respectively. All surviving children but 1 remain disease-free, with a median follow up of 6.8 years (range, 0.9-14.9). There were 5 deaths at a median of 13 months post-transplantation, secondary to tumor recurrence (4) and respiratory failure (1). Liver transplantation is an established treatment for unresectable hepatoblastoma confined to the liver following chemotherapy. LRLT is a therapeutic option given that the outcome is similar to that of resection and cadaveric transplantation.

Auxiliary liver transplantation (ALT) permits the serial assessment of regeneration in livers of patients with acute liver failure (ALF). Forty-nine ALF patients [32 adults (median age, 23 years; range, 16-40 years) and 17 children (median age, 12 years; range, 1-15 years)] underwent ALT between 1994 and 2004 at King's College Hospital. Twenty-four patients had seronegative liver failure, 15 had acetaminophen toxicity, 4 had hepatitis B virus (HBV) infection, 3 had drug-induced liver failure, 2 had autoimmune hepatitis, and 1 had mushroom poisoning. Nine patients without post-ALT native liver histology were excluded from review. All acetaminophen-induced, HBV, and drug-related patients had diffuse injury. Twelve seronegative patients and the autoimmune hepatitis patient had a map-like injury. On follow-up, 9 acetaminophen-induced patients, 9 seronegative patients, 2 drug-induced ALF patients, 3 HBV patients, and the autoimmune patient recovered to a near-normal native liver with inconsequential scarring. The hepatocyte proliferative rate in diffuse necrosis was 27.4% (range, 3.1%-69.4%) at hepatectomy and sharply decreased after 8 days post-ALT, being minimal months and years after ALT. In conclusion, in patients undergoing ALT for ALF with a diffuse pattern of liver injury-mainly acetaminophen toxicity-hepatocyte proliferation occurs in the native liver within a few days of transplantation. If the injury is map-like (most cases of seronegative ALF), regeneration seems to involve variable hepatocellular proliferation and potential ductular hepatopoiesis, but sequential assessment is difficult because of sampling variation. The likelihood of histological recovery appears to be minimal in livers with total hepatocyte loss at the time of ALT., ((c) 2008 AASLD.)

Mycophenolate mofetil (MMF) has been used to rescue liver allografts with steroid-resistant rejection (SRR). However, the long-term outcome of these patients is not known. This study evaluates the long-term outcome of MMF rescue therapy for SRR in pediatric liver allograft recipients. Twenty-six children (who received 28 liver transplants), including 16 girls, were given MMF for SRR. The median age at transplant was 1.7 (range 0.4-13.6) years. Primary immunosuppression was cyclosporine-based in 22 and tacrolimus-based in 6. All patients except one had been converted to tacrolimus prior to MMF, having already received a median of 2 (1-5) courses of high-dose intravenous methylprednisolone. The median time to MMF rescue therapy was 1.8 (0.4-35.8) months. Twenty-one of 28 episodes of SRR responded to MMF therapy. The median follow-up was 8.8 (7.7-11.5) years. In responders, there was 1 death from posttransplant lymphoproliferative disease, and no grafts were lost to chronic rejection. In the 7 nonresponders, 3 grafts were lost to chronic rejection with 2 patient deaths. Surviving children are clinically well with good liver function, and 17 remain on MMF. Three children have glomerular filtration < 80 mL/minute/1.73 m(2). Side effects of MMF were seen in 12 patients; diarrhea (n = 5) and leukopenia (n = 5) being the most common. MMF was found to be effective in treating SRR in pediatric allograft recipients, with good long-term graft function and an acceptable side-effect profile.

Background: Living related liver transplantation (LRLT) has become established for treating children with end-stage liver disease. The aim of this study was to review a single-centre experience of left lateral segment liver transplants from living donors in children., Methods: Fifty left lateral segment LRLT procedures have been performed since 1993. There were 17 girls and 33 boys, of median age 1.5 years (range 0.5 to 13 years), with a median weight of 10 (range 0.7-44) kg. Donors included 23 mothers, 26 fathers and one uncle, with a median age of 33 (range 19-46) years., Results: At a median follow-up of 86 months, there was no donor mortality and low morbidity. Patient and graft survival rates were 98, 96 and 96 per cent, and 98, 96 and 93 per cent at 1, 3 and 5 years respectively. Three children had a second transplant at a median of 9 years after the first. The incidence of hepatic artery thrombosis, portal vein thrombosis and biliary complications was 6, 4 and 14 per cent respectively., Conclusion: Living related liver transplantation has good long-term results in children., ((c) 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody (SMA/ANA, type 1) or liver kidney microsomal antibody (LKM1, type 2). There is a female predominance in both. LKM1 positive patients tend to present more acutely, at a younger age, and commonly have partial IgA deficiency, while duration of symptoms before diagnosis, clinical signs, family history of autoimmunity, presence of associated autoimmune disorders, response to treatment, and long-term prognosis are similar in both groups. The most common type of paediatric sclerosing cholangitis is ASC. The clinical, biochemical, immunological, and histological presentation of ASC is often indistinguishable from that of AIH type 1. In both, there are high IgG, non-organ specific autoantibodies, and interface hepatitis. Diagnosis is made by cholangiography. Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates, times to normalization of biochemical parameters, and decreased inflammatory activity on follow up liver biopsies. However, the cholangiopathy can progress. There may be evolution from AIH to ASC over the years, despite treatment. De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH, including elevated titres of serum antibodies, hypergammaglobulinaemia, and histological findings of interface hepatitis, bridging fibrosis, and collapse. Like classical AIH, it responds to treatment with prednisolone and azathioprine. De novo AIH post liver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection. Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to the development of autoimmune phenomena is unclear. Whatever its etiology, the recognition of this potentially life-threatening syndrome is important since its management differs from that of standard anti-rejection therapy.

