Lorenzo D'Antiga

Isolated Hepatocyte Transplantation for Crigler-Najjar Syndrome Type 1:

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 × 109 hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean ± SD bilirubin level was 530 ± 38 μmol/L before and 359 ± 46 μmol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure.

Liver and Cardiac Function in the Long Term After Fontan Operation

BACKGROUND Patients who underwent Fontan operation have some degree of liver disease. We aimed to assess the long-term liver and cardiac function after Fontan operation. METHODS Patients enrolled underwent physical examination, biochemical tests (aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, bilirubin, international normalized ratio, coagulation factor V, protein profile, fecal alpha-1-antitrypsin), echocardiogram, and liver ultrasonography. A liver disease score was adopted to compare the degree of liver involvement with hemodynamic features. RESULTS The study enrolled 34 patients, median age 14.7 years (range, 4.1 to 26.7), 26 with a residual left ventricle, 8 with a residual right ventricle, affected by tricuspid atresia (17), pulmonary atresia (4), hypoplastic left heart syndrome (5), double-outlet right ventricle (2), single left ventricle (2), and miscellaneous (4), with median follow-up of 11.5 years (range, 1.7 to 23.3). We found hepatomegaly in 18 of 34 (53%), splenomegaly in 3 of 33 (9%), abnormal transaminases in 10 of 33 (30%), elevated gamma GT in 19 of 31 (61%), elevated bilirubin in 10 of 31 (32%), coagulopathy in 17 of 29 (58%), and protein-losing enteropathy in 4 of 21 (19%). Median heart rate z-score was -1.72. Hepatic dysfunction was strictly correlated to low cardiac index (r(2) = 0.34, p = 0.008) and to a lesser extent to reduced heart rate (r(2) = 0.18, p = 0.07). CONCLUSIONS In children who underwent Fontan operation, hepatic dysfunction is correlated with low cardiac index and reduced heart rate. Maintaining or reestablishing a normal cardiac index might prevent or reduce liver disease in the long-term.

Neonatal hemochromatosis - medical treatment vs. transplantation : The King's experience

The aim of our study was to compare the outcome of medical treatment vs. liver transplantation in infants with neonatal hemochromatosis (NH) referred to Kings College Hospital from 1990‐2002. We conducted a retrospective review of 19 children from 14 families. Fifteen children presented at birth and 4 during the first week of life. One child was diagnosed by cordocentesis at 30 weeks of gestation. NH recurred in 7 of 9 families with further children. In one family, 2 children from different fathers were affected. All patients had elevated ferritin levels, hypoalbuminemia, and coagulopathy. Liver histology showed parenchymal collapse, diffuse fibrosis, and moderate to severe hepatocyte hemosiderin deposition. Extrahepatic siderosis was demonstrated by magnetic resonance in 2 patients, lip biopsy in 3, and autopsy in 10. Ten patients received a chelation‐antioxidant cocktail: 1 survived, 4 died, and 5 required liver transplantation, of whom 2 died. One of the 9 infants who did not receive the cocktail survived with medical support, 3 died, and 5 required transplantation, of whom 3 died. Seven children are alive, 5 after transplantation, at a median follow‐up of 5.6 years, with excellent quality of life and no recurrence of the disease. In conclusion, chelation‐antioxidant treatment does not appear to modify the prognosis of NH, at least in severe cases. Liver transplantation, with 50% long‐term survival, remains the treatment of choice and should be promptly offered to those infants who do not improve with supportive medical treatment. (Liver Transpl 2005;11:1417–1424.)

Late cellular rejection in paediatric liver transplantation : aetiology and outcome

Background. Acute cellular rejection, though mostly encountered during the first 3 months after liver transplant, may occur later on. Clinical features and outcome of children experiencing late cellular rejection (LCR) have not been described to date. Patients and Methods. A total of 20 children who developed acute rejection 6 months or more after liver transplant were studied for history of early rejection, levels of immunosuppression, causes of low immunosuppression, viral infections, signs of autoimmunity, and HLA mismatch. All liver biopsies were reviewed. Fifteen patients with no history of LCR were randomly selected as controls. Results. Of 20 children 5 were appropriately immunosuppressed, although 15 were not. Causes of low immunosuppression were: unknown (seven), poor compliance (three), posttransplant lymphoproliferative disease, (two), hepatocellular carcinoma recurrence (one), tuberculosis (one), gastroenteritis (one). Of 20 patients early rejection occurred in 13 and cytomegalovirus infection in 5. At last follow‐up 10 children have persistent graft dysfunction, of whom 5 have progressed to de novo autoimmune hepatitis, 2 to chronic rejection, one has persistent graft dysfunction with recurrent cytomegalovirus activation, one has hepatic artery thrombosis and one is likely to have persistent poor compliance. None of the 15 controls developed de novo autoimmune hepatitis or any other form of persistent graft dysfunction at the time of last follow‐up. Conclusion. Late cellular rejection in children is usually due to low or decreased immunosuppression and is associated with long‐term complications. Prompt intervention to correct inadequate immunosuppression and careful follow‐up of the other patients to identify other treatable conditions is essential.

