Liver disease associated with ZZ alpha1-antitrypsin deficiency and ursodeoxycholic acid therapy in children.

OBJECTIVES: To investigate the effect of ursodeoxycholic acid (UDCA) in children with liver disease associated with ZZ alpha1-antitrypsin (AAT) deficiency. PATIENTS AND METHODS: A total of 42 affected children received UDCA (30 mg x kg x day(-1)) and underwent clinical and biochemical follow-up at least yearly. RESULTS: In group 1, 22 children whose mean initial gamma-glutamyl-transpeptidase (GGT) was 7.4 x N normalized serum liver test results after a mean treatment of 2.6 years. In 16 of these children, UDCA was discontinued. Relapse was observed in 11 children, and liver test results returned to normal after UDCA resumption. In the other 5 children, liver test results remained normal during a mean period of 2.5 years. In group 2, 11 children (mean initial GGT 12.8 x N) had improved liver test results after a mean treatment of 2.3 years. In group 3, 9 children (mean initial GGT 33.8 x N) had no liver test result improvement and evolution toward cirrhosis, requiring liver transplantation in 7. Most of the children in group 1 had normal results of clinical examination after UDCA treatment, versus none in group 3 (P < or = 0.00001). Initial GGT (P < or = 0.002) and total bilirubin (P < or = 0.05) levels were significantly lower in group 1 than in group 3. Combined initial values of GGT < or =5.5 x N and total bilirubin < or =66 micromol/L were associated with normalization of liver test results in 90% of children. CONCLUSIONS: UDCA may significantly improve clinical status and liver test results in some children with liver disease associated with ZZ AAT deficiency. No beneficial effect of UDCA was shown in children with the most severe liver involvement. Initial levels of GGT and total bilirubin may be of prognostic value for therapy effectiveness.

Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver.

To define the long-term prognosis of children undergoing the Kasai operation for biliary atresia, a retrospective study was undertaken comprising 271 patients operated between 1968 and 1983. Twenty years after surgery, 63 (23%) were alive with their native liver. Serum bilirubin was normal in 21 of these patients, 12 also had normal serum aminotransferase and gamma-glutamyltransferase activities, all but 2 had signs of cirrhosis, 44 had signs of portal hypertension, 19 had late bacterial cholangitis, and 6 had gallstones. Seven female patients gave birth to 9 children, and 3 male patients fathered 6 children. After age 20, 2 patients died of liver failure and 14 underwent or are awaiting liver transplantation. Twenty-year survival with native liver was significantly better in children with biliary atresia restricted to the hepatic ducts or with cysts at the porta hepatis. In conclusion, in the long term, less than 18% of infants with biliary atresia who are treated with corrective surgery may avoid liver transplantation, but even these patients require assiduous lifelong care.

Tacrolimus and steroids versus ciclosporin microemulsion, steroids, and azathioprine in children undergoing liver transplantation: randomised European multicentre trial.

BACKGROUND: Results of studies in adult recipients of liver allograft suggest that tacrolimus is more efficacious than ciclosporin microemulsion in the prevention of acute rejection. We aimed to compare these drugs in children undergoing liver transplantation. METHODS: This 12-month multicentre, open-label, parallel-group, randomised study compared a dual tacrolimus regimen (tacrolimus/corticosteroids, n=93) with a triple ciclosporin microemulsion regimen (ciclosporin microemulsion/corticosteroids/azathioprine, n=92) in children who had had liver transplants (age < or =16 years, bodyweight < or =40 kg). Initial oral daily doses were 0.30 mg/kg for tacrolimus and 10 mg/kg for ciclosporin microemulsion. Primary endpoint was the incidence of and time to first histologically proven acute rejection. We excluded patients from analysis if they did not receive the study drug, or were given incorrect medication. Otherwise patients were analysed in accordance with their random treatment allocation, irrespective of whether they switched medication during the trial. FINDINGS: Median age was 22 months (IQR 9-56) in the tacrolimus group and 17 months (9-54) in the ciclosporin microemulsion group. We noted no difference between treatment groups with respect to patient survival (93.4% vs 92.2%; p=0.77) or graft survival (92.3% vs 85.4%; p=0.16) at month 12 after transplant. The acute rejection free rate at study end (Kaplan-Meier method) was 55.5% for patients on tacrolimus and 40.2% for patients on ciclosporin microemulsion (p=0.0288). The Kaplan-Meier estimate of patients free from corticosteroid-resistant acute rejection at study end was 94.0% for tacrolimus-treated patients and 70.4% for ciclosporin-microemulsion-treated patients (p<0.0001). Overall, incidence of adverse events did not differ between groups. INTERPRETATION: Tacrolimus is a safe and effective treatment for the prevention of rejection after liver transplantation in children.

Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.