We report the first successful use of hepatocyte transplantation as a bridge to subsequent auxiliary partial orthotopic liver transplantation (APOLT) in a child antenatally diagnosed with severe ornithine transcarbamylase (OTC) deficiency. A total of 1.74 x 10(9) fresh and cryopreserved hepatocytes were administered intraportally into the liver over a period of 6 months. Immunosuppression was with tacrolimus and prednisolone. A sustained decrease in ammonia levels and a gradual increase in serum urea were observed except during episodes of sepsis in the first 6 months of life. The patient was able to tolerate a normal protein intake and presented a normal growth and neurological development. APOLT was successfully performed at 7 months of age. We conclude that hepatocyte transplantation can be used in conjunction with APOLT as an effective treatment for severe OTC-deficient patients, improving neurodevelopmental outcomes.

Orthotopic liver transplantation (OLT) is an established treatment for patients with liver-based metabolic disorders that produce structural and functional impairment. Auxiliary liver transplantation (ALT) has been proposed as an alternative approach due to the potential advantage of preserving the native liver that could be used for future gene therapy and also serves as a back-up should the graft fail. The aim of our study was to determine if ALT has the long-term potential to correct the underlying abnormality in propionic acidemia (PA). A retrospective analysis was performed on graft function, metabolic parameters and effects on development in a child who underwent ALT for PA at our institute. The clinical and biochemical parameters are near normal with no diet restrictions and with good graft survival. A normal growth and an acceptable neurological and psychomotor development were achieved in the child. ALT is feasible and provides adequate liver mass to prevent metabolic decompensation in PA.

In this article, the impact of autoimmunity on the hepatocyte is analyzed in three distinct settings: classical autoimmune hepatitis, chronic hepatitis C virus infection with autoimmune manifestations, and de novo autoimmune hepatitis after liver transplantation. (1) Classical autoimmune hepatitis: Using as model autoimmune hepatitis type 2, whose main autoantigen is known, complementary aspects of the autoimmune response are revisited, including the targeting of discrete antigenic regions by humoral and cellular effectors of damage and a defect in the counterbalancing immunoregulatory mechanisms. (2) Chronic hepatitis C virus infection: This condition provides clues to the possible role of viruses as triggers of autoimmunity. The interaction between hepatitis C virus and its receptor on B lymphocytes is the likely trigger of a polyclonal activation leading to the production of autoantibodies. These appear not to be an epiphenomenon but to be markers of hepatocyte damage. (3) De novo autoimmune hepatitis after liver transplantation: The intriguing observation that autoimmune hepatitis can arise de novo after liver transplantation is presented and its possible pathogenic mechanisms are discussed.

Liver transplantation (LT) is now a standard treatment for children with end-stage liver disease with excellent 1- and 5-year survival. This has been achieved through improvement of surgical techniques and anti-rejection treatment and management. The donor pool for children has been extended by the use of cut-down, split, living-related and, recently, non-heart-beating donor and isolated hepatocyte transplantation. Though the majority of transplanted children enjoy an excellent quality of life, there remain a high number of possible complications, including short-term primary non-function, vascular and biliary problems, bowel perforation, severe rejection, infection, hypertension and long-term renal impairment, chronic rejection, de novo autoimmunity, lymphoproliferative disease and cancer, most of which are related to anti-rejection drug toxicity. Hence, the focus of research for paediatric LT should be induction of tolerance, avoiding long-term immunosuppression and its toxicity.

The aim of our study was to compare the outcome of medical treatment vs. liver transplantation in infants with neonatal hemochromatosis (NH) referred to King's College Hospital from 1990-2002. We conducted a retrospective review of 19 children from 14 families. Fifteen children presented at birth and 4 during the first week of life. One child was diagnosed by cordocentesis at 30 weeks of gestation. NH recurred in 7 of 9 families with further children. In one family, 2 children from different fathers were affected. All patients had elevated ferritin levels, hypoalbuminemia, and coagulopathy. Liver histology showed parenchymal collapse, diffuse fibrosis, and moderate to severe hepatocyte hemosiderin deposition. Extrahepatic siderosis was demonstrated by magnetic resonance in 2 patients, lip biopsy in 3, and autopsy in 10. Ten patients received a chelation-antioxidant cocktail: 1 survived, 4 died, and 5 required liver transplantation, of whom 2 died. One of the 9 infants who did not receive the cocktail survived with medical support, 3 died, and 5 required transplantation, of whom 3 died. Seven children are alive, 5 after transplantation, at a median follow-up of 5.6 years, with excellent quality of life and no recurrence of the disease. In conclusion, chelation-antioxidant treatment does not appear to modify the prognosis of NH, at least in severe cases. Liver transplantation, with 50% long-term survival, remains the treatment of choice and should be promptly offered to those infants who do not improve with supportive medical treatment.

