Predictors of cost of liver transplantation in children: a single center study.

OBJECTIVE: Efforts to decrease the cost of orthotopic liver transplantation (OLT) must address the impact of specific interventions on clinical outcome. We hypothesized that an intervention designed to decrease the length of hospitalization would reduce costs without jeopardizing clinical outcome. We further sought to identify predictors of length of stay and cost for hospitalization after liver transplantation. METHODS: The study group included 47 children who underwent OLT from September 1996 to April 1999, and the control group included 36 children who underwent OLT from March 1994 to August 1996. The intervention was a transition to home program in which patients were discharged to a family living center when they met established clinical criteria and their families met predefined educational goals. We analyzed patients who survived 3 months after OLT. RESULTS: For the intervention group, the mean length of stay, total costs, and surgical costs were 29%, 36%, and 34% lower, respectively. Organ type, height z score, race, hepatic artery thrombosis, early allograft rejection, and participation in the transition to home program predicted length of stay and total costs. CONCLUSION: An early discharge program based on defined criteria can be used to decrease length of stay and cost after OLT without jeopardizing clinical outcome.

Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study.

Prostaglandin E1 (PGE1) and N-acetylcysteine (NAC) have been used as single agents to decrease reperfusion injury and improve outcome after solid-organ transplantation (Tx). We hypothesized that combined treatment with NAC and PGE1 would be safe and reduce reperfusion injury. We therefore carried out a pilot study to assess the safety of this drug combination and gain information regarding the efficacy of treating pediatric liver transplant recipients with NAC and PGE1. The pilot study took the form of an open-label study incorporating 25 pediatric liver transplant recipients (12 children in the treatment group and 13 children as controls). NAC (70 mg/kg) was given intravenously over 1 h following reperfusion and then every 12 h for 6 days. PGE1 (0.4 mg/kg/h) was given as a continuous intravenous infusion for 6 days, starting after the first NAC dose. The primary outcome was the safety of combined treatment with NAC and PGE1. Patient survival, graft survival, allograft rejection within the first 90 days after Tx, peak post-transplant serum alanine aminotransferase (ALT) concentration, post-transplant length of hospitalization, and post-operative complications were secondary outcomes. Post-operative complications occurred at similar rates in both control and treated groups. No complications or adverse events occurred in the treated group as a result of study drugs. The 3-month patient survival rate was 100% for both groups. For the group treated with NAC and PGE1, peak serum ALT was lower and median length of stay was shorter but the differences did not reach statistical significance. The proportion of patients with allograft rejection was not significantly different between the two groups. However, rejection was more severe in the control group than in the treated group. In summary, infusions of NAC and PGE1 were safely administered to pediatric liver transplant recipients. However, a randomized controlled study is needed to determine the efficacy of treatment with NAC and PGE1.

Cholestatic syndromes of infancy and childhood.

Cholestasis results from structural and functional impairment of the hepatobiliary system, which is often the target of several environmental factors and disease processes. This review focuses on the clinical consequences of this impairment. When evaluating an infant or child with cholestasis, a broad differential diagnosis must be considered; viral infections, metabolic disorders, and toxic insults may often lead to cholestasis. In the infant, cholestasis associated with severe hepatic synthetic dysfunction points to life-threatening metabolic disorders. In this setting, early diagnosis and prompt treatment offer the only chance for survival. Fortunately, cholestasis in infants presents more frequently with initially normal liver synthetic function. In those infants without evidence of infection, evaluation for patency of the extra-hepatic biliary system is a high priority. Biliary atresia comprises a significant portion of these patients and requires surgical intervention with portoenterostomy in an attempt to improve biliary flow. In a substantial group of infants and older children in whom the cause for cholestasis is not apparent, typical clinical and biochemical markers may allow the identification of specific genetic defects of syndromes that result from abnormal canalicular transporters.

Transmission, natural history, and treatment of hepatitis C virus infection in the pediatric population.

Compared with the adult population, hepatitis C virus infection may differ in the pediatric age group with respect to transmission, course, and response to treatment. The prevalence of hepatitis C in children is between 0.05% and 0.4%. The major mode of acquisition has shifted from parenteral transmission to maternal-infant transmission. However, the actual rate of maternal-infant transmission is low. The natural history of hepatitis C in children is not well characterized, although the available information suggests a milder disease than in adults. In the eight studies of treatment with interferon for hepatitis C in children, the incidence of a complete sustained response varied from 0 to 45%. No pediatric studies have evaluated quality of life or the effect of treatment on the development of cirrhosis and hepatocellular carcinoma. Children may respond better to treatment than adults. We recommend that children with hepatitis C are considered for treatment only as part of a controlled clinical trial.

Long-term outcome after partial external biliary diversion for intractable pruritus in patients with intrahepatic cholestasis.