Intestinal absorption and permeability in paediatric short-bowel syndrome: a pilot study.

BACKGROUND Sugar absorption tests are an effective, noninvasive way to assess intestinal permeability. The role of intestinal barrier integrity in complications and outcome of short-bowel syndrome is not known. The purpose of the study was to evaluate whether such tests provide information on the status of intestinal mucosa of these patients. METHODS Six children with short-bowel syndrome--median age, 12 months, and median small bowel length at birth, 30 cm--had a sugar test with 3-o-methyl-D-glucose, D-xylose, D-rhamnose, and melibiose approximately 2 months after operation. The melibiose/L-rhamnose ratio was used as an index of permeability, and percentages of 3-o-methyl-D-glucose and D-xylose absorbed were used as indices of absorption. Parenteral nutrition requirement, bowel length, liver disease, recent sepsis, and bacterial overgrowth were recorded. RESULTS Three patients had increased permeability, and all of them had had a recent episode of sepsis and severe liver disease. All subjects had malabsorption of 3-o-methyl-D-glucose, and five of six had malabsorption of D-xylose and L-rhamnose. The absorption of 3-o-methyl-D-glucose correlated with bowel length (r2 = 0.78; P = 0.04), whereas the absorption of D-xylose correlated with parenteral requirement (r2 = 0.66; P = 0.04) at that time. CONCLUSIONS Increased permeability was observed in three of six patients with short-bowel syndrome associated with a recent episode of sepsis and severe liver disease. Other indices of malabsorption correlated significantly with different clinical features of the disease. A prospective larger scale study in a homogeneous population is indicated to assess at multiple points during the disease course whether the test can be helpful in the management of these patients.

Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation.

Background. Osteodystrophy is a well-described complication of chronic liver disease. Previous reports in adults and children undergoing liver transplantation (LT) were discordant, with the former showing no improvement of bone disease in the first year after transplantation and the latter demonstrating remarkable benefit from it. Our aim was to perform a pilot study on osteodystrophy in children undergoing LT and evaluate the contribution of growth on bone mineral density (BMD) changes. Methods. We studied six patients (two male), with a median age at transplantation of 8.8 (range 3.8–16.6) years. Indications for transplantation were biliary atresia and progressive familial intrahepatic cholestasis (three patients each). BMD was studied with dual-energy x-ray absorptiometry and biochemical markers of liver and bone function in patients before and at 3, 6, and 12 months after LT. Results. Median L2-L4 spinal BMD was 0.54 g/cm2 (range 0.29–0.87) before LT, and 0.58 g/cm2 (0.27–0.86) at 3 months, 0.66 g/cm2 (0.36–1.00) at 6 months, and 0.76 g/cm2 (0.44–1.02) at 12 months after LT (P =0.005). Median height was 133 (range 93–167) cm before LT, and 134 (93–167) at 3 months, 136 (97–167) at 6 months, and 139 (102–167) at 12 months after LT. There was direct correlation between height gain and total body BMD improvement (r =0.929, P =0.007). Conclusion. BMD in children with chronic cholestatic liver disease improves remarkably by 12 months after LT. Catch-up growth in children can account for the different effect of LT on bone density between adult and pediatric populations in the first year after surgery.

Sustained Epstein-Barr virus detection in paediatric liver transplantation. Insights into the occurrence of late PTLD