Fungal infection (FI) is a major and potentially fatal complication in liver transplantation (LT). Published experience of FI in paediatric LT is limited. We therefore reviewed case records of 79 children, aged between 0.16 and 16 yr, who underwent LT between 1997 and 1998 to document the incidence of, and identify risk factors for, FI. Sixty-eight pre-, peri- and post-LT variables were assessed in relation to FI by univariate and multivariate analyses. The major indications for LT were biliary atresia in 26 (33%) patients, fulminant hepatic failure in 16 (20%) and intrahepatic cholestasis in 11 (14%); eight patients required re-LT. Thirty-two (40.5%) children developed a FI within 1 yr of LT. The median time to FI was 42 days (range 1-342 days). Candida spp. caused 29 (90.7%) FIs; 21 (66%) of these were Candida albicans. Although FI was associated with increased mortality, most patients responded well to antifungal treatment. The variables independently associated with FI were pre-LT fungal colonization and pyrexia and, post-LT, bacterial infection, Epstein-Barr virus (EBV) infection and tacrolimus administration. Identifying risk factors for FI should contribute to the development of strategies for prophylaxis or preemptive therapy.

Wilson's disease (WD) is a rare liver-based disorder of copper metabolism. Prognostic criteria described by our group in 1986 to predict death without transplantation have not been universally validated. The clinical features of 88 children were reviewed, retrospectively in 74 and prospectively in 14. Data from the retrospectively recruited patients that died or survived on long-term chelation were used to evaluate the validity of our old scoring system and to devise a new prognostic index, then assessed in the 14 prospectively recruited patients. Using the old scoring system, 5 children scoring > or = 7, the cutoff value for death without transplantation, survived, whereas 4 scoring < or = 7 died (sensitivity 87% and specificity 90%). A new index based on serum bilirubin, international normalized ratio, aspartate aminotransferase (AST), and white cell count (WCC) at presentation identified a cutoff score of 11 for death and proved to be 93% sensitive and 98% specific, with a positive predictive value of 88%. When the new index was evaluated prospectively in 14 patients, it predicted the need for transplantation in only the 4 who required it, although 1 child with a score of 11 survived on medical treatment. In conclusion, the new Wilson Index is more sensitive and specific in predicting mortality without transplantation than the old scoring system, but needs to be validated in a larger number of patients.

Renal dysfunction of variable severity is being increasingly recognized as a major complication of calcineurin inhibitors (CI), in some patients even necessitating renal transplantation. Close and effective monitoring of the renal function is indicated. Current methods for this monitoring are calculation of the glomerular filtration rate (GFR) based on creatinine or exogenous substances like 51Cr-EDTA. The first method is unreliable in children and the second is expensive and cumbersome. Cystatin C has been shown to be an accurate marker of glomerular filtration but has not been evaluated in a large cohort of pediatric patients before and after liver transplantation (LT). We evaluated the accuracy of cystatin C in 62 children (30 male) with LT, who had their 51Cr-EDTA measured on 40 occasions prior to LT and on 47 occasions after LT. The reciprocal of cystatin C correlated better with 51Cr-EDTA GFR (r = .78) than the reciprocal of creatinine (r = .40). Diagnostic accuracy in the identification of reduced GFR was assessed by ROC analysis. Cystatin C yielded the highest area under the ROC curve (AUC) in all groups assessed. From these data a cutoff level of cystatin C predicting 51Cr-EDTA GFR < 80 ml/min/1.73 m2 was calculated. A level of 1.06 mg/L was found to have a sensitivity of 91% and a specificity of 81%. Applying this cutoff level in our patient group would have avoided 51Cr-EDTA GFR estimation in 43 of the 87 estimations. In conclusion, the use of this simple test could be recommended as screening of renal dysfunction in children with liver disease and after LT.

Unlabelled: We report a case of neonatal herpes presenting with liver failure and disseminated coagulopathy which followed unrecognised maternal primary genital herpes and was diagnosed by herpes simplex virus DNA detection in blood by polymerase chain reaction 2 weeks after initiation of empiric intravenous aciclovir. The child underwent liver transplantation while receiving suppressive antiviral therapy and remains well after 10 months of follow-up., Conclusion: our case highlights potential pitfalls in the diagnosis of neonatal herpes and indicates a role for blood herpes simplex virus polymerase chain reaction as a sensitive diagnostic tool in disseminated infection. It is one of very few reports where liver transplantation has been successfully carried out in a neonate with herpes simplex virus-induced liver failure.

Background: Wilson's disease associated with severe liver disease is effectively cured by orthotopic liver transplantation (OLT). However, there are also anecdotal reports of improved or resolved neurologic symptoms after OLT in patients with stable or normal liver function. Side effects with conventional chelating agents are common, and it has been suggested that OLT should be considered in patients with severe progressive neurologic symptoms. However, the decision to apply this therapeutic modality to a subgroup of patients without significant liver disease is a quality-of-life issue., Methods: Long-term follow-up and quality-of-life data were obtained prospectively for 24 patients who underwent OLT between 1988 and 2000 for Wilson's disease associated with severe liver disease. In long-term survivors, quality of life was assessed using the 36-Item Short Form 36 Health Survey Questionnaire., Results: One patient who had multiorgan failure before OLT died within 24 hr of surgery and two patients died within 1 year because of immunosuppressant-related complications. There have been no deaths or graft loss in patients who have undergone transplantation since 1994, and after a median follow-up of 92 months, all survivors have satisfactory graft function (5-year patient and graft survival, 87.5%), with quality-of-life scores (assessed in 86% of survivors) comparable to age- and sex-matched controls from the general population., Conclusions: The authors' results suggest that liver transplantation can be safely performed in patients with Wilson's disease, with excellent long-term results and quality of life. Further study of the utility of liver transplantation in the management of patients with severe neurologic symptoms is justified.