BACKGROUND: Chronic intrahepatic cholestasis is associated with severe pruritus that is often refractory to maximal medical management and leads to significantly impaired quality of life. The hypothesis in this study was that partial external biliary diversion (PEBD) can substantially improve intractable pruritus secondary to intrahepatic cholestasis with subsequent improvement of functional quality of life. METHODS: Parents' and/or patients' clinical rating of pruritus, growth percentiles, biochemical parameters, and liver biopsies performed before and after surgery were compared in a retrospective medical record review. RESULTS: Eight children underwent PEBD from 1990 through 1997. Complete follow-up data were available for seven patients. Before surgery, all patients had intense pruritus, which was not responsive to maximal medical therapy. Specimens obtained in preoperative liver biopsies showed moderate (n = 1), minimal (n = 6), or no (n = 1) portal fibrosis. After PEBD, all patients received ursodeoxycholic acid (10-15 mg/kg/dose two to three times daily) until resolution of pruritus. Of the seven patients with complete follow-up data, six had complete resolution of pruritus and sustained resolution up to 8 years after surgery. The patient with mild to moderate residual pruritus was the youngest to undergo PEBD. Growth improved from below the 5th percentile before surgery to the 5th through the 25th percentiles for five of six patients with more than 6 years' follow-up. All families reported improved quality of life, defined by school attendance and ability to resume normal activity with peers. There has been no clinical evidence of progression of liver disease. CONCLUSION: Partial external biliary diversion is effective in the long-term treatment of pruritus refractory to medical therapy and provides a favorable outcome in a select group of patients with chronic intrahepatic cholestasis without cirrhosis.

Pediatric hepatology. A half-century of progress.

Treating a pediatric patient offers a unique opportunity to develop effective strategies to prevent progressive liver injury and to develop novel therapeutic regimens to reduce the need for OLT. Universal vaccination against hepatitis viruses will prevent cirrhosis and liver cancer. Education and counseling may reduce the incidence of alcoholic liver disease. Precise and early screening for metabolic liver disease and genetic or targeted therapy may prevent disease progression. A retrospective look at the 1983 National Institutes of Health Consensus Conference on Liver Transplantation, after more than 15 years of experience among many centers, indicates that liver transplantation can be effectively used to childhood liver disease. Projections 10 years into the future offer hope that liver transplantation may not be needed in the treatment of certain diseases such as metabolic liver disease and fulminant hepatic failure. Focusing on prevention or treatment of liver disease in early life, thoughtful medical management, precise decision making, and conscientious, creative, and courageous use of nontransplant options, can save both livers and lives.

Long-term survival after liver transplantation.

BACKGROUND: Liver transplantation (LT) remains a high-risk operation, especially during the first months after LT when technical complications and preexisting illness exert their influence on survival. However, there are late deaths. The authors have reviewed their experience to identify factors impacting on long-term survival. METHODS: A total of 150 patients who had undergone liver transplantation over an 11-year period were reviewed. Thirty-three patients died after LT (22%). Of these, 18 of 33 (55%) died in the first 3 postoperative months. One hundred thirty-two patients survived beyond 3 months, and 15 patients (11%) suffered late deaths. This review concentrates on the latter group. RESULTS: The primary cause of death was sepsis in 11 of 15 (73%). In two, sepsis complicated retransplantation in chronically debilitated patients. Two additional patients had late-presenting postoperative complications (bile leak or abscess, intestinal obstruction with perforation). In two cases, pneumocystis carinii pneumonia occurred; noncompliance or unplanned discontinuation of prophylaxis was directly responsible. Multiple organ system failure from presumed immunoincompetence developed in four patients; one had undergone bone marrow transplantation for aplastic anemia (AA) after fulminant hepatic failure (FHF). Lymphoproliferative disease (LPD) was the cause of death in 3 of 15 cases (20%). In only three cases was the cause of death related to the patient's primary disease (chronic hepatitis, Alper's syndrome or seizures, and AA with FHF). Pretransplant diagnosis, and UNOS status at the time of LT did not influence the long-term survival. CONCLUSIONS: Long-term survival in patients who have undergone LT was compromised by immunosuppressive complications and sepsis. Early mortality factors, such as UNOS status, age at LT, primary diagnosis, and technical complications do not predict late deaths. In children who adhere to their medical regimen and have good initial allograft function, late postoperative infection, especially with Ebstein-Barr virus, accounts for most of the late mortality. Improved and decreased immunosuppression may further improve these long-term results.

Inborn errors of bile acid biosynthesis and transport. Novel forms of metabolic liver disease.

Defective bile acid biosynthesis, metabolism, and transport can now be delineated in a wide variety of disease states. This ability to recognize specific aberrations, such as the documented inborn errors in bile acid biosynthesis manifesting as neonatal cholestasis, offers new opportunities for therapeutic intervention. Future studies should determine the incidence of bile acid biosynthetic and transport defects in patients with enigmatic and unexplained liver diseases.

Nefazodone-induced liver failure: report of three cases.

