R. W. Shepherd

Screening and outcomes in biliary atresia: Summary of a National Institutes of Health workshop

Biliary atresia is the most common cause of end‐stage liver disease in the infant and is the leading pediatric indication for liver transplantation in the United States. Earlier diagnosis (<30‐45 days of life) is associated with improved outcomes following the Kasai portoenterostomy and longer survival with the native liver. However, establishing this diagnosis is problematic because of its rarity, the much more common indirect hyperbilirubinemia that occurs in the newborn period, and the schedule for routine infant health care visits in the United States. The pathogenesis of biliary atresia appears to involve immune‐mediated fibro‐obliteration of the extrahepatic and intrahepatic biliary tree in most patients and defective morphogenesis of the biliary system in the remainder. The determinants of the outcome of portoenterostomy include the age at surgery, the centers experience, the presence of associated congenital anomalies, and the postoperative occurrence of cholangitis. A number of screening strategies in infants have been studied. The most promising are early measurements of serum conjugated bilirubin and a stool color card given to new parents that alerts them and their primary care provider to acholic stools. This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006, in Bethesda, MD, that addressed the issues of outcomes, screening, and pathogenesis of biliary atresia. (HEPATOLOGY 2007;46:566–581.)

Children With Persistent Feeding Difficulties: An Observational Analysis of the Feeding Interactions of Problem and Non-Problem Eaters

This study examined the relationship between parents feeding practices and the feeding behavior of toddlers and preschool-age children with (n = 19) or without (n = 29) persistent feeding difficulties. Specifically, patterns of parent-child interaction were assessed during standardized family mealtime observations in the clinic. Parents also kept observational records of their childrens mealtime behavior at home and rated the degree of difficulty they experienced in feeding their child during each meal on a daily basis. Observational results showed that feeding-disordered children engaged in higher levels of disruptive mealtime behavior (food refusal, noncompliance, complaining, oppositional behavior, and playing with food) and lower levels of chewing during mealtime. There were several significant age effects, with younger children (under age 3) engaging in more vomiting and less aversive demanding and verbalizations. Parents of feeding-disordered children were more negative and coercive in their feeding practices and engaged in higher levels of aversive instruction giving, aversive prompting, and negative eating-related comments. There were several significant associations between coercive parental behaviors and childrens food refusal and noncompliance in the sample as a whole. Measures of childrens disruptiveness at mealtimes in the clinic were significantly correlated with measures of mealtime behavior in the home.

Nutritional rehabilitation in cystic fibrosis: Controlled studies of effects on nutritional growth retardation, body protein turnover, and course of pulmonary disease

The effects of a sustained increase in energy and protein intake on weight gain, growth, body protein metabolism, and the course of pulmonary disease were studied in 10 undernourished patients with cystic fibrosis unable to maintain nutrition and growth by the oral route and with declining nutritional and pulmonary status in the year prior to study. A 1-year course of nutrient supplementation using a semielemental high-nitrogen formula was delivered by nocturnal intragastric feeding or as an orally administered supplement; progress was compared with that of 14 height-, sex- and FEV1-matched patients with cystic fibrosis receiving conventional therapy. Supplementation resulted in a catch-up weight gain and sustained improvement in linear growth, with fewer pulmonary infections per year than during the initial observation period. Better weight gain and linear growth than in the comparison group were observed, as well as a significant reversal of the trend for deteriorating lung function. Compared with data from healthy children, 15N-glycine kinetics demonstrated increased protein breakdown and negligible net protein deposition in the treatment group prior to supplementation. After supplementation, synthesis in excess of breakdown, with net protein accretion, occurred by 1 month of supplementation. By 6 to 12 months a significant reduction in the previously high rate of mean synthesis and breakdown was observed, with maintenance of net anabolism. These dynamic changes in whole-body protein turnover reflect a long-term improvement in energy and protein intake, which can favorably affect nutrition, growth, and the course of pulmonary disease in problem cases of cystic fibrosis.

