Andrea Richter

Liver Transplantation in Children With Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is caused by mutations of the bile salt export pump or the multidrug resistance P-glycoprotein, resulting in chronic hepatic failure. Partial external diversion of bile or ileal bypass is effective in some cases and, in others, liver transplantation (OLT) is necessary. Forty-two children were included in this study. Twenty-six children suffered from PFIC type 2 and 16 from PFIC type 3. Symptoms included pruritus, cholestasis, liver cirrhosis, and growth retardation. Seventeen patients received external biliary diversion. Ten had to undergo OLT in the following course. As of this report, three of the remaining patients were on the wait list for OLT. Twenty-three children received a liver graft primarily with excellent outcome. Our data show that OLT is the option of choice in symptomatic PFIC and whenever liver cirrhosis is present. We suggest a very restrictive recommendation of external biliary diversion. However, gene therapy may be a future option for children with PFIC.

Neonatal hemochromatosis: long-term experience with favorable outcome.

OBJECTIVE. Neonatal hemochromatosis is a severe, often fatal multiorgan disorder of iron metabolism. Liver transplantation can be curative; the benefit of antioxidant treatment is discussed controversially. We summarize our experience with neonatal hemochromatosis over the past 13 years. METHODS. A retrospective study was performed of 16 patients with acute liver failure attributable to neonatal hemochromatosis between 1992 and 2004. RESULTS. Median age at the onset of neonatal hemochromatosis was 2 days (range: 0–21 days). Median weight at the time of diagnosis was 2900 g (range: 1520–4200 g). All patients had elevated ferritin levels (median: 4179 μg/L), and transferrin saturation (median: 99%). Fourteen patients (87.5%) showed significant hepatocyte siderosis in biopsies; 4 children had additional iron deposition in extrahepatic tissue. Four patients were diagnosed by MRI. Seven infants received liver transplants, 5 of them in combination with a preceding antioxidant treatment. Four children (25%) received antioxidants without the necessity of liver transplantation and were in good clinical condition at the time of this evaluation. Five patients (31.3%) died, 3 of them without any treatment because of initial fulminant multiorgan failure. In September 2005, 68.7% of the patients were still alive after a median follow-up of 5 years. CONCLUSIONS. Neonatal hemochromatosis is a severe metabolic disease, but early antioxidant treatment and liver transplantation in addition to optimal medical care can improve the outcome dramatically. Children with moderate liver failure can survive without liver transplantation, but should be monitored closely for deterioration.

Clinical relevance of autoantibodies after pediatric liver transplantation

Abstract:  Background:  The presence of autoantibodies and development of autoimmune hepatitis after liver transplantation has recently been reported as one of the causes for chronic graft dysfunction. The pathogenesis and clinical significance of this disease still remains unclear.

Emergency Liver Transplantation in Neonates With Acute Liver Failure: Long-term Follow-up

Background. Acute neonatal liver failure is a rare condition that is often fatal. Liver transplantation (LTx) in affected neonates may be life saving, but there are only few data on the long-term outcome of neonatal LTx. Patients and Methods. We conducted a retrospective study of 11 LTx performed in 10 pediatric patients with acute liver failure in the first month of life. Median age at LTx was 15 days (range: 7–31 days) and median weight was 3.25 kg (range: 2–4 kg). The reasons for liver failure were neonatal hemochromatosis (n=5), hemangioendothelioma (n=2), infection caused by echovirus type 11 (n=1), mitochondrial disorder (n=1), unknown (n=1), and primary nonfunction after LTx (n=1). In 10 patients, LTx organs of deceased donors were used (reduced size n=5, split n=5), and living donor LTx was performed in one neonate. The patients were evaluated with respect to survival, graft function, perioperative complications, and neurodevelopmental outcome. Results. After a median follow-up time of 5 years (range: 1–14 years), 8 of 10 patients (80%) were alive. Seven of them were in good clinical condition and had normal liver function tests. One patient had to undergo retransplantation because of primary nonfunction and another is currently listed for retransplantation because of chronic graft dysfunction. Neurodevelopment was normal in 75% of the surviving patients. Conclusions. Liver transplantation provides good short- and medium-term results in neonatal acute liver failure.

Tacrolimus-induced cholestatic syndrome following pediatric liver transplantation and steroid-resistant graft rejection.

Abstract:  Several factors may contribute to post‐transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus‐based immunosuppression following liver transplantation and all of them suffered from previous steroid‐resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid‐resistant graft rejection, even if given in therapeutic doses.

Hepatoblastoma in a child with progressive familial intrahepatic cholestasis

Abstract:  End‐stage liver cirrhosis because of metabolic or infectious diseases predisposes to hepatic malignancies like hepatocellular carcinoma. We report the first case of hepatoblastoma incidentally detected in the explanted liver of a 2‐yr‐old child undergoing liver transplantation for cirrhosis because of progressive familial intrahepatic cholestasis (PFIC). The diagnosis was difficult to obtain. The hepatoblastoma was not seen on ultrasound examination of the cirrhotic liver. As we could confirm retrospectively, alpha fetoprotein (AFP) was found elevated prior to transplantation. Two years after successful transplantation, there are no signs of malignancy detectable by clinical and radiological methods. We conclude from this case that PFIC may induce hepatoblastoma and that children with liver cirrhosis should undergo routine screening of serum AFP concentration.

