Allah Haafiz

Down‐regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet

Intrauterine growth restriction (IUGR) represents an important risk factor for perinatal complications and for adult disease. IUGR is associated with a down‐regulation of placental amino acid transporters; however, whether these changes are primary events directly contributing to IUGR or a secondary consequence is unknown. We investigated the time course of changes in placental and fetal growth, placental nutrient transport in vivo and the expression of placental nutrient transporters in pregnant rats subjected to protein malnutrition, a model for IUGR. Pregnant rats were given either a low protein (LP) diet (n= 64) or an isocaloric control diet (n= 66) throughout pregnancy. Maternal insulin, leptin and IGF‐I levels decreased, whereas maternal amino acid concentrations increased moderately in response to the LP diet. Fetal and placental weights in the LP group were unaltered compared to control diet at gestational day (GD) 15, 18 and 19 but significantly reduced at GD 21. Placental system A transport activity was reduced at GD 19 and 21 in response to a low protein diet. Placental protein expression of SNAT2 was decreased at GD 21. In conclusion, placental amino acid transport is down‐regulated prior to the development of IUGR, suggesting that these placental transport changes are a cause, rather than a consequence, of IUGR. Reduced maternal levels of insulin, leptin and IGF‐1 may link maternal protein malnutrition to reduced fetal growth by down‐regulation of key placental amino acid transporters.

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.

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.

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.

Immunohistochemical localization of transforming growth factor β-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 (TGFβ1) and establish the relationship between TGFβ1-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 TGFβ1 protein in explant liver specimens from patients with BA. The intensities of portal and lobular TGFβ1 expressions were compared. Immunofluorescence technique was carried out to determine the relationship between α-smooth muscle actin (α-SMA)-positive-MFB and TGFβ1-positve cells. Results: Lobular TGFβ1 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). TGFβ1 expression was more in the center of nodules versus MFB in surrounding fibrous septa. Contrary to TGFβ1 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 TGFβ1. Conclusions: TGFβ1 protein expression is mostly localized to hepatocytes in advanced BA. These findings suggest a paracrine mechanisms of TGFβ1-driven fibrogenesis in advanced BA.

Growth hormone therapy improves growth in children with cystic fibrosis related liver disease.

Growth impairment in cystic fibrosis (CF) is worsened by liver disease. Children with CF have serum levels of insulin-like growth factor-I (IGF-I) that are lower than expected for their normal growth hormone (GH) production. In children with CF-related liver disease (CFLD), response to endogenous GH is further reduced. We present our experience with two young children with CFLD given recombinant human GH (rhGH). The first patient was a 5 year-old female with CFLD and poor growth who responded well for 1 1/2 years to rhGH therapy during her initial course and without a significant increase in serum IGF-I, but with a substantial increase in IGF-I concentration when the GH dose was increased. The second patient was a 5 month-old male with advanced liver disease who had transient improved growth and liver function following rhGH. These patients suggest that rhGH is safe and may be effective in children with CFLD.

Isoniazid-Induced Severe Hepatotoxicity: An Infrequent but Preventable Cause of Liver Failure in Children Treated for Latent Tuberculosis Infection

Isoniazid (INH) monotherapy has gained widespread acceptance as an efficacious therapy for latent tuberculosis infection (LTBI) especially in low-prevalence settings. Although INH related hepatotoxicity is well recognized, progression to severe liver dysfunction requiring care at a transplant center remains unpredictable. We report the management of a five year-old girl who developed progressive liver failure due to INH prophylaxis. This highlights the potential severity of INH related hepatic injury and underscores the significance of vigilant clinical monitoring throughout the duration of the therapy in children.

Elevated Alkaline Phosphatase in Children: An Algorithm to Determine When a "Wait and See" Approach is Optimal.

