History of the first description of childhood liver disease in AATD.

This supplement celebrates the 50th anniversary of Alpha-1 antitrypsin deficiency (AATD). Initially AATD was associated with an inherited form of emphysema. This historical article describes the predisposition of AATD to liver disease. The morphologic findings contributed to a better understanding of low serum levels of A1 AT by the finding of AAT accumulating and stuck in the lumen of the rough endoplasmic reticulum of the hepatocyte. Thus, only low levels of PiZ were secreted for the rest of the human body and the only clinical correction was by liver transplantation.

Status of bacterial colonization, Toll-like receptor expression and nuclear factor-kappa B activation in normal and diseased human livers.

Epidemiological data on bacterial translocation (BT), colonization and inflammation in normal human livers is lacking. In this study we investigated the status of bacterial colonization and inflammation in the normal, cirrhotic primary biliary cirrhosis (PBC), and nonalcoholic steatohepatitis (NASH) human liver tissues. Comparatively normal livers showed increased bacterial colonization than PBC and NASH. We analyzed mRNA levels of Toll-like receptors (TLR) 2 and TLR4, and protein levels of TLR4. Phosphorylated IKKα (pIKKα) protein estimation served as a marker for nuclear factor-kappa B (NF-κB) activation. In spite of the increased bacterial colonization in normal liver tissues, lower levels of TLR2/4 mRNA and TLR4 and pIKKα proteins were found compared to PBC and NASH indicating the maintenance of suppressed inflammation and immune tolerance in normal livers. To our knowledge, this is the first clinical evidence showing suppressed inflammation despite bacterial colonization in normal human livers thus maintaining liver immune homeostasis.

Isoniazid-related hepatic failure in children: a survey of liver transplantation centers.

BACKGROUND: Isoniazid (INH) therapy for tuberculosis carries a known risk for hepatoxicity, and leads to hepatic failure in a small subset of patients. This incidence has been described for adults, but is uncertain in children. Our aim was to estimate the incidence of pediatric referrals for INH-related liver failure, and to describe the characteristics and outcomes of these patients. METHODS: The 84 U.S. centers performing pediatric liver transplants between 1987 and 1997 were surveyed regarding patients with INH-induced liver failure. Additional transplant statistics were obtained from the United Network for Organ Sharing. Estimates of the number of children taking preventive INH were derived from a nationwide public health database. RESULTS: Twenty cases of INH-related liver failure were found during a 10-year period. Four patients (20%) recovered spontaneously; 10 (50%) underwent orthotopic liver transplantation (OLT), while six (30%) died awaiting OLT. Mean age at presentation was 9.8 years (range 1.3-17). Mean length of INH therapy was 3.3 months (range 0.5-9). Notably, five patients seen for symptoms of hepatitis were initially told not to stop treatment. INH-associated liver failure accounted for 0.2% (8 of 4679) of all pediatric OLTs, and 14% (8/56) of transplants for drug hepatoxicity. The estimated incidence of liver failure was up to 3.2/100,000 for children on prophylactic INH. CONCLUSIONS: While INH-associated liver failure in children is rare, discontinuation at the onset of symptoms does not assure recovery. This indicates a need for increased awareness of hepatotoxicity risk, expanded biochemical monitoring for children receiving INH, and prompt withdrawal in symptomatic patients.

Morbidity from congenital hepatic fibrosis after renal transplantation for autosomal recessive polycystic kidney disease.

Presentation of autosomal recessive polycystic kidney disease (ARPKD) ranges from severe renal impairment and a high mortality rate in infancy to older children and adolescents with minimal renal disease and complications of congenital hepatic fibrosis (CHF), cholangitis and portal hypertension. Renal transplantation improves prognosis but it is unclear whether CHF in transplanted children follows the same clinical course as in older children with less severe renal disease. The aim of this study was to evaluate morbidity from CHF in ARPKD post renal transplantation. Data were analyzed for six males and eight females, transplanted for ARPKD (mean age 8.3 years, range 1-22.3 years) at the University of Minnesota between 1972 and 1998. Follow-up was for a mean of 14.5 years (range 3.1-33.6 years). One and 5 years patient survival rates were 93% and 86%, respectively. Overall five patients (36%) died; 4/5 deaths were related to CHF. Causes of death were hepatic failure immediately post transplant (n = 1), septicemia related to bile duct dilatation (n = 3) and multiorgan failure (n = 1). One and 5years graft survival rates were 87% and 70%, respectively. One patient had a combined liver-kidney transplant and two were re-transplanted. Initial signs of CHF were splenomegaly (n = 5), hepatosplenomegaly (n = 4) and gastrointestinal bleed (n = 2). Progression of CHF through childhood included hypersplenism (n = 7), esophageal varices with gastrointestinal bleeding (n = 5) and bile duct dilatation (n = 5). Portal hypertension was treated with portosystemic shunt (n = 3), sclerotherapy (n = 2), banding of varices (n = 1) and transjugular intrahepatic portosystemic shunt (n = 1). Of the nine survivors (mean age 12.8 years) 78% have functioning grafts (one liver-kidney transplant), 63% have portal hypertension and 22% have asymptomatic biliary dilatation. Complications of CHF developed in 79% of children who received a renal transplant for ARPKD. Mortality related to CHF occurred in 29% and accounted for 80% (4/5) of the deaths.

Biliary stricture in living-related donor liver transplantation: management with balloon dilation.

Biliary stricture is a recipient graft complication, occurring late in the post-operative period, which appears to occur with increased frequency in living-related donor liver transplantation (LRD LTx). We reviewed the experience at the University of Minnesota in managing a biliary complication of LRD LTx. Since January 1997, 13 LRD transplants have been performed using the technique of transplantation of the left lateral segments with a small portion of segment IV. All patients had hepaticojejunostomies using a Roux-en-Y loop. Of the 11 surviving patients, eight had evidence of cholangitis (Gram-negative sepsis, two patients; ascending cholangitis, three patients; or unexplained fever with elevated liver enzymes, three patients) 4-8 months after otherwise successful transplantation. Six of the patients underwent percutaneous transhepatic cholangiography (PTC) with demonstration of a stenosis at the site of the biliary anastomosis. Repeated dilation of the anastomosis led to resolution of the stenoses, normalization of liver enzymes, and prevention of further episodes of infection. No patient required revision of the hepaticojejunostomy. Computed axial tomography evidence of ductal stenosis may be subtle in this group of patients, but PTC is diagnostic. We suggest a high index of suspicion of biliary stricture in the LRD LTx population. Biliary dilation reduces the risk of life-threatening sepsis.