BACKGROUND/AIMS: Progressive familial intrahepatic cholestasis characterized by normal serum gamma-glutamyltransferase activity can be due to mutations in familial intrahepatic cholestasis type 1 (FIC1) (ATP8B1), a gene expressed in several organs. In some cases, it is associated with extrahepatic features. We searched for FIC1 mutations and analyzed the outcome of extrahepatic features after liver transplantation in two children with this form of progressive familial intrahepatic cholestasis associated with chronic unexplained diarrhea and short stature. METHODS: FIC1 sequence was determined after polymerase chain reaction (PCR) of genomic lymphocyte DNA and/or reverse transcription-PCR of liver or lymphocyte RNA. RESULTS: A homozygous amino acid change deletion was found in one child. The second child harboured compound heterozygous missense and nonsense mutations. In both children, despite successful liver transplantation, evolution (follow-up: 9.5-11 years) was characterized by exacerbation of diarrhea and no catch-up of stature growth, and appearance of liver steatosis. CONCLUSIONS: Progressive familial intrahepatic cholestasis characterized by normal serum gamma-glutamyltransferase activity and extrahepatic features corresponds to progressive familial intrahepatic cholestasis type 1. Extrahepatic symptomatology is not corrected or may be aggravated by liver transplantation, impairing life quality.

Clostridium difficile colitis associated with inflammatory pseudotumor in a liver transplant recipient.

The aim of this report is to describe a rare complication of clostridium difficile (CD) disease, the occurrence of an inflammatory pseudotumor that caused intestinal obstruction in a liver transplant recipient. A 9-month-old girl underwent liver transplantation for biliary atresia. She was given tacrolimus as primary immunosuppressive therapy. Three months after liver transplantation, she presented with febrile protracted bloody diarrhea and failure to thrive. A diagnosis of post-transplant lymphoproliferative disease associated with Epstein-Barr virus infection was initially made on histological examination of duodenal biopsies. Tacrolimus was discontinued. Despite treatment with anti-CD20 monoclonal antibodies the child's condition deteriorated and she presented with intestinal occlusion. A mass at the ascending colon was seen on the computed tomography scan mimicking lymphoma and the child underwent surgical laparotomy. Histological examination of the mass showed typical pathological lesions of inflammatory pseudotumor and CD pseudomembranous colitis. Diagnosis of CD disease was confirmed upon the identification of CD toxin A in stools. She was successfully treated by metronidazole and gamma-globulin perfusions. Delayed diagnosis and anti-CD20 monoclonal antibodies therapy (associated with hypogammaglobulinemia) possibly played a major role in the severity of CD pseudomembranous colitis and in the occurrence of an inflammatory pseudotumor.

Angioedema in pediatric liver transplant recipients under tacrolimus immunosuppression.

BACKGROUND: The authors report on their experience with food-induced angioedema in tacrolimus-immunosuppressed pediatric liver recipients. METHODS: Among 121 children treated with tacrolimus after liver transplantation, those who presented with angioedema are reported. RESULTS: Twelve children (10%) experienced angioedema related to food allergy while on tacrolimus. Mean ages at transplantation and angioedema were 1.3 years and 3.75 years, respectively. Angioedema occurred within a mean of 28 months from onset of tacrolimus. Eleven children experienced two or more angioedema attacks without consequences. One child presented with anaphylactic shock that caused postischemic cerebral damage. Besides eviction of food allergens, eight children were switched from tacrolimus to cyclosporine, whereas tacrolimus dosage was decreased in four. Reintroduction of food allergens was successfully performed only in those who were switched to cyclosporine. CONCLUSION: A causal relationship between tacrolimus and the occurrence of food-induced angioedema is suggested. The switch from tacrolimus to cyclosporine should be considered.

Bleeding tendency in children with Alagille syndrome.

OBJECTIVE: Spontaneous intracranial bleeding is now a widely recognized complication and cause of mortality in patients with Alagille syndrome. The pathogenesis of intracranial bleeding in these patients remains unclear. The aim of the study was to look for other sites of bleeding in these patients that could suggest a factor of multiorgan morbidity. METHODS: The records of 174 patients with Alagille syndrome were reviewed, and 38 (22%) patients without liver failure who experienced hemorrhage that led to a drop in hemoglobin level of at least 3 g/dL or to blood transfusion were identified. RESULTS: In 38 patients, 49 bleeding episodes occurred at a median age of 3.75 years (range: 1 month-27 years). Seventeen patients had 23 episodes of spontaneous bleeding; 21 patients bled during surgery or other medical procedures, and 5 among these 21 patients also had a spontaneous bleeding episode. Nine patients bled at least twice. Median platelets count and prothrombin time were normal. Severe cholestasis existed in 33 patients. One patient has a deletion of the 20p12 region, and 13 of 17 patients studied have a JAGGED1 mutation. Blood transfusion was necessary in 23 patients. Eight patients died secondary to bleeding (4 after surgery, 2 after gastrointestinal bleeding, 1 after needle liver biopsy, and 1 after intracranial bleeding). CONCLUSION: These results suggest that patients with Alagille syndrome are at special risk for bleeding; this should be taken into account before deciding on an invasive procedure. The mechanism of the bleeding is still unclear; the role of hypercholesterolemia cannot be excluded, but it may be speculated that JAGGED1 signaling abnormalities may impair the hemostatic function.