J. Jeffrey Malatack

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.

Treatment of Neonatal Hemochromatosis with Exchange Transfusion and Intravenous Immunoglobulin

OBJECTIVE To determine if immunomodulatory treatment including intravenous immunoglobulin (IVIG) can favorably affect survival in neontatal hemochromatosis (NH) diagnosed postnatally because it can effectively prevent occurrence of NH when applied during gestations at risk. STUDY DESIGN We treated 16 newborn infants with liver failure due to NH with high-dose IVIG, in combination with exchange transfusion in 13 (ET/IVIG), and compared the outcome with 131 historical controls treated conventionally. RESULTS The severity of liver disease as estimated by prothrombin time was similar in the subjects receiving ET/IVIG and the historical controls, and the medical therapy was equivalent with the exception of the ET/IVIG therapy. Twelve subjects (75%) had good outcome, defined as survival without liver transplantation, whereas good outcome was achieved in only 17% (23/131) of historical control patients (P < .001). Four subjects died, 2 without and 2 after liver transplant. Survivors were discharged 6 to 90 days after receiving ET/IVIG therapy, and those followed for more than 1 year are within normal measures for growth, development, and liver function. CONCLUSIONS Immune therapy with ET/IVIG appears to improve the outcome and reduce the need for liver transplantation in patients with NH.

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.

Liver and kidney transplantation in children receiving cyclosporin A and steroids

The new immunosuppressive agent, cyclosporin A, was used with low doses of steroids to treat eight patients undergoing hepatic transplantation and three patients undergoing cadaveric renal transplantation. Seven of the eight liver recipients are well, including one who was given two livers. The three kidney recipients who had developed cytotoxic antibodies after previously rejecting grafts with conventional immunosuppressive therapy, have had good results despite conditions which usually preclude attempts at transplantation. The ability to control rejection effectively and safely without chronic high-dose steroid therapy may make the described therapeutic regimen valuable for pediatric recipients of whole organs.

Echocardiographic findings before and after liver transplantation

Echocardiographic studies were performed in 73 patients with various types of chronic liver disease. They were 0.5 to 19 years old (mean 5). Thirteen patients underwent follow-up echocardiography 1 to 13 months (mean 6) after liver transplantation. Preoperatively 60 patients (82%) showed evidence of high cardiac output (cardiac index greater than 4 liters/min/m2); these patients manifested increased left ventricular (LV) and left atrial dimensions and a thickened LV posterior wall. Transvenous contrast echocardiographic study confirmed the presence of intrapulmonary arteriovenous shunting in 4 patients. Studies after liver transplantation revealed a reduced LV end-diastolic dimension in 12 patients. Cardiac index was reduced a mean of 35% after transplantation (p less than 0.001). This study suggests that liver transplantation improves common hemodynamic abnormalities in chronic liver disease.

Isolated Congenital Malabsorption of Folic Acid in a Male Infant: Insights Into Treatment and Mechanism of Defect

An instructive case of isolated congenital folate malabsorption provides insight into the understanding of this rare disease. Folate loading tests with both timed serum and cerebrospinal fluid folate determinations suggest that both of the two mechanisms involved in gastrointestinal folate absorption are defective in this condition.

Failure of immunosuppressive drug levels to predict T-cell reactivity in pediatric transplant patients.

