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Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

A major factor in poor bioavailability of cyclosporine in children undergoing orthotopic liver transplantation appears to be poor absorption of the drug. Our hypothesis is that the Roux-en-Y choledochojejunostomy used for biliary drainage in these children causes cyclosporine malabsorption by reducing the length of bowel available for absorption and by distally displacing the entry of bile into the intestine. In these experiments, we determined the effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in Sprague-Dawley rats. Experimental rats (n = 24) were prepared for study by constructing self-emptying jejunal blind loops. Sham rats (n = 9) had jejunal transection and reanastomosis. Control rats (n = 26) had no operation. Two to 4 weeks later, chronic biliary-enteric fistulae were formed in all animals. In experiments, [3H]cyclosporine was delivered into the duodenum while the site of bile delivery varied. Hourly and cumulative [3H]cyclosporine excretion into bile was quantitated, which our preliminary data show to be a valid estimate of absorption. In control rats, bile was delivered into the duodenum or was replaced with saline and sucrose solution. In experimental rats, bile was infused either into the duodenum, which tested bowel shortening only, or into the proximal end of the blind loop, which tested the combined effects of bowel shortening and distal displacement of bile entry. In sham rats, bile was infused into the duodenum, which controlled for previous abdominal surgery, or into the mid-jejunum, which tested for distal bile entry only. Two effects of biliary enteroenterostomy on cyclosporine absorption were observed. First, distal displacement of bile entry into the intestinal lumen reduced drug absorption by about 50%. Compared to control rats with duodenal bile (n = 15), which excreted 14.8 ± 3.3% of the label into bile in 24 hr, and sham rats with duodenal bile (n = 4), which excreted 14.6 ± 1.3%, experimental animals with loop bile (n = 13) excreted 7.7 ± 2.1% and sham rats with midjejunal bile (n = 5) excreted 7.2 ± 1.8%. Control rats with no bile (n = 11) excreted 3.2 ± 1.6%. Second, reduction of bowel length by constructing the enteroenterostomy reduced absorption by 25%. Experimental rats with duodenal bile (n = 11) excreted 11.2 ± 2.5%. These data suggest that the surgical approach to biliary reconstruction after orthotopic liver transplantation in children can contribute to poor cyclosporine bioavailability.