A mechanism based approach to management of children with end-stage liver disease.

INTRODUCTION: Due to parallel advances in surgical and acute care disciplines, liver transplantation (LT) has revolutionized the outlook for children with end-stage liver disease (ESLD). Contrary to advances in technical aspects of LT and the peri-operative care, pre-transplant management of ESLD remains quite a formidable challenge. Areas covered: This review provides mechanisms based management strategies to address common complications of ESLD including malnutrition, amended metabolic pathways, gastrointestinal dysfunction, and development of ascites. Clinically relevant discussion of each paradigm is followed by an account of high impact therapeutic interventions which can be used as guides for formulating management plans. A tabulated summary of the suggested interventions is also provided. Indeed, execution of a dynamic plan tailored to the evolution of pathophysiologic derangements can further enhance outcomes of pediatric LT. Expert commentary: LT has evolved as a dependable therapeutic option for a variety of fatal pediatric liver diseases. However, relative organ shortage remains a formidable challenge. Similarly, consumer expectations continue to grow for sustained improvement of graft and patient survival after LT. In this environment, the level of sophistication applied to the management ESLD before LT stands out as a major opportunity with lasting impact on the future of pediatric LT.

Herpes simplex virus hepatitis in infants: clinical outcomes and correlates of disease severity.

OBJECTIVE: To better characterize the clinical outcomes of infants with herpes simplex virus (HSV) infection and identify useful correlates of disease severity. STUDY DESIGN: Infants aged ≤6 months with HSV infection treated between 1999 and 2009 were identified. In patients with concurrent hepatitis, laboratory and clinical variables were examined to identify predictors of specific outcomes, including death or the need for liver transplantation and the need for intensive care. RESULTS: Of the 15 patients enrolled, 4 (27%) had fatal disease and 2 (13%) required liver transplantation. Infants who lacked skin lesions (P = .04), had a positive HSV polymerase chain reaction result (P = .01), had more severe thrombocytopenia (P = .001), or had other organ system dysfunction (P = .002) were more likely to require intensive care. A higher International Normalized Ratio value (P = .001) and peak total bilirubin level (P = .0002) were predictive of death or the need for liver transplantation. Peak direct bilirubin level was predictive of the need for intensive care and of death or the need for liver transplantation (P = .04 and .009, respectively). CONCLUSIONS: HSV hepatitis represents a broad spectrum of disease from mild aminotransferase elevation to fulminant liver failure and death. HSV DNA detected by polymerase chain reaction, a lack of skin lesions, and the degree of coagulopathy, thrombocytopenia, and cholestasis portend unfavorable outcomes.

Liver fibrosis in biliary atresia.

Biliary atresia (BA) is the most common cholestatic liver disorder requiring liver transplantation in children. Hepatic fibrosis is not only a universal and prominent feature of BA, it is also the most important predictor of outcome following portoenterostomy (PE). Without PE, the progression of hepatic fibrosis is quite dramatic, such that liver cirrhosis is established within a few weeks after birth. Etiologies and molecular networks underpinning such an expeditious fibrogenic process have not been well established. However, immune and nonimmune factors implicated in the pathogenesis of BA, and the resultant cholestasis and oxidative stress, appear to be the main triggers of hepatic fibrosis in BA. Owing to a lack of validated noninvasive tools to monitor liver fibrosis, current prognostic models of BA entail clinical and biochemical variables reflecting liver dysfunction rather than hepatic fibrogenesis. Further work is necessary to validate the results of preliminary studies indicating a good relationship between liver fibrosis determined by transient elastography and other clinical and routinely performed biochemical parameters in pediatric patients. Although a prime candidate for a number of antifibrotic therapies on the horizon, owing to poor understanding of molecular mechanisms, a clear framework of antifibrotic targets has not been outlined in BA. Similarly, specific antifibrotic therapies have not yet been incorporated in clinical practice, limiting these measures to prompt diagnosis and PE operation, prevention and treatment of cholangitis and optimal nutritional support including the administration of fat-soluble vitamins.

Immunohistochemical localization of transforming growth factor ß-1 and its relationship with collagen expression in advanced liver fibrosis due to biliary atresia.

PURPOSE: Biliary atresia (BA) is the most common indication of liver transplantation in children. Pathogenesis of hepatic fibrosis, which is a prominent feature of BA, remains obscure. The purpose of this work was to determine the cellular sources of transforming growth factor beta-1 (TGFß1) and establish the relationship between TGFß1-producing cells and extracellular matrix producing myofibroblasts (MFBs) in advanced BA. METHODS: Trichrome staining and immunohistochemistry were carried out to determine the expression pattern of collagen and TGFß1 protein in explant liver specimens from patients with BA. The intensities of portal and lobular TGFß1 expressions were compared. Immunofluorescence technique was carried out to determine the relationship between α-smooth muscle actin (α-SMA)-positive-MFB and TGFß1-positve cells. RESULTS: Lobular TGFß1 protein expression was significantly higher than portal (89 ± 6 versus 10 ± 1 arbitrary units, P ≤ 0.05), whereas no difference was noted in livers used as control (10 ± 1.6 versus 19 ± 5 arbitrary units, P = 0.11). TGFß1 expression was more in the center of nodules versus MFB in surrounding fibrous septa. Contrary to TGFß1 expression, α1-SMA was mostly expressed in the portal structures and the adjacent fibrous septa enacting lobulation of the parenchyma. The results obtained by coimmunofluorescence staining showed no colocalization of α-SMA and TGFß1. CONCLUSIONS: TGFß1 protein expression is mostly localized to hepatocytes in advanced BA. These findings suggest a paracrine mechanisms of TGFß1-driven fibrogenesis in advanced BA.

Antibodies to Escherichia coli outer membrane porin C in the absence of anti-Saccharomyces cerevisiae antibodies and anti-neutrophil cytoplasmic antibodies are an unreliable marker of Crohn disease and ulcerative colitis.

OBJECTIVES: Antibodies to Escherichia coli outer membrane porin C (anti-OmpC), Saccharomyces cerevisiae, and neutrophil-specific nuclear antigens are associated with inflammatory bowel disease (IBD) in children and young adults. We hypothesized that anti-OmpC, in the absence of anti-S cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies (ANCA), is an assay that overestimates the presence of Crohn disease (CD) and ulcerative colitis (UC). PATIENTS AND METHODS: A retrospective review of patients evaluated at our institution between January 2002 and June 2006 revealed that 170 had serodiagnostic immunological assays performed as part of an evaluation for possible IBD. The assays were screened for a pattern in which anti-OmpC was present in the absence of ASCA and ANCA. RESULTS: Seven patients between 3 and 20 years of age were discovered to be positive for anti-OmpC but negative for ASCA and ANCA. These patients were determined to have significant medical conditions without combined radiographic, endoscopic, or histological evidence of IBD. Despite the reported 85% positive predictive value of anti-OmpC for IBD, none of the 7 patients with isolated anti-OmpC had a diagnosis of CD or UC. CONCLUSIONS: Anti-OmpC, in the absence of ASCA and ANCA, is a serological pattern noted in a subset of medically complex cases in children and young adults without CD or UC.