The aim of this study is to study mycophenolic acid (MPA) pharmacokinetics in stable pediatric liver transplant recipients and determine which times best represent the area under the concentration versus time curve (AUC) of MPA plasma concentrations. MPA pharmacokinetic profiles were determined in 21 liver transplant recipients (age, 2 to 15 years; 12 boys) administered mycophenolate mofetil (MMF) for at least 6 months. Ten patients were coadministered cyclosporine A (CsA), and 11 patients were coadministered tacrolimus (Tac). Plasma MPA levels were analyzed by enzyme-multiplied immunoassay technique in blood samples at 0, 0.33, 0.67, 1.25, 2, 3.5, 5, and 7 hours after MMF administration. The AUC of plasma concentrations to 7 hours (AUC(0-7)) was calculated using the linear trapezoidal rule. MPA plasma trough concentration (C(0)), maximal concentration, and AUC(0-7) values ranged 9- to 14-fold at a median of 1.81 mg/L (range, 0.4 to 3.7 mg/L), 10.5 mg/L (range, 2.8 to 40.0 mg/L), and 30.2 mg/L.hr (range, 9.3 to 80.3 mg/L.hr), respectively. AUC(0-7) correlated significantly with MMF dose (r = 0.552; P =.010) and C(0) (r = 0.844; P <.001). Median AUC(0-7) (29.6 v 31.4 mg/L.hr; P =.918) was similar in children comedicated with CsA or Tac. Median MMF dose was greater in the CsA group (500 v 250 mg; P =.006). Consequently, median AUC(0-7) was significantly lower in the CsA group when equalized for dose and body weight (2.02 v 3.85 microg/L.hr per mg of MMF dose per kg of weight; P =.002). Variations of MPA pharmacokinetics in pediatric liver transplant recipients suggest that monitoring MPA plasma levels is required. C(0) correlates closely with AUC. Comedication with CsA increased MMF dosage requirements compared with children on Tac therapy.

Background: The role of interleukin-2 receptor antibodies as rescue therapy in steroid-resistant rejection (SRR) has not been studied. We evaluated the safety and efficacy of an interleukin-2 receptor antibody, basiliximab (Simulect, Novartis, East Hanover, NJ), in treating SRR in pediatric liver transplant recipients., Methods: This was a prospective study of seven pediatric liver transplant recipients with biopsy-proven SRR who would have otherwise received OKT3 or antithymocyte globulin. The primary immunosuppression consisted of cyclosporine (Neoral, Novartis), azathioprine, and prednisolone in four patients and tacrolimus and prednisolone in three patients who had undergone retransplantation for chronic rejection (n=2) and hyperacute rejection (n=1). Four patients had received two cycles of high-dose steroids, and three patients had received a single cycle; all had been converted to tacrolimus, followed by the addition of mycophenolate mofetil., Results: The median time from transplant to SRR was 30 days (range, 8 days-23 months). Five children received two doses of basiliximab (10 mg, 3-7 days apart), and two children received a single dose. Aspartate aminotransferase levels normalized in three children 12, 21, and 30 days after basiliximab treatment. Aspartate aminotransferase levels decreased without normalizing in two children, but there was no further evidence of cellular rejection on repeat biopsies. All five children are rejection-free with a median follow-up of 22 months (range, 5-32 months). Biochemical abnormalities persisted in the remaining two children, and both developed chronic rejection. There were no immediate side effects associated with basiliximab. Two patients were treated empirically for possible cytomegalovirus infection 21 and 57 days after basiliximab treatment, with no evidence of cytomegalovirus disease., Conclusion: Five of seven pediatric liver transplant recipients with SRR experienced successful outcomes with basiliximab treatment without major side effects, indicating that it is a safe alternative to OKT3 and other antilymphocyte antibodies.

Background: Retransplantation of the liver is the only means of prolonging survival in children whose initial graft has failed. Patient and graft survival rates after retransplantation in most series have been inferior to rates after first transplantation., Patients and Methods: Of 450 pediatric liver transplantations performed between January 1990 and March 2001, 50 were first retransplantations, 9 were second retransplantations, and 1 was a third retransplantation. The overall retransplantation rate was 13.3% (median age at retransplantation 4 years and median weight 15 kg). The median post-retransplantation follow-up was 73 (range, 6-139) months., Results: Kaplan-Meier patient survival rates for the group (n=50) were 71.7%, 64.7%, and 64.7% at 1, 3, and 5 years, respectively. Graft survival rates were 65.6%, 56.7%, and 56.7% at 1, 3, and 5 years, respectively. This is significantly worse than rates for children undergoing first liver transplantation. There were 17 deaths, of which 9 occurred in the first month. Biliary complications occurred in 5 (10%) patients and vascular complications in 6 (12%). Improved patient and graft survival rates were observed in the later phase of the program, although the difference was not significant. Higher preoperative serum creatinine (P=0.001) and serum bilirubin (P=0.02) levels were associated with a higher postoperative mortality., Conclusion: Results of retransplantation in children remain inferior to those after first transplantation. There is a trend toward improving results. Liver retransplantation makes an important contribution to overall survival in children.