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

INCREASED ENERGY EXPENDITURE IN YOUNG CHILDREN WITH CYSTIC FIBROSIS

To investigate the role of energy expenditure in the altered energy balance in cystic fibrosis (CF), total energy expenditure (TEE) was measured by the doubly-labelled water method in 9 clinically well CF infants (body weight 7.3-10.9 kg) without chronic lung disease. CF infants had 25% higher rates of energy expenditure when compared with data derived from measurements of TEE obtained by the same method in 16 healthy infants, matched for age and body weight. Mean TEE (SEM) for CF was 950 (38) kcal, vs 876 (72) kcal for controls matched for age and 758 (46) kcal for controls matched for weight. Although subclinical disease activity cannot be excluded as a determinant of the excess TEE, the possibility of an energy-requiring basic defect is suggested, because further analysis indicated that factors other than body weight, degree of underweight, presence of pancreatic insufficiency, or presence of lung disease were important. Increased TEE may contribute to undernutrition in CF, even in the absence of chronic lung disease.

The Role of Hepatic Stellate Cells and Transforming Growth Factor-β1 in Cystic Fibrosis Liver Disease

Liver disease causes significant morbidity and mortality from multilobular cirrhosis in patients with cystic fibrosis. Abnormal bile transport and biliary fibrosis implicate abnormal biliary physiology in the pathogenesis of cystic fibrosis-associated liver disease (CFLD), yet the mediators linking biliary events to fibrosis remain unknown. Activated hepatic stellate cells (HSCs) are the pre-eminent mediators of fibrosis in a range of hepatic disorders. The dominant stimulus for matrix production by HSCs is the cytokine transforming growth factor (TGF)-beta(1). In CFLD, the role of HSCs and the source of TGF-beta(1) have not been evaluated. Liver biopsy tissue obtained from 38 children with CFLD was analyzed. Activated HSCs, identified by co-localization of procollagen alpha(1)(I) mRNA and alpha-smooth muscle actin, were demonstrated as the cellular source of excess collagen production in the fibrosis surrounding the bile ducts and the advancing edge of scar tissue. TGF-beta protein and TGF-beta(1) mRNA expression were shown to be predominantly expressed by bile duct epithelial cells. TGF-beta(1) expression was significantly correlated with both hepatic fibrosis and the percentage of portal tracts showing histological abnormalities associated with CFLD. This study demonstrates a definitive role for HSCs in fibrogenesis associated with CFLD and establishes a potential mechanism for the induction of HSC collagen gene expression through the production of TGF-beta(1) by bile duct epithelial cells.

Body Composition in Nonalcoholic Cirrhosis: The Effect of Disease Etiology and Severity on Nutritional Compartments

BACKGROUND/AIMS Previous studies of body composition in cirrhosis have either measured only one body compartment, used alcoholic subjects, or not corrected body composition for physical characteristics. The aim of this study was to perform a detailed analysis of body composition in subjects with nonalcoholic cirrhosis. METHODS Simultaneous measurements of total body potassium and total body water were performed and values of body cell mass and body fat were corrected for physical characteristics. RESULTS Childs class C patients had a significantly lower mean total body potassium index (i.e., percent observed value/expected value) and body fat index than class A or B patients. Eighty-one percent of class C patients had simultaneous reductions in body fat and body cell mass, and 71% of patients with class A disease had a significant reduction in either or both compartments. Nine patients showed the pattern of tissue loss seen with short-term starvation. Fourteen patients showed the pattern of tissue loss seen in physiological stress. CONCLUSIONS Severe liver disease is characterized by significant reductions in body fat and body cell mass, most class A patients have a significant reduction in some nutritional compartments, and the pattern of tissue loss may reflect mechanisms of tissue wasting.

Survival, growth and quality of life in children after orthotopic liver transplantation : a 5 year experience