Hypogammaglobulinemia in pediatric liver transplant recipients.

Abstract:  Hypogammaglobulinemia has been reported after solid organ transplantation in adults, however immunoglobulin replacement [intravenous immunoglobulins (IVIG)] is only necessary in a minority of affected patients. We here present three pediatric patients with severe post‐transplant hypogammaglobulinemia following liver transplantation (LTx) receiving a cyclosporine‐based standard immunosuppression. Patient 1 was transplanted at the age of 10 months for biliary atresia. Eight weeks post‐Ltx the serum IgG was 1.7 g/L. Patient 2 was transplanted at the age of 12 yr for acute liver failure. Four weeks post‐Ltx the IgG dropped to 2.6 g/L. Patient 3 was transplanted at the age of 4 months for biliary atresia. Ten weeks post‐Ltx severe hypogammaglobulinemia (IgG < 1.48 g/L) was diagnosed during a severe infectious complication. Patients 1 and 3 received a steroid bolus therapy for acute graft rejection. All patients had normal IgG concentrations prior to Ltx and lymphocyte subsets were post‐operatively in the normal range. There was no extensive loss of protein by ascites. IGIV were replaced in the three patients monthly without further complications. In two of the patients (1 and 3) IVIG therapy was discontinued 8 and 10 months after Ltx when the immunosuppression has been reduced and serum IgG concentrations were found in the normal range without further immunoglobulin replacement. Severe hypogammaglobulinemia is a rare phenomenon following pediatric LTx and seems to be mainly caused by immunosuppressive drugs, however, the exact underlying mechanisms are unclear. A screening for hypogammaglobulinemia is useful after pediatric LTx, especially in patients with an intensified immunosuppression. Moreover, further immunologic research in affected patients is necessary.

Neonates with severe infantile hepatic hemangioendothelioma: Limitations of liver transplantation

Abstract:  IHHE as the most common vascular tumor of the liver in infancy can present with acute postnatal liver and congestive heart failure. LTx may be a lifesaving option, but can be complicated by extrahepatic involvement and bleeding complications, especially in neonates. Here we discuss the benefit of LTx in cases of acute postnatal deterioration and massive extent of the hepatic tumor. Three infants with IHHE were transplanted at our institution between 2005 and 2007. Two were neonates with acute postnatal decompensation and progressive liver and heart failure within days. Treatment with steroids and chemotherapy was ineffective; resection surgery and interventional treatment were not considered appropriate. LTx was performed at the age of 7 and 24 days, respectively. An additional infant with a bilobar tumor that evolved more slowly was transplanted on day‐of‐life 56. Patients 1 and 2 had to be resuscitated during the LTx procedure because of massive bleeding and both died during the procedure. Patient 3 had a complicated post‐operative course but is doing well one‐yr post‐LTx. Neonates with extended hepatic and extrahepatic involvement of IHHE should be evaluated carefully prior to LTx. Whenever possible, alternative interventional treatment options should be considered.

Analysis of the CC chemokine receptor 5Δ32 polymorphism in pediatric liver transplant recipients

Abstract:  In adult liver graft recipients, it has been shown that certain chemokine polymorphisms (CCR5Δ32) may correspond to ischemic type biliary lesions leading to chronic graft dysfunction. The aim of our present study was to assess the importance of CCR5Δ32 polymorphism in a cohort of pediatric liver graft recipients with regard to acute or chronic graft dysfunction. A total of 137 children post‐liver transplantation have been included for genetic analysis (CCR5Δ32 polymorphism), and the incidence of acute and chronic graft dysfunction was analyzed. The most common diagnosis leading to LTx was biliary atresia (56.2%), the median age was 14 months, and 33.5% of the patients received a living‐related graft. In all, 110 of the subjects were found to have the CCR5 wild type, 25 children were heterozygous for CCR5Δ32, and two patients were homozygous. Of 137, 44 (32.1%) developed acute graft rejection, nine out of 137 (6.6%) chronic graft dysfunction (vanishing bile duct syndrome), and 84 (61.3%) children had neither acute nor chronic graft rejection. There was no significant correlation between acute graft rejection or chronic graft dysfunction and the CCR5Δ32 allele in the study population. We conclude that CCR5Δ32 polymorphism may not play a role in acute or chronic liver graft dysfunction in children.

Neonatal cholestasis and glucose-6-P-dehydrogenase deficiency†

We report a Caucasian neonate with chronic non‐spherocytic hemolytic anemia due to a class I G6PD deficiency. A novel mutation missense mutation in exon eight of the G6PD gene was detected (c.827C>T p.Pro276Leu). Bilirubin peaked on day 5 at 24 mg/dl with a conjugated bilirubin of 17 mg/dl. Jaundice resolved within 4 weeks. A detailed work‐up failed to reveal other specific factors contributing to cholestasis. Severe hemolytic disease of the newborn may cause cholestasis even in the absence of associated primary hepato‐biliary disease. Pediatr Blood Cancer 2010;54:758–760.