BACKGROUND: Liver failure is a rare but devastating result of drug toxicity. OBJECTIVE: To describe three cases of subfulminant liver failure that were probably caused by nefazodone, a new antidepressant that is a synthetically derived phenylpiperazine. DESIGN: Case series. SETTING: Two university medical centers and a children's hospital. PATIENTS: Three women 16 to 57 years of age. INTERVENTION: Two patients underwent liver transplantation; the third was listed for transplantation but subsequently improved. MEASUREMENT: Liver biopsy. RESULTS: Nefazodone was administered for 14 to 28 weeks before the onset of symptoms. The duration of jaundice before onset of encephalopathy ranged from 4 to 6 weeks. All cases of liver failure had similar histologic appearance, with prominent necrosis in the centrolobular areas (zone 3). One patient had successful liver transplantation, one underwent transplantation but died, and one improved without transplantation. The temporal onset of disease after the start of nefazodone therapy suggested severe hepatocellular injury caused by the drug. CONCLUSIONS: Because nefazodone seems to cause severe hepatocellular injury in an idiosyncratic manner, routine liver chemistries should be performed before starting nefazodone therapy and patients should be monitored regularly. Therapy should be discontinued if liver enzyme concentrations become abnormal.

The relationship of hepatotoxic risk factors and liver histology in methotrexate therapy for juvenile rheumatoid arthritis.

OBJECTIVE: To examine the relationship between hepatotoxic risk factors and liver histopathology in patients with juvenile rheumatoid arthritis (JRA) treated with methotrexate (MTX). STUDY DESIGN: We graded the histology of 33 percutaneous liver biopsy specimens from 25 patients with JRA treated at Children's Hospital Medical Center, Cincinnati, Ohio, using the Roenigk Classification Scale. Stepwise linear and logistic regression analyses were performed to examine the relationship of the Roenigk grade and presence of liver fibrosis of biopsy specimens with potential risk factors. RESULTS: Twenty-seven biopsy specimens (82%) were classified as grade I, 4 (12%) as grade II, and 2 (6%) as grade IIIA; none demonstrated significant fibrosis. The frequency of biochemical abnormalities (P <.001) and body mass index (P =.05) were the only risk factors found to significantly relate to the Roenigk grade. The following factors were not significantly associated with the Roenigk grade: age, gender, disease duration, JRA subtype and course, duration of MTX administration, weekly MTX dose, cumulative dose of MTX, route of MTX administration, use of folic acid supplementation, concurrent use of other medications, and potential hepatotoxic comorbidities. CONCLUSIONS: Serial biochemical abnormalities are significantly associated with Roenigk grade and the presence of liver fibrosis. These findings concur with studies of patients with rheumatoid arthritis, suggesting that guidelines for monitoring MTX hepatotoxicity in rheumatoid arthritis may be applicable to patients with JRA.

Viral hepatitis: expanding the alphabet.

Progress in understanding viral hepatitis has occurred at a rapid pace during the last 10 years; this has led directly to improvements in prevention, detection, and treatment. In previous reviews of viral hepatitis, only two forms of infectious hepatitis, hepatitis A and B, were recognized, and other unrecognized or uncharacterized agents were classified as "non-A, non-B." Currently, many more letters of the alphabet are required to designate the growing number of viral agents discovered through the application of the techniques of epidemiology and molecular virology. Furthermore, understanding of these viruses on the molecular level has led to the discovery of multiple subsets of these agents. This expansion of knowledge has immediate implications for bedside management, including the use of polymerase chain assays for diagnosis and management of chronic viral hepatitis, potent therapeutic antiviral drugs, and new vaccination strategies. In this chapter, we discuss these recent advances in the detection and management of viral hepatitis in children.

Nontransplant alternatives for the treatment of patients with metabolic disease.

Orthotopic liver transplantation is an accepted therapy for patients with acute and chronic liver disease including patients with hepatic based metabolic disease. In this review non-transplant options for the treatment of patients with liver disease including those with metabolic disorders are discussed.

Transplantation for childhood liver disease: an overview.

The advances made in surgical technique, postoperative care, and immunosuppression during the 1980s have permitted orthotopic liver transplantation (OLT) to evolve into an effective and widely accepted therapy for infants and children with end-stage liver disease. Biliary atresia, a progressive, obliterative disease of the bile ducts, is the most common indication for OLT in children, accounting for approximately 50% of cases. Metabolic liver disease (MLD) accounts for 20% to 25%; other common indications for OLT include fulminant hepatic failure (FHF) and forms of intrahepatic cholestasis. The principal problem associated with the increasing application of OLT is the burden placed on resources, particularly the availability of donor organs. The limited pool of size-matched donor organs has led to the application of a variety of alternatives to address the needs of the pediatric recipient; these include (1) reduced-size liver transplantation, (2) "split-liver" transplantation, and (3) use of living-related organ donors. In view of the impact on overall organ availability, the use of nontransplant options, including liver cell transplantation, especially for FHF and MLD, deserves broader application. Despite the success of transplantation, major challenges in childhood liver transplantation remain, including (1) improved preoperative management to ensure adequate growth, (2) more precise posttransplant management of immunosuppression to ensure graft viability and avoidance of lymphoproliferative disease, (3) earlier recognition of cytomegalovirus and Epstein-Barr virus infection, and (4) provision of services in a more cost-effective manner. The ultimate solution is to prevent liver disease through vaccination and research.