Diagnosis of Neonatal Cholestasis

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. Copyright © 2008 Nestec Ltd., Vevey/S. Karger AG, Basel Muriel Girard Pediatric Gastroenterology-Hepatology-Nutrition Unit Necker-Enfants Malades Hospital, 149 rue de Sèvres FR–75015 Paris (France) E-Mail [email protected] © 2008 Nestec Ltd., Vevey/S. Karger AG, Basel 0517–8606/08/0663–0109$24.50/0 Accessible online at: www.karger.com/ane D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /5 /2 01 7 1: 29 :1 0 P M Girard/Lacaille Ann Nestlé [Engl] 2008;66:109–120 110 (secondary to hepatocyte injury or to external factors such as infection or parenteral nutrition) or to intraor extrahepatic biliary alterations. Bile production is an active process, involving the transport of bile acids and other osmotic compounds across a concentration gradient into the bile canaliculus. This osmotic concentration induces the passive movement of water into the canaliculus. Active transporters are localized at the basolateral membrane of the hepatocyte for sinusoidal blood uptake ( fig. 1 ): Na taurocholate cotransporting polypeptide (NTCP), organic anion transporting protein (OATP) and, at the canalicular membrane for biliary excretion, bile salt export pump (BSEP), canalicular multispecific organic anion transporter (cMOAT) and multidrug resistance protein 3 (MDR3). The expression of these transporters is modified by liver disease, injury or sepsis in order to protect the hepatocyte from the cytotoxic effects of elevated bile acid concentration. This regulation could probably explain why jaundice may be an early sign of sepsis. Bile flow is low in the fetus and newborn because of the immaturity of bile acid synthesis and transport processes. In animal models, NTCP and BSEP are present already before birth, but at a very low level in comparison with adults. The development process for human hepatocyte transporters has not yet been quantified, but plasma bile acids do not fall into the normal adult range until 6 months of age. These observations strongly suggest the predisposition of the neonate to cholestasis [2, 3] . Diagnosis of Cholestasis Cholestasis should be suspected if jaundice has not disappeared during the second week of life. Cholestatic jaundice is associated with pale stools and dark urines; there is no pruritus in the neonatal period. The liver may be enlarged, firm or hard. Sometimes, a splenomegaly is present. Acholic stools, hard liver and abdominal or thoracic situs inversus are very suggestive of biliary atresia. Biological features of cholestasis are hyperbilirubinemia, mainly conjugated, and often elevated -glutamyl transferase, as well as alkaline phosphatase activities and serum bile salts. It is important to differentiate jaundice of liver insufficiency and a chole static jaundice (in this situation, prothrombin time is normalized after vitamin K 1 injection). In cholestasis, there is liposoluble vitamin malabsorption and vitamin K 1 deficiency, predisposing to bleeding; an injection of vitamin K 1 should always be performed. Abdominal ultrasonography should be performed in all cholestatic infants, by an experienced radiologist. Intrahepatic bile ducts are rarely dilated, suggestBlood Canaliculus Hepatocyte Hepatocyte OATP