Basil J. Zitelli

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.

SUCCESSFUL TREATMENT OF HOMOZYGOUS PROTEIN C DEFICIENCY BY HEPATIC TRANSPLANTATION

A child with homozygous protein C deficiency was treated at age 20 months by orthotopic hepatic transplantation. Postoperatively there was complete reconstitution of protein C activity and resolution of the thrombotic condition.

Cyclosporine Absorption Following Orthotopic Liver Transplantation

Blood concentrations of cyclosporine were determined in adult and pediatric patients following orthotopic liver transplantation to quantitate cyclosporine blood clearance and oral absorption. Seventeen bioavailability studies were performed following transplantation surgery in nine children and seven adults. The intravenous cyclosporine study was performed following an average dose of 2.1 mg/kg. The patients were again studied when they received the same intravenous dose plus an oral dose of cyclosporine of 8.6 mg/kg or an oral dose alone. Blood samples were collected and analyzed for cyclosporine using high‐performance liquid chromatography. Cyclosporine blood clearance ranged from 29 to 203 mL/min (1.9–21.5 mL/min/kg) in children and from 253 to 680 mL/min (3.2–7.6 mL/min/kg) in adults. The mean cyclosporine clearance value was 9.3 mL/min/kg in the pediatric patients and 5.5 mL/min/kg in the adults. Cyclosporine bioavailability was less than 5% in six studies on five pediatric patients in the immediate postoperative period. The bioavailability varied from 8% to 60% in adult liver transplant patients (mean, 27%). We conclude that: (1) cyclosporine clearance is highly variable between patients, (2) pediatric patients clear the drug more rapidly than adults and therefore need a higher cyclosporine dose on a body weight basis, (3) cyclosporine is poorly and variably absorbed in liver transplant patients, and (4) cyclosporine blood concentration monitoring is essential following orthotopic 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.

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.

Fatal Hepatic Necrosis Due to Pyrimethamine-Sulfadoxine (Fansidar)

Pyrimethamine-sulfadoxine has been associated with severe and fatal cutaneous reactions as well as transient liver damage. We report the case of a patient who died of progressive hepatic failure caused by pyrimethamine-sulfadoxine administration. In addition, we summarize reports made to the Food and Drug Administration since 1982 that focus on hepatotoxic reactions to pyrimethamine-sulfadoxine. We suggest that fatal hepatic injury can occur after treatment with pyrimethamine-sulfadoxine and that physicians who prescribe the drug should be aware of this possibility.

Erythromycin-induced Drug Interactions An Illustrative Case and Review of the Literature

The authors report a case of erythromycin-induced carbamazepine toxicity in a 6-year-old child following use of erythromycin ethylsuccinate (50 mg/kg/day). Within 5 days of erythromycin use, vomiting, weakness, lethargy, ataxia, nystagmus, and cogwheeling movements developed. A serum carbamazepine concentration had increased from 11.9 mg/L (measured 1 week prior to antibiotic use) to 25.8 mg/L. Following erythromycin withdrawal, serum concentrations returned toward baseline, and symptoms resolved. Erythromycin has known effects on hepatic enzyme function, with altered cytochrome P-450 function. The dramatic reduction in carbamazepine clearance observed in this patient is similar to that reported when erythromycin is used concurrently with other drugs. A brief review of potentially significant erythromycin drug interactions is presented.