PURPOSE In children, therapeutic management of immunosuppression relies on allograft function, drug levels, and clinical insight. Using a Food and Drug Administration-approved test for T-cell response, T-cell activation in vitro can be measured to monitor the immune response. METHODS In a retrospective study, 92 posttransplant children who received either a liver and/or kidney transplant and were followed by routine screening had their T-cell response tested by the Cylex ImmuKnow assay (Columbia, MD). After phytohemagglutinin-L stimulation of T-cells, adenosine triphosphate (ATP) concentrations were measured. In this assay, light emission at lambda = 562 nm is proportional to the ATP concentration (ng/mL). Immunosuppressive drug trough levels were also measured. Quantitative real-time polymerase chain reaction Epstein-Barr virus (EBV) viral titers were determined for 2 patients. RESULTS Separating the results into younger than 12 years and 12-year or older populations, we found that for the younger than 12 years, 28% of patients were in the low immune function category, 47% in the moderate, and 25% in the high category. For the 12 years or older, 25% of patients were in the low immune function category, 47% in the moderate, and 28% in the high category. The immune function distribution was not different (P = not significant) between the younger than 12 years and 12-year or older groups. Tacrolimus trough levels were 6.3 +/- 2.4 ng/mL for younger than 12 years and 5.6 +/- 3.3 ng/mL for 12 years or older (P = not significant), and rapamycin was similar, but both showed no correlation to immune function. We observed increased ATP values with decreased EBV viral loads. CONCLUSIONS These results suggest that tacrolimus and/or rapamycin levels do not adequately determine the biologic effect of immunosuppression. We expect that future T-cell activation monitoring will allow us to diminish rejection and infection events posttransplantation and lead to a healthier pediatric transplant population.

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.

Liver transplantation as treatment for familial homozygous hypercholesterolemia: Too early or too late

In 1982, now nearly 30 yr ago, Starzl et al. (1) reported on the first orthotopic liver transplantation performed outside the usual setting of a failing liver. Performed, rather, for familial homozygous hypercholesterolemia, this was likely the first time that an anatomically normal appearing liver was surgically removed. It is notable that Starzl s six-yr-old patient underwent not only orthotopic liver transplantation as presumptive treatment for the hypercholesterolemic state but also heart transplantation to replace the native organ, which had been ravaged by arteriosclerotic heart disease and multiple ischemic myocardial infarctions. It was only in the years preceding this procedure that the biology of cholesterol metabolism had been established by Brown and Goldstein (2), groundbreaking work for which they were subsequently awarded the Nobel Prize in Physiology or Medicine in 1985. Through their research, Brown and Goldstein recognized that homozygous hypercholesterolemia was in large part a manifestation of an intrinsic hepatocyte defect, specifically a reduction in LDL cholesterol (LDL-c) hepatocyte receptors leading to loss of cholesterol homeostasis, which in turn leads to extraordinary elevation in serum LDL-c (2). The patient described in the 1982 Starzl report eventually died because of intractable myocardial dysfunction/arrhythmia that was a manifestation of cardiac allograft rejection. However, the child did survive long enough to establish unequivocal clinical support of the Brown s and Goldstein s thesis as a much improved, though not normalized, serum lipid profile was documented. The article by Maiorana et al. appearing in this issue of Pediatric Transplantation raises the issue of whether liver transplantation for medically uncontrolled hypercholesterolemia is warranted before there are any indications of arteriosclerotic vascular disease. It also begs a question regarding the patient in the Starzl report. Had that child received successful orthotopic liver transplantation in the first year(s) of life, would the cardiovascular disease have been avoided, and, therefore, the necessity for heart transplantation circumvented, resulting in a longer-term survivorship? The manuscript prompts additional questions, the most obvious of which are the medical concerns raised whenever one extends the indications for a known therapy into a new area. These are questions regarding cost/benefit ratio of the old procedure for this new indication. Liver transplantation has had a remarkable evolution with improvement in outcome from its inception in the 1960s until coming of age with the use of calcineurin therapy in the 1980s (3). The evolution has continued since the 1980s such that the most recent series indicate a five-yr survival rate nearing the 90% range (4), and even higher for metabolic transplantations in which the abdomen is naive to the surgeon s knife at the time of the transplantation surgery. Liver transplantation or, for that matter, any critical organ transplantation is not without both short-term and long-term risk. Maiorana appreciates these risks but it is worth reiterating the more important of these here. There exists an immediate post-transplantation surgical complication risk that accounts for a significant portion of both those grafts that fail and patients who die. While these risks have been reduced in frequency since the early 1980s, they have not been eliminated. Renal dysfunction with or without hypertension to varying degree is a constant when calcineurin inhibitors are used as the primary immune suppressor (calcineurins remain the state of the Pediatr Transplantation 2011: 15: 123–125 2011 John Wiley & Sons A/S.