Determinants of the wide interindividual variability of the pharmacokinetics of mycophenolic acid (MPA) in 21 stable pediatric liver transplant recipients were investigated in relation to the kinetics of the drug's major phenolic glucuronide metabolite (MPAG), cyclosporin (CsA), or tacrolimus (Tac) co-medication and liver and renal function. Trough concentrations (C(0) ) most reliably predicted the area under the curve (AUC) of 0-7 hours MPA plasma concentrations (r (2) = 0.650). Co-medication with CsA demanded higher MPA mofetil (MMF) doses to achieve equivalent trough levels than Tac (362 vs. 178 mg per mg/L, P= 0.004). Median MPA C(0) (range) was significantly lower during CsA co-therapy when corrected for MMF dose (2.8 vs. 5.6 mg MPA/L for Tac, P= 0.006). The AUC of MPAG was correspondingly higher during CsA co-medication (229 vs. 94 mg/L/h for Tac, P = 0.012) with the MPA-to-MPAG ratio at C(0) correspondingly lower (0.10 vs. 0.14, respectively, P = 0.04). This suggested contrasting effects of CsA and Tac on MPA glucuronidation or its excretion and enterohepatic recirculation. MPAG AUC was correlated to body weight and creatinine clearance. Children with elevated aspartate transaminase (AST; but with no evidence of rejection on liver biopsy, n = 7) had significantly lower MPA trough levels compared with those in whom AST was normal (0. 77 vs. 1.76 mg/L, P = 0.05), but there was no difference in the MMF dose per body weight. Examination of the MPA profiles in these subjects showed significantly lower MPA concentrations from 120 minutes after dose until the end of the 7-hour profile and suggest an accelerated clearance or decreased enterohepatic recirculation.)

Objective: To analyze the outcome of 80 consecutive pediatric split liver transplants performed at the authors' center between 1994 and 2000., Summary Background Data: Split liver transplantation has become an accepted method of increasing the number of available grafts for pediatric liver transplant recipients., Methods: The age of the patients at the time of transplantation ranged from 5 days to 16 years (median 3 years). Sixteen transplants were performed for acute liver failure and 64 for chronic liver failure. The ex situ splitting technique was used for all but four grafts. Fourteen livers were split for two pediatric recipients. Posttransplant follow-up ranged from 6 to 84 months (median 42 months)., Results: Overall patient survival at 6 months follow-up was 96.2%. Graft survival at six months was 93.7%. The Kaplan-Meier patient survival rates at 1 and 3 years were 93.5% and 88.1%, and the graft survival rates were 89.7% and 86.1%, respectively. Four patients required retransplantation. In the acute group (n = 16), the patient survival rates were 93.7% at 1 year and 76.4% at 3 years; there were three deaths due to posttransplant lymphoproliferative disease (PTLD), sepsis, and chronic rejection. In the chronic group (n = 64), the 1- and 3-year patient survival rates were 93.6% and 90.9%, respectively. There were six deaths in this group. Four patients died in the first year after the transplant due to intracranial bleeding, cerebral tumor recurrence, PTLD, and chronic rejection. There were two deaths at 3 years, one due to progressive renal failure secondary to cyclosporin toxicity and the other due to sepsis, portal hypertension, and recurrent bleeding. Vascular complications occurred in six (7.5%) patients and biliary complications in seven (8.7%)., Conclusions: These results, which represent the experience of a single institution over the last 6 years, indicate that ex situ split liver transplantation can be performed in children with good overall outcome and acceptable morbidity.

Background: Osteodystrophy is a well-described complication of chronic liver disease. Previous reports in adults and children undergoing liver transplantation (LT) were discordant, with the former showing no improvement of bone disease in the first year after transplantation and the latter demonstrating remarkable benefit from it. Our aim was to perform a pilot study on osteodystrophy in children undergoing LT and evaluate the contribution of growth on bone mineral density (BMD) changes., Methods: We studied six patients (two male), with a median age at transplantation of 8.8 (range 3.8-16.6) years. Indications for transplantation were biliary atresia and progressive familial intrahepatic cholestasis (three patients each). BMD was studied with dual-energy x-ray absorptiometry and biochemical markers of liver and bone function in patients before and at 3, 6, and 12 months after LT., Results: Median L2-L4 spinal BMD was 0.54 g/cm2 (range 0.29-0.87) before LT, and 0.58 g/cm2 (0.27-0.86) at 3 months, 0.66 g/cm2 (0.36-1.00) at 6 months, and 0.76 g/cm2 (0.44-1.02) at 12 months after LT (P=0.005). Median height was 133 (range 93-167) cm before LT, and 134 (93-167) at 3 months, 136 (97-167) at 6 months, and 139 (102-167) at 12 months after LT. There was direct correlation between height gain and total body BMD improvement (r=0.929, P=0.007)., Conclusion: BMD in children with chronic cholestatic liver disease improves remarkably by 12 months after LT. Catch-up growth in children can account for the different effect of LT on bone density between adult and pediatric populations in the first year after surgery.

Background: Pediatric orthotopic liver transplantation (OLT) has a low mortality. Some children, however, have an adverse outcome defined as a prolonged ventilatory support requirement and protracted pediatric intensive care unit (PICU) stay. The aim of this study was to determine if that adverse outcome related to the child's condition pre-OLT and/or the development of a pleural effusion or diaphragmatic dysfunction., Methods: The study included 210 children with a median age at transplantation of 45.5 months (range 0.2-252 months). Fourteen had undergone retransplantation. The duration of ventilatory support (intermittent positive pressure ventilation [IPPV]) and PICU admission and development of a pleural effusion and/or diaphragmatic dysfunction were documented for each child. The patients were divided into three groups according to whether they had acute liver failure (ALF), chronic liver disease at home (CHOM), or chronic liver failure sufficiently ill to be in the hospital awaiting transplantation (CHOSP)., Results: The 36 children with ALF were of similar age to the 138 CHOM and 36 CHOSP children but required longer IPPV (P<0.0001) and PICU stay (P<0.0001). Overall, 17 children developed diaphragmatic dysfunction and 138 pleural effusions; affected children required longer IPPV and PICU stay (P<0.01). Regression analysis demonstrated that diaphragmatic dysfunction, but not pleural effusion development, was associated with prolonged ventilation (P<0.01) and protracted PICU stay (P<0.05). Other risk factors were ALF (P<0.01), retransplantation (P<0.01), and young age (P<0.05)., Conclusion: Diaphragmatic dysfunction adversely influences PICU morbidity after OLT. Early assessment of diaphragmatic function, and if necessary aggressive management, might improve outcome.