Due to the possibility of underlying hepatobiliaryor bone diseases, the diagnostic work up of a child with elevated alkaline phosphatase (AP) levels can be quite costly. In a significant proportion of these patients, elevated AP is benign, requiring no intervention: hence, known as transient hyperphosphatasemia (THP) of infants and children. A 27-month old previously healthy Caucasian female was found to have isolated elevation of AP four weeks after the initial symptoms of acute gastroenteritis. One month later, when seen in hepatobiliary clinic, signs and symptoms of gastrointestinal, hepatobiliary, or bone disease were absent and physical examination was normal. The diagnosis of THP was made, and, as anticipated, AP levels normalized after four months. Using this case as an example, we suggest an algorithm that can be utilized as a guide in a primary care setting to arrive at the diagnosis of THP and avoid further tests or referrals.

Liver transplantation in a 7-month-old girl with Caroli's disease.

Carolis disease (including Carolis syndrome) is a rare autosomal recessive disorder of the liver characterized by diffuse cystic dilatation of the intrahepatic bile ducts. The disease may present at any age and is characterized by recurrent episodes of biliary obstruction, cholangitis, hepaticolithiasis, and liver abscesses. Carolis syndrome is further associated with congenital hepatic fibrosis and portal hypertension. Patients with recurrent complications or cirrhosis may die because of recurrent infection, portal hypertension, liver failure, or cholangiocarcinoma. Liver transplantation is the treatment of choice for these complicated patients. Here we describe the youngest reported patient with Carolis syndrome treated successfully using liver transplantation and review the recent literature.

relationship between hepatic CTGF expression and routine blood tests at the time of liver transplantation for biliary atresia: hope or hype for a biomarker of hepatic fibrosis

Background: Progressive hepatic fibrosis (HF) is a prominent feature of biliary atresia (BA), the most common indication for liver transplantation (LT) in children. Despite its importance in BA, HF is not evaluated in routine patient care because the invasiveness of liver biopsy makes histologic monitoring of fibrosis unfeasible. Therefore, the identification of noninvasive markers to assess HF is desirable especially in children. Purpose: The main goal of this pilot project was to establish an investigational framework correlating hepatic expression of fibrogenic markers with routine blood tests in BA. Methods: Using liver explants from patients with BA (n = 26), immune-expression of connective tissue growth factor (CTGF), a key fibrogenic cytokine was determined using horseradish-labeled antibodies. Expression intensities of lobular (L-CTGF) and portal (P-CTGF) CTGF were determined by using ImageJ software. These CTGF intensities were correlated with blood tests performed at the time of LT. Correlation coefficients were determined for each blood test variable versus mean L-CTGF and P-CTGF expression intensities. A P-value of less than 0.05 was considered statistically significant. Results: All patients had end-stage liver disease and persistent cholestasis at the time of LT. Kendall tau (τ) rank correlation coefficient for L-CTGF and white blood cell (WBC) was inversed (−0.52; P ≤ 0.02). Similar but statistically nonsignificant inverse relationships were noted between L-CTGF and prothrombin time (PT) (−0.15; P ≤ 0.4), international normalized ratio (INR) (−0.14; P ≤ 0.5), and platelet count (−0.36; P ≤ 0.09). Inversed (τ) rank correlation coefficients were also evident between P-CTGF expression and gamma-glutamyl transpeptidase (GGT), PT, INR, and platelet count. Pearson correlation coefficients for combinational analysis of standardized total bilirubin (TB), alkaline phosphatase, GGT, and platelet count with L-CTGF (0.33; P = 0.3) and P-CTGF (0.06; P = 0.8), were not significant. Similar analysis for alanine aminotransferase, TB, and GGT combination (L-CTGF, 0.16; P = 0.5; P-CTGF −0.3; P = 0.2) as well as WBC, platelet count, and TB (L-CTGF: −0.36; P = 0.09; P-CTGF −0.33; P = 0.13) also revealed nonsignificant results. Conclusion: Hepatic expression of fibrogenic markers can be correlated with routinely performed blood tests in patients with BA. We document that although a trend of inverse relationship is noted, hepatic CTGF expression does not correlate well with routinely performed blood tests in advanced BA. Further work is required to determine more reliable ways of noninvasive diagnosis of HF.