Epstein‐Barr virus (EBV) infection is the main cause of post‐transplant lymphoproliferative disease (PTLD). Little is known on chronic carrier state and its relation with late PTLD. We aimed to study EBV infection in the long‐term after paediatric liver transplantation (OLT). We conducted a retrospective review of 34 children monitored for a median of 5.8 years (range 1.5‐17.7). 21 were IgG seronegative (group A) and 13 seropositive (group B) before OLT. Primary infection was the appearance of VCA‐IgM or VCA‐IgG or Real‐Time Polymerase Chain Reaction (RT‐PCR) in patients previously IgG seronegative; positive VCA‐IgM or EA‐IgG or RT‐PCR lasting longer than 6 months was defined sustained viral detection (SVD). 18/21 patients of group A had a primary infection at a median time of 3 months after transplant (0.5‐60). 14/18 of group A and 0/13 of group B had a SVD (P < 0.0001). Viral loads greater than 500 copies/10mononuclear cells occurred in 12/18 patients in group A and 0/13 patients in group B (P < 0.0001). The 3 patients who developed late PTLD (median time after OLT 47 months, range 15‐121) were from group A, and presented with SVD before developing PTLD. In conclusion, EBV infection in seronegative patients at OLT is associated with greater viral loads and sustained viral detection. Late PTLD occurred only in naïve patients with markers of SVD. Three to 4 monthly long‐term monitoring of EBV in pre‐OLT naïve patients might help preventing the occurrence of late PTLD. Liver Transpl 13:343‐348, 2007. 2006.

Features predicting unresectability in hepatoblastoma

Approximately 20% of patients who have hepatoblastoma (HB) still have unresectable disease after preoperative chemotherapy (POC). In these circumstances, orthotopic liver transplantation (OLT) should be performed 1 month after POC. The authors sought to identify presenting features that would predict unresectability in patients with HB and to provide suggestions for early referral and listing for OLT.

Results of a Stepwise Approach to Extrahepatic Portal Vein Obstruction in Children

Background: The management of extrahepatic portal vein obstruction (EHPVO) in children is controversial. We report our experience with a prospective evaluation of a stepwise protocol based on severity of portal hypertension and feasibility of mesoportal bypass (MPB). Methods: After diagnosis, children with EHPVO underwent surveillance endoscopies and received nonselective &bgr;-blockers (NSBBs) or endoscopic variceal obliteration (EVO) when large varices were detected. In patients who failed NSBBs and EVO, we considered MPB as first-line and shunts or transjugular intrahepatic portosystemic shunt (TIPS) as second-line options. Results: Sixty-five children, median age 12.5 (range 1.6–25.8), whose age at diagnosis was 3.5 (0.2–17.5) years, were referred to our unit. Forty-three (66%) had a neonatal illness, 36 (55%) an umbilical vein catheterisation. Thirty-two (49%) presented with bleeding at a median age of 3.8 years (0.5–15.5); during an 8.4-year follow-up period (1–16), 43 (66%) had a bleeding episode, 52 (80%) were started on NSBBs, 55 (85%) required EVO, and 33 (51%) required surgery or TIPS. The Rex recessus was patent in 24 of 54 (44%), negatively affected by a history of umbilical catheterisation (P = 0.01). Thirty-four (53%) patients underwent a major procedure: MPB (13), proximal splenorenal (13), distal splenorenal (2), mesocaval shunt (3), TIPS (2), and OLT (1). At the last follow-up, 2 patients died, 53 of 57 (93%) are alive with bleeding control, 27 of 33 (82%) have a patent conduit. Conclusions: Children with EHPVO have a high rate of bleeding episodes early in life. A stepwise approach comprising of medical, endoscopic, and surgical options provided excellent survival and bleeding control in this population.

Titration of bile acid supplements in 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase/isomerase deficiency.

Objectives: 3β-Hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency is a bile acid synthesis defect responsive to primary bile acids. We reviewed its clinical features and response to treatment with a mixture of ursodeoxycholic (UDCA) and chenodeoxycholic acid (CDCA) to titrate the dose of supplements required for disease control. Patients and Methods: We studied our patients by liquid chromatography-tandem mass spectrometry, liver function tests, and histology. After diagnosis all of the patients received a balanced mixture of UDCA/CDCA and the dose was titrated according to urinary levels of 3β,7α-dihydroxy-5-cholenoic acid (u-3β-D-OH-5C). Results: Five patients presenting with giant cell hepatitis, biliary cirrhosis, and cryptogenic cirrhosis (1 each), and picked up by neonatal screening (2 patients) were diagnosed at a median age of 2.5 years (range 0.1–5.5). Normal levels of u-3β-D-OH-5C were achieved after 4 months (range 3–28 months) from the start of the treatment. The minimum dose of UDCA/CDCA required to maintain normal u-3β-D-OH-5C levels was 5/5 mg · kg−1 · day−1. A follow-up biopsy in 2 patients showed no progression of liver disease. Conclusions: A mixture of UDCA/CDCA can effectively control 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase deficiency. Dose titration by liquid chromatography-tandem mass spectrometry warrants the maintenance of negative feedback on the abnormal synthetic pathway and avoids disease progression.