Andrew H. Urbach

HEART-LIVER TRANSPLANTATION IN A PATIENT WITH FAMILIAL HYPERCHOLESTEROLAEMIA

A girl aged 6 years 9 months with severe heart disease secondary to homozygous familial hypercholesterolaemia underwent orthotopic cardiac transplantation and her liver was replaced with the liver of the same donor. In the first 10 weeks after transplantation serum cholesterol fell to 270 mg/dl from preoperative concentrations of more than 1000 mg/dl.

Orthotopic liver transplantation, Epstein-Barr virus, cyclosporine, and lymphoproliferative disease: A growing concern

Lymphoproliferative disease (LPD) is a well-recognized complication of both solid organ and bone marrow transplantations. The occurrence of LPD in these settings is related in part to the use of the immunosuppressive agent cyclosporine. We report 12 cases of LPD after orthotopic liver transplantations in 132 pediatric patients. Lymphoproliferative disease occurred as one of three clinical syndromes: (1) lymphadenopathic, (2) systemic, and (3) lymphomatous. Effective management of LPD with excisional therapy or reduction of immunosuppressive medications or both resulted in the survival of 7 of 12 patients. In an alarming and increasing percentage of patients after orthotopic liver transplantation, progressive LPD develops with lethal outcome (5/12 patients). Early recognition of LPD and aggressive intervention may improve outcome in this group.

Choosing a pediatric recipient for orthotopic liver transplantation.

Between March 3, 1981, and June 1, 1984, 216 children were evaluated for orthotopic liver transplantation. Of the 216 patients, 117 (55%) had received at least one liver transplant by June 1, 1985. Fifty-five (25%) died before transplantation. The 117 patients who received transplants were grouped according to severity of disease and degree of general decompensation at the time of transplantation. The severity of a patients medical condition with the possible exception of deep hepatic coma, did not predict outcome following orthotopic liver transplantation. Seventy variables were assessed at the time of the evaluation. Twenty-three of the 70 variables were found to have prognostic significance with regard to death from progressive liver disease before transplantation. These 23 variables were incorporated into a multivariate model to provide a means of determining the relative risk of death among pediatric patients with end-stage liver disease. This information may allow more informed selection of candidates awaiting liver transplantation.

Changing concepts: Liver replacement for hereditary tyrosinemia and hepatoma*

In recent years there has been increased use of hepatic transplantation for the treatment of liver-based inborn errors of metabolism.1,2 In 1976, a 9-year-old girl with chronic hereditary tyrosinemia who had developed a 15-cm hepatoma in her cirrhotic liver underwent liver replacement with immunosuppression therapy with azathioprine, prednisone, and antilymphocyte globulin. The abnormal metabolic profile of tyrosinemia was promptly and completely corrected, but a pulmonary metastasis from the hepatoma was discovered shortly afterward. The new liver was rejected in 3 months, and the patient died during a second attempt at transplantation.3 We have had subsequent experience with four additional patients with the same diagnoses, in whom immunosuppression therapy after liver replacement was with cyclosporine and prednisone. These four recipients are well and metabolically normal 3 months to almost 3 years after transplantation and have no evidence of recurrent tumor. These observations suggest the desirability of liver transplantation earlier in the course of this disease. The point has been supported by experience with a fifth candidate whose proposed transplantation was interdicted by metastases to the diaphragm, which were discovered at the time of operation. This 4-year-old girl died 1½ months later. The four recipients, who received treatment in the cyclosporine era, were 2½ to 21 years of age. Each had cirrhosis and multiple abnormalities of liver function, including prolonged prothrombin time and low-grade hyperbilirubinemia (Table). The diagnosis had been made early in life by the demonstration at established metabolic centers of hypertyrosinemia, tyrosinuria, and marked excretion of tyrosine metabolites in the urine, which were managed with a diet low in tyrosine and phenylalanine. Table Clinical features In three of the patients, elevations of α-fetoprotein (Table) originally aroused suspicion of hepatoma development. However, a definite mass was detectable with computed tomography and other radiographic techniques only in the oldest (patient 1). This patient underwent a right hepatic lobectomy at another hospital, at which time the main portal vein was accidentally tied off; the hepatoma was thought to be cleanly removed. After the right-sided lobectomy, she developed very severe liver failure and was bedridden until the time of transplantation 2 months later. There was no residual tumor in the hepatic remnant. In patient 2 the diagnosis of hepatoma had been suspected after a routine ultrasound examination, and was confirmed by open liver biopsy. Patients 2, 3, and 4 had multiple small hepatomas in all parts of the excised livers. However, the surgical margins were free of tumor. Although the livers were cirrhotic, they were relatively soft. The transplantation procedures were by well-standardized techniques,1,4 except in the child who had undergone right hepatic lobectomy, whose portal vein was thrombosed from the site of surgical ligature back to the confluence of the splenic and superior mesenteric veins. In this recipient a cloaca was fashioned at the superior mesenteric–splenic venous junction, to which a free inferior vena caval graft from the liver donor was anastomosed. The donor portal vein was anastomosed, in turn, to the proximal end of this graft.5 Cyclosporine and prednisone were given intravenously or orally from the time of operation, with rapid weaning from prednisone to maintenance doses, presently 2.5 to 7.5 mg/day. Despite therapy, one of the recipients (patient 2) slowly rejected the graft, and retransplantation was carried out without incident 18 months after the primary procedure. She is well 15½ months after retransplantation. The other three recipients also are well after 3, 7, and 17 months, respectively. The α-fetoprotein levels, which ranged from 4600 to 25,000 ng/ml before liver replacement (or before hepatic resection in patient 1) fell to within the normal range within a few days or weeks, and have remained normal. There has been no evidence of recurrent hepatoma in any patient, and all four now have normal liver function. The metabolic abnormalities characteristic of tyrosinemia were normalized immediately after transplantation, even though the patients were given a regular diet. Detailed studies of amino acid metabolism have been or are being carried out in the referring centers (Table) and will be described separately. It is now thought that hereditary tyrosinemia is caused by fumarylacetoacetate hydrolase deficiency.6–8 In other liver-based inborn errors of metabolism with or without a specific and identifiable enzyme defect, the metabolic phenotype of the graft has remained permanently that of the donor.1,2 Thus the metabolic amelioration in our patients with tyrosinemia should be for the lifetime of the grafts. The use of liver transplantation for “metabolic engineering” has been a tantalizing prospect for a number of years, but the poor results with liver replacement discouraged the wide application of this approach until recently. With the advent of immunosuppression therapy with cyclosporine and steroids, the prognosis after liver replacement has improved so dramatically, particularly in pediatric recipients, that reluctance to go forward with this aggressive therapy has diminished.1 Furthermore, the increasingly recognized risk of hepatoma formation9 is an additional and potent reason to consider liver transplantation at an earlier time and under semielective conditions. In the early days of liver transplantation, efforts to treat hepatomas that could not be excised by conventional techniques resulted in an incidence of tumor recurrence so high that the potential value of the operation was vitiated.1,4 With better patient selection in more recent times, this incidence of recurrence has been reduced,1 and in patients with hepatomas incidental to tyrosinemia, α1-antitrypsin deficiency, sea-blue histiocyte syndrome, or biliary atresia, the incidence of recurrence has been zero. Thus, the threat of late metastases in the four surviving patients with tyrosinemia is not as great as might have been predicted from the older literature.