Background: Acute cellular rejection, though mostly encountered during the first 3 months after liver transplant, may occur later on. Clinical features and outcome of children experiencing late cellular rejection (LCR) have not been described to date., Patients and Methods: A total of 20 children who developed acute rejection 6 months or more after liver transplant were studied for history of early rejection, levels of immunosuppression, causes of low immunosuppression, viral infections, signs of autoimmunity, and HLA mismatch. All liver biopsies were reviewed. Fifteen patients with no history of LCR were randomly selected as controls., Results: Of 20 children 5 were appropriately immunosuppressed, although 15 were not. Causes of low immunosuppression were: unknown (seven), poor compliance (three), posttransplant lymphoproliferative disease, (two), hepatocellular carcinoma recurrence (one), tuberculosis (one), gastroenteritis (one). Of 20 patients early rejection occurred in 13 and cytomegalovirus infection in 5. At last follow-up 10 children have persistent graft dysfunction, of whom 5 have progressed to de novo autoimmune hepatitis, 2 to chronic rejection, one has persistent graft dysfunction with recurrent cytomegalovirus activation, one has hepatic artery thrombosis and one is likely to have persistent poor compliance. None of the 15 controls developed de novo autoimmune hepatitis or any other form of persistent graft dysfunction at the time of last follow-up., Conclusion: Late cellular rejection in children is usually due to low or decreased immunosuppression and is associated with long-term complications. Prompt intervention to correct inadequate immunosuppression and careful follow-up of the other patients to identify other treatable conditions is essential.

Aim: To study the efficacy of mycophenolate mofetil (MMF) as renal rescue in paediatric liver transplant recipients with calcineurin-inhibitor- (CI) related nephrotoxicity., Methods: Pediatric liver transplant recipients with stable graft function and a glomerular filtration rate (GFR) <80 ml/min/1.73 m2 were enrolled. MMF was introduced at 20 mg/kg/day and increased to 40 mg/kg/day after 1 week. CI dose was then reduced 6 weeks to achieve blood levels 25% of baseline. GFR was reassessed after 6 and 12 months., Results: Fourteen children with a median (range) interval from transplant of 57 (4-111) months were studied. Their median (range) GFR in ml/min/1.73 m2 increased from a baseline of 52 (31-71), to 69 (38-111) and 73 (35-98) at 6 and 12 months, respectively (P=0.00014). Side effects of MMF include leucopaenia in two and backache in one, two of whom discontinued MMF. Acute allograft rejection occurred in three children. All 14 are well with a median (range) follow-up of 24 (14-38) months from MMF introduction., Conclusion: MMF allows the recovery of renal function from CI related nephrotoxicity in more than 70% of paediatric liver transplant recipients with renal impairment.

Background/purpose: Hepatic artery thrombosis (HAT) represents a significant cause of graft loss and mortality after pediatric orthotopic liver transplantation (OLT). The incidence and etiology of this complication have been investigated in detail but relatively little is known about outcome., Methods: A review was conducted of all children with confirmed HAT complicating OLT during a 10-year period (1990 through 1999) in a single center. HAT was established by angiography or at operation in all cases., Results: From a consecutive series of 400 pediatric OLTs, there were 31 (7.8%) instances of HAT in 29 children of median age 3.8 years (range, 8 days to 16 years). Twenty-four (83%) are alive after a median follow-up of 3.6 years. Fourteen cases occurred after transplantation of whole grafts and 17 after reduced or split livers. Of the 18 episodes resulting in retransplantation, there were 5 deaths and 2 second episodes of HAT; surviving children are alive with good graft function. Of the 13 episodes managed without retransplantation, 4 patients underwent attempted early revascularisation of the graft, which was successful in 2, and the remainder initially were treated conservatively. All 13 children are alive after a median follow-up of 4.1 years (range, 0.6 to 5.8), but 5 required radiologic or surgical intervention for biliary or septic complications; biochemical liver function is normal in 8, mildly abnormal in 3, and poor in 2. Retransplantation was less likely in those who had received reduced or split grafts (7 of 17) compared with those who had received whole grafts (11 of 14), but this difference just failed to reach statistical significance (chi(2) = 3.01, 0.1 > P > .05)., Conclusions: Using a selective policy of retransplantation, revascularisation, and conservative treatment, 83% of children survived HAT complicating OLT. Approximately 40% of children with HAT survived without retransplantation. J Pediatr Surg 36:888-891., (Copyright 2001 by W.B. Saunders Company.)

Background: Individuals undergoing therapeutic immunosuppression are at risk of severe varicella-zoster virus (VZV) infection, particularly those without evidence of previous infection., Methods: Eleven children, median age 10 months (range 5.5 months to 7 years and 9 months) received one dose of varicella vaccine (Varilrix, SmithKline Beecham plc, UK) before liver transplantation (median interval 95 days, range 40-289 days). The serological response to varicella vaccine was evaluated retrospectively and matched with the outcome and management of any subsequent exposures to VZV., Results: Three children responded postimmunization, six children showed no response, and in two children the outcome was difficult to interpret having received blood products. Four children required varicella-zoster immunoglobulin prophylaxis posttransplantation, two of whom developed mild chickenpox., Conclusions: Only 3 of 11 children developed a clear antibody response to varicella vaccine. Administration of varicella vaccine did not affect the management of subsequent VZV exposures.

