Cholestasis may be defined physiologically as a reduction in canalicular bile flow. Although it is clinically manifested as jaundice due to conjugated hyperbilirubinemia, its main consequences are due, on the one hand, to the cellular toxicity of accumulated bile acids, ultimately leading to biliary cirrhosis and, on the other hand, to decreased intraluminal bile acid concentration responsible for fat and fat-soluble vitamin malabsorption. Because the hepatobiliary excretory system is functionally immature at birth, the neonate has a particular tendency to develop cholestasis. Indeed, cholestatic diseases have been central in the development of pediatric hepatology. Around biliary atresia, the main cause of cholestasis in infants, multiple other causes have been recognized, related either to anatomic or genetic anomalies or to infectious or toxic agents, with very different prognoses.
Cholestasis is frequent in neonates (1/2,500 live births) and in young children. It includes many etiologies with sometimes poor prognosis. In case of neonatal cholestasis, the most important point is to look at the stool color and to rule out biliary atresia which needs to be surgically treated before the 45th day of life. Biliary atresia represents almost 50% of cases of neonatal cholestasis, the other causes being numerous. Some cases can be treated with success, such as tyrosinemia type I or inborn errors of bile acid synthesis. However, in the majority of cases, there is no specific treatment, and the evolution of the disease is toward cirrhosis or liver insufficiency leading to liver transplantation. Nowadays, liver transplantation has good results, but it is a difficult procedure with frequent side effects. In the future, analysis and a better understanding of the mechanisms of the different cholestatic diseases could allow the development of other treatments such as liver cell transplantation or gene therapy, bringing new perspectives for children.
The term ‘familial’ is an unfortunate one. Although the definition includes ‘hereditary’, the inference is that it will usually have occurred in other family members. For many of the conditions described in this article this is often not the case, and for this reason, ‘familial’ conditions may be overlooked when reaching a diagnosis. Cholestasis is defined differently by clinicians, pathologists and biochemists. In addition, what is meant by cholestatic liver disease very often varies for paediatricians and adult hepatologists. However, the pathogenic mechanisms are increasingly similar. Biliary atresia, which is the most frequent cholestatic liver disease presenting to paediatricians, is strikingly different from most diseases as there appears to be no ‘late-onset’ equivalent and it is almost never familial. Several international collaborations have now been established in the hope of overcoming these hurdles (http://www.barcnetwork.org/, http://www.orpha. net/nestasso/EFBAR/, http://www.biliary-atresia.com/index_ frameset_ebar.html). On a day-to-day basis, paediatric hepatologists are faced with a group of infants with jaundice in whom the cause is not readily apparent. In many ways, this has been worsened by the fact that we have known for a long time that a significant proportion will improve spontaneously, whereas others will do badly. In the first few months of life, we still have difficulty forecasting outcomes for individual patients. The underlying cause, at least in the group with a poor outcome, is now becoming apparent in an increasing number of cases. Most of the improvements in our unravelling of this group of children have come about as the result of advances in our understanding of the genetic aetiology. It has also become clear that genetic cholestatic liver disease is not restricted to paediatrics. The exact extent to which genetics contributes to ‘late-onset’ disease is only now being unravelled.
Few specific treatments for children with chronic cholestasis are available. Most therapy strategies relieve bile component retention or palliate some of the consequences of chronic cholestasis. Ursodeoxycholic acid is the most frequently used pharmacological agent in children with chronic cholestasis. This bile acid is administered at dosages between 10 and 30 mg/kg/day to patients with cystic fibrosis, inborn errors of bile acid metabolism, progressive familial intrahepatic cholestasis, sclerosing cholangitis, biliary atresia, Alagille syndrome, or those receiving total parenteral nutrition. Ursodeoxycholic acid mainly increases bile flow and has a membrane-stabilizing effect, reducing the toxicity of more hydrophobic bile acids. Rifampicin, an antibiotic, at dosages between 10 and 20 mg/kg/day is very efficient in relieving pruritus. Similar effects are obtained using nonabsorbable ion exchange resins. In addition, these molecules decrease the serum cholesterol levels contributing to reduce xanthomas. Replacement of some deficiencies created by total parenteral nutrition by administration of essential fatty acids or cysteine can prevent or contribute to improve the associated liver disorders. In some cholestatic diseases, surgical procedures can help to relieve the obstacle to the bile flow, as it is the case for portoenterostomy in patients with biliary atresia. In cases of intrahepatic cholestasis, a clinical and biochemical improvement can be recorded after bile diversion or other procedure (ileum exclusion) limiting the absorption of bile acids by the intestine. In the future, the association of these different pharmacological agents, increasing the bile flow, protecting cell membranes, or restoring nutritional deficiencies, could contribute to an improvement in quality of life in children with chronic cholestasis and eventually delay the need of a more drastic therapy such as liver transplantation. Advances in gene therapy and hepatocyte transplantation could also be of great help; however, many years of intense research are still necessary before even a pilot study using one of these therapies can be considered on liver diseases resulting in chronic cholestasis.
Cholestatic liver disease causes severe risk of malnutrition which includes protein-energy malnutrition and specific nutritional deficiencies. The nutritional status can be assessed based on anthropometric measurements, which can be misleading because of ascitis and peripheral edema. Biochemical determinations of lipid-soluble vitamin status are important to evaluate requirements. Based on nutritional status assessment, nutritional therapy should be planned according to a well-defined schedule. The basic principle of nutritional management is to correct the nutritional status as well as to reduce the risk of nutritional deficiencies. Children with cholestasis usually need extra energy supply that can be obtained by increasing energy density of feeds or addition of glucose polymers and lipids. For catch-up growth, usually, protein intake should be increased. Lipid-soluble vitamin supplementation deserves special attention and it is not easy to correct poor vitamin E status. For some children, parenteral administration of vitamin K is needed. Since recently, a water-soluble vitamin E (d- -tocopheryl polyethylene glycol 1000 succinate) given by oral route is used with a good therapeutic effect. As the liver disease progresses to liver failure in many chronic cholestatic diseases, nutritional therapy can often be regarded as ‘bridging’ for liver transplantation to improve prognosis. Thus, invasive nutritional support is justified in severe liver disease which usually includes nocturnal nasogastric tube feeding, or even parenteral nutrition.