The aims of this study were to investigate outcome and to evaluate areas of potential ongoing concern after orthotopic liver transplantation (OLT) in children. Actuarial survival in relation to age and degree of undernutrition at the time of OLT was evaluated in 53 children (age 0.58‐14.2 years) undergoing OLT for endstage liver disease. Follow‐up studies of growth and quality of life were undertaken in those with a minimum follow‐up period of 12 months (n= 26). The overall 3 year actuarial survival was 70%. Survival rates did not differ between age groups (actuarial 2 year survival for ages <1,1‐5 and >5 years were 70, 70 and 69% respectively) but did differ according to nutritional status at OLT (actuarial 2 year survival for children with Z scores for weight <−1 was 57%, >−1 was 95%; P=0.004). Significant catch‐up weight gain was observed by 18 months post‐transplant, while height improved less rapidly. Quality of life (assessed by Vineland Adaptive Behaviour Scales incorporating socialization, daily living skills, communication and motor skills) was good (mean composite score 91±19). All school‐aged children except one were attending normal school. Two children had mild to moderate intellectual handicap related to post‐operative intracerebral complications. Satisfactory long‐term survival can be achieved after OLT in children regardless of age but the importance of pre‐operative nutrition is emphasized. Survivors have an excellent chance of a good quality of life and of satisfactory catch‐up weight gain and growth.

Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte‐derived monocyte chemotaxis protein‐1 in hepatic stellate cell recruitment

Cholestatic liver diseases, such as cystic fibrosis (CF) liver disease and biliary atresia, predominate as causes of childhood cirrhosis. Despite diverse etiologies, the stereotypic final pathway involves fibrogenesis where hepatic stellate cells (HSCs) are recruited, producing excess collagen which initiates biliary fibrosis. A possible molecular determinant of this recruitment, monocyte chemotaxis protein‐1 (MCP‐1), an HSC‐responsive chemokine, was investigated in CF liver disease and biliary atresia. The bile‐duct‐ligated rat and in vitro coculture models of cholestatic liver injury were used to further explore the role of MCP‐1 in HSC recruitment and proposed mechanism of induction via bile acids. In both CF liver disease and biliary atresia, elevated hepatic MCP‐1 expression predominated in scar margin hepatocytes, closely associated with activated HSCs, and was also expressed in cholangiocytes. Serum MCP‐1 was elevated during early fibrogenesis. Similar observations were made in bile‐duct‐ligated rat liver and serum. Hepatocytes isolated from cholestatic rats secreted increased MCP‐1 which avidly recruited HSCs in coculture. This HSC chemotaxis was markedly inhibited in interventional studies using anti‐MCP‐1 neutralizing antibody. In CF liver disease, biliary MCP‐1 was increased, positively correlating with levels of the hydrophobic bile acid, taurocholate. In cholestatic rats, increased MCP‐1 positively correlated with taurocholate in serum and liver, and negatively correlated in bile. In normal human and rat hepatocytes, taurocholate induced MCP‐1 expression. Conclusion: These observations support the hypothesis that up‐regulation of hepatocyte‐derived MCP‐1, induced by bile acids, results in HSC recruitment in diverse causes of cholestatic liver injury, and is a key early event in liver fibrogenesis in these conditions. Therapies aimed at neutralizing MCP‐1 or bile acids may help reduce fibro‐obliterative liver injury in childhood cholestatic diseases. (HEPATOLOGY 2008.)

Risk factors for rejection and infection in pediatric liver transplantation.

Rejection and infection are important adverse events after pediatric liver transplantation, not previously subject to concurrent risk analysis. Of 2291 children (<18 years), rejection occurred at least once in 46%, serious bacterial/fungal or viral infections in 52%. Infection caused more deaths than rejection (5.5% vs. 0.6% of patients, p < 0.001). Early rejection (<6 month) did not contribute to mortality or graft failure. Recurrent/chronic rejection was a risk in graft failure, but led to retransplant in only 1.6% of first grafts. Multivariate predictors of bacterial/fungal infection included recipient age (highest in infants), race, donor organ variants, bilirubin, anhepatic time, cyclosporin (vs. tacrolimus) and era of transplant (before 2002 vs. after 2002); serious viral infection predictors included donor organ variants, rejection, Epstein‐Barr Virus (EBV) naivety and era; for rejection, predictors included age (lowest in infants), primary diagnosis, donor‐recipient blood type mismatch, the use of cyclosporin (vs. tacrolimus), no induction and era. In pediatric liver transplantation, infection risk far exceeds that of rejection, which causes limited harm to the patient or graft, particularly in infants. Aggressive infection control, attention to modifiable factors such as pretransplant nutrition and donor organ options and rigorous age‐specific review of the risk/benefit of choice and intensity of immunosuppressive regimes is warranted.