Two girls were diagnosed with Langerhans cell histiocytosis (LCH) at the age of 16 and 7 months and developed end stage chronic liver disease related to LCH-induced sclerosing cholangitis at 28 and 8 months, respectively. They received liver transplants at 34 and 14 months of age. Five months post-orthotopic liver transplantation (OLT) one of the patients developed posttransplant lymphoproliferative disease, successfully treated with a combination of surgery and reduction of immunosuppression. Fourteen months post-OLT she developed diabetes insipidus, bilateral ear discharge, and new osteolytic lesions. After transplantation both girls had mild skin reactivations of LCH, requiring minimal steroid increments. At 60 and 5 months post-OLT intrahepatic LCH recurrence was diagnosed on the basis of abnormal biliary enzymes and presence of Langerhans cells in the grafts. Initial cholangiography in both patients was unremarkable. LCH activity was controlled by maintenance chemotherapy with vinblastine, etoposide, and prednisolone. Ten months after reappearance of LCH in the liver graft a follow-up cholangiography in one of the girls demonstrated a low grade cholangiopathy. Residual elevation of liver enzymes probably represents an ongoing pathogenic process.

Objectives: To study the incidence, clinical presentation, management, complications and outcome of tuberculosis in pediatric liver transplant recipients., Methods: A retrospective review of the medical records of children who underwent liver transplantation between 1991 and 1998., Results: Mycobacterium tuberculosis infection occurred in 6 of 254 (2.4%) children undergoing liver transplantation between 1991 and 1998. Cough, pyrexia and poor appetite were common presentations; one-half had normal chest radiographs. The median time to confirmation of diagnosis was 8 months (range, 1 to 17 months). Tests contributing to diagnosis included: Ziehl-Neelsen (ZN) stain (2 patients), M. tuberculosis polymerase chain reaction (1 patient), Mantoux test (1 patient) and histopathology (4 patients). Family health screening was productive for 4 patients. Duration of treatment varied from 9 to 18 months. Isoniazid-induced hepatitis was observed in 2 patients but resolved with dose reduction. Two patients died while receiving treatment, one of Klebsiella spp. septicemia and the other of pulmonary hemorrhage., Conclusions: Tuberculosis after liver transplantation has a significant morbidity and mortality. Pretransplantation a personal and family history of tuberculosis must be sought, and screening of patients and their families should be considered. Standard regimens incorporating isoniazid and rifampin are effective, but regular monitoring of liver function is essential to detect drug-induced hepatotoxicity.

Liver dysfunction is a well-recognized complication of intestinal failure in children. Advances in total parenteral nutrition (TPN) have allowed these children to survive while their intestinal tract gradually adapts. Unfortunately TPN may lead to cholestatic liver disease particularly in the young children. Progression of liver disease is associated with a poor prognosis and is an indication for small bowel transplantation. We report our experience of orthotopic liver transplantation in four children with short gut and sequential liver and small bowel transplantation in one child. All children had TPN-related liver failure. Causes of intestinal failure included necrotising enterocolitis (n=2), gastroschisis (n=1), intestinal atresia (n=1), and megacystic, microcolon syndrome (n=1). At the time of liver transplantation the children's mean age was 10.9 months (2.5-24) and weight 6.7 kg (4.8-10.1). The mean serum bilirubin was 522 micromol/liter (299-823), aspartate transaminase 423 IU/liter (49-1024) and international normalized ratio 2.8 (2-3.9). There were two deaths both from respiratory failure secondary to adenovirus pneumonia including the child who received a sequential small bowel transplant. Three children with isolated liver grafts are alive and off TPN at 20 months (mean) follow up (range 6-35). Isolated orthotopic liver transplantation has a role in selected children with intestinal failure, particularly those with short but normally functioning gut and progressing with satisfactory intestinal adaptation but developing liver disease. Those children with TPN-related liver disease and unadapted gut or irreversible intestinal disease need combined liver and small bowel transplantation. Sequential small bowel transplantation is feasible after orthotopic liver transplantation and may provide an option for the child with terminal liver and small bowel failure.

Alpha-1-antitrypsin (a1-AT) deficiency is an inborn error of metabolism, which can cause liver disease. The condition is one of the most common genetic disorders in the Caucasian population. Here we review our experience with 21 children suffering from end-stage liver disease due to a1-AT deficiency. All children are PIZZ homozygotes. Nineteen of them initially presented with neonatal jaundice and two with hepatosplenomegaly in childhood. Twenty-five liver transplantations were performed. All children are currently alive at a median followup of 40 months. Liver replacement provides the only definite treatment for children with end-stage liver disease associated with a1-AT deficiency. Excellent results can be achieved by reducing waiting time for transplantation and by early referral to a liver transplant centre.