Acquired immunodeficiency syndrome in the child of a haemophiliac

Oral thrush developed during the second month of life in the 5-month-old son of a patient with haemophilia A. He did not feed well, and interstitial pneumonitis, lymphadenopathy, hepatosplenomegaly, and a cellular immune defect consistent with the acquired immunodeficiency syndrome (AIDS) followed. Both parents had signs of pre-AIDS during the year before their sons illness. Transmission presumably occurred in 3 steps: parenterally, via factor VIII concentrate in the haemophiliac; heterosexually, from the haemophiliac to his wife; and vertically, from mother to infant, or via close paternal-infant or maternal-infant contact. This first report of AIDS in the child of a haemophiliac supports the theory that AIDS is caused by an infectious agent. Concentrate-treated haemophiliacs may transmit this agent to their spouses or children, resulting in pre-AIDS or AIDS.

Hepatic infarction and acute liver failure in children with extrahepatic biliary atresia and cirrhosis

Acute hepatic failure developed in four patients (aged 7 to 13 months) who had extrahepatic biliary atresia treated initially by portoenterostomy. Two were stable outpatients with minimal jaundice, while the other two were hospitalized for metabolic or nutritional complications. Postmortem examination in each patient revealed massive acute hepatic infarction with few surviving hepatocytes. In all cases, the hepatic failure had been preceded by an episode of hypotension and/or hypovolemia. The exact pathogenesis of the infarction remains unclear but it may be related to decreased hepatic blood flow secondary to biliary obstruction. The only effective treatment for these patients is intensive supportive care and urgent liver transplantation.

HIV-1 isolates from children with or without AIDS have similar in vitro biologic properties

Objective: To compare biologic properties of HIV-1 isolates from children with and without AIDS as a measure of viral cytopathogenicity. Patients and participants: Virus isolates from peripheral blood mononuclear cells of 13 perinatally infected children were compared for specific in vitro biologic properties. Methods: Virus isolates were examined for biologic properties as measured by their ability to infect H9 cells and to induce syncytia in susceptible cells. Results: Most of the pediatric HIV-1 isolates failed to infect CD4+ H9 cells and induce syncytia in susceptible cells, regardless of whether they were from children with or without AIDS. All of the isolates, however, grew well in mitogen-stimulated normal adult lymphocytes. These results are in contrast to those with HIV-1 isolates from adults, whose biologic properties were related to the stages of the disease. Conclusions: These results indicate that, unlike adult HIV-1 isolates, the biologic properties of pediatric isolates are not related to the stages of the disease. The rapid development of disease in children may therefore be due to factors other than intrinsic properties of HIV-1 strains present in children. AIDS 1993, 7:1561–1564

Lymphoma and hypercalcemia in a pediatric orthotopic liver transplant patient.

We present a case report of a pediatric orthotopic liver transplant recipient who developed lymphoma with hypercalcemia on cyclosporine and prednisone immunosuppression. This is the first reported posttransplant lymphoproliferative disorder complicated by hypercalcemia, with a finding of an elevated 1,25 dihydroxyl vitamin D state, suggesting that it has a role in the pathophysiology of this B cell lymphoma hypercalcemia. The clinical course and management of this disorder with a 31-month follow-up are described.

Animal-induced injuries and disease, Neonatal jaundice, Viral infections, and Immunizations

This section features recent information in four areas of interest to the practicing pediatrician: animal-induced injuries and disease, neonatal jaundice, viral infections, and immunizations. The focus is on areas of major current discussion: the clinical spectrum and etiology of cat-scratch disease, the debate on new neonatal bilirubin recommendations, viral etiology of previously recognized clinical diagnoses, new immunization recommendations, and new vaccines. In addition, isolated but thought-provoking papers in the four areas over the past year are briefly discussed. By paying careful attention to highlighted articles, the busy practitioner should be able to keep abreast of rapid new developments.