Objective: To determine if auxiliary partial orthotopic liver transplantation (APOLT) has the long-term potential to correct the underlying abnormality in Crigler-Najjar syndrome type 1 (CNS1) without the need for total liver replacement., Background: Orthotopic liver transplantation has been used successfully to replace the defective enzyme in CNS1. Experimental studies have shown that only 1% to 2% of the normal hepatocyte mass is needed for bilirubin conjugation. If APOLT corrects the underlying metabolic abnormality, it has the advantage of preserving the native liver, which would serve as a "safety net" should the graft fail, and there is the potential for gene therapy in the future with possible withdrawal of immunosuppression., Methods: Seven APOLT procedures were performed in six recipients with CNS1. Median age at transplantation was 10.5 years. Six transplants were performed as a left auxiliary liver transplant, and one was performed as a right auxiliary liver transplant. Median serum bilirubin level at transplantation was 320 micromol/L. All patients required 12 to 16 hours of phototherapy daily before the transplant to maintain serum bilirubin levels between 250 and 350 micromol/L., Results: Median serum bilirubin level was 50 micromol/L at day 5 after the transplant and 23 micromol/L at a median follow-up of 32 months. In four children, early severe acute rejection developed, requiring conversion to tacrolimus; one underwent a second transplant for chronic rejection and graft atrophy but died from lymphoproliferative disease 6 months after the second transplant., Conclusions: This report shows that APOLT is technically feasible and provides adequate hepatocyte mass to correct the underlying metabolic abnormality in CNS1.

Background: Living related liver transplantation has been developed as an important potential source of organs for treatment of children with acute and chronic liver disease. A single UK centre performing living related liver transplantation was established in 1993., Methods: Parents who were potential donors for their children for living related liver transplantation were assessed for suitability according to a protocol based on one developed and published by the University of Chicago Transplant Group. Records kept by the transplant coordinators were retrieved and data were extracted., Results: Of 64 potential donors for 32 potential recipients ten were excluded at a preliminary stage. Fourteen ultimately became donors. Of 54 parents who began evaluation 23 were finally considered to be suitable. There were 19 non-disease-related reasons for unsuitability: blood group mismatch (eight cases), size discrepancy (six), pregnancy (two), oral contraceptive medication (one), vascular anatomy variant (one) and age (one). Sixteen were unsuitable because disease was found, namely fatty liver (four), thyroid disease (two), hepatitis B positivity (two), cardiac murmur (one), anaemia (one), glucose-6-phosphate dehydrogenase deficiency (one), diabetes mellitus (one) and psychological problems (one), and three parents were affected by the same disorder as the child (Alagille syndrome, one; mitochondrial disorder, one; recurrent cholestasis, one). Three parents were rejected for more than one reason. Both parents were unsuitable for donation in 21 per cent of cases., Conclusion: Parents approach living related liver transplantation with enthusiasm. They should be advised of the high chance of unsuitability, including the finding of significant pathology. The limitation of living related liver transplantation as the major source of organs for children is recognized.

Cyclosporine (Sandimmune) is an effective immunosuppressive drug but may be poorly absorbed in the early postoperative period after liver transplantation, exposing the recipient to an increased risk for rejection. Neoral is a new oral formulation of cyclosporine that uses a mixture of surfactant, lipophilic, and hydrophilic solvents to permit microemulsification that leads to potentially better absorption. This oral drug has not been evaluated in children immediately posttransplantation. The aim of this study was to evaluate the pharmacokinetics, bioavailability, and safety of Neoral during the first week post-liver transplantation in children. Twelve children, 8 boys and 4 girls, with a median age of 2.6 years (range, 1 to 8 years) were administered Neoral within 12 hours posttransplantation. Pharmacokinetic profiles were performed over a 12-hour period on each child on days 1, 3, and 5 and twice-daily trough levels were obtained on days 2, 4, 6, and 7. The maximum concentration (Cmax), time to reach Cmax (Tmax), 12-hour trough levels, and area under the curve were calculated, and rejection episodes and adverse events were documented over a 12-week period. Neoral was well absorbed, even on the first postoperative day. After the introduction of enteral feeding, the peak levels increased (Cmax, 655 ng/mL) and were achieved significantly sooner (Tmax, 2 hours). There was no significant difference in drug exposure between days 1, 3, and 5 (P > .05). The incidence of acute rejection was 25% and hypertension was reported in 4 of 12 patients during the first week. Neoral was well absorbed in the early post-liver transplantation period, provided effective immunosuppression, and was not associated with a high incidence of adverse events or toxicity. The introduction of enteral feeding improved absorption.

Background: Gender is not a selection criterion for orthotopic liver transplantation (OLT), and reports in adults have shown a less favorable outcome for male recipients of female organs; the only pediatric study did not support this finding. The aim of the present study was to assess the impact of donor and recipient gender on graft and patient survival rates after pediatric OLT., Methods: We have reviewed retrospectively 137 children (male=63; median age: 3.4 years; range: 14 days to 15 years) undergoing primary OLT from January 1991 to June 1996. These children were divided into donor-recipient gender match (M; n=64) and nonmatch (NM; n=73) groups and then classified into female to female (FF; n=30), female to male (FM; n=29), male to female (MF; n=44), and male to male (MM; n=34) subgroups., Results: The M group had better graft and patient survival rates at both 1- and 5-year follow-up compared with the NM group (P<0.01). Graft and patient survival rates were different among gender subgroups (P<0.04). Graft and patient survival rates in the FM group were poorer than in the MM subgroup at both 1 and 5 years (P<0.03, P<0.01). The FM group had a higher incidence of early complications than the MM (P<0.01) group, with 50% and 33% of graft losses, respectively, related to the complications. To minimize the influence of hormonal factors, we have analyzed separately the patients younger than 12 and 10 years who had similar findings., Conclusion: Graft and patient survival rates after pediatric OLT are worse in gender mismatch groups, particularly for male recipients of female organs. Early complications play a role in the decreased survival rates.