Hyperbilirubinemia is the most common condition that requires evaluation and treatment in newborn infants. Increased bilirubin production in neonates can be due to shortened erythrocyte life span, larger erythrocyte volume, heme degradation from the fetal extramedullary hematopoietic tissue, immaturity of hepatic uptake and intracellular transport, and increased enterohepatic circulation. The risk factors associated with hyperbilirubinemia are multifactorial that include exclusive breastfeeding, glucose-6-phosphate dehydrogenase deficiency, ABO hemolytic disease, oriental ethnicity, early onset jaundice observed within 24 hours after birth, cephalohematoma, adrenal hemorrhage, significant bruising, late preterm gestational age, and history of a previous sibling treated with phototherapy.

Identifying among newborns at risk to develop marked hyperbilirubinemia is a clinical challenge. Total serum bilirubin is usually the standard method for detecting the bilirubin levels. However, blood sampling for measuring total serum bilirubin by heel sticks may induce pain and potentially result in infection in the neonates. The incidence of severe hyperbilirubinemia among the East Asian neonates is higher than the Caucasian neonates and repeated measurements by heel stick may be necessary in the oriental neonates. Transcutaneous measurement of bilirubin is a viable option in screening neonates to determine if they are at risk for hyperbilirubinemia, but the correlation between the transcutaneous bilirubin detection and total serum bilirubin remains controversial especially when the total serum bilirubin level is beyond 11mg/dL (188μmole/L). Most clinicians regarded transcutaneous bilirubin measurement only as a screening tool for severe hyperbilirubinemia. We evaluate the accuracy of transcutaneous bilirubin measurement and try to establish the cutoff point of transcutaneous bilirubin levels that require total serum bilirubin measurement.

Parents usually face a paradox when they are feeding their newly born infants: They are told that breast milk is best and bottle-feeding maybe hazardous to health. But breast-fed babies are more likely to become jaundiced than bottle-fed babies, and at risk of developing kernicterus. Prospective study exploring the impact of breastfeeding and formula supplements on neonatal jaundice may provide important information concerning the feeding paradox. East Asian and American Indian neonates are at risk of neonatal hyperbilirubinemia suggesting that genetic factors are involved in the development of neonatal hyperbilirubinemia. Uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) is the one of the key enzymes for bilirubin conjugation, and mutations of UGT1A1 cause the unconjugated hyperbilirubinemia syndromes known as Crigler-Najjar syndrome and Gilbert's syndrome. Homozygous A (TA)7TAA variation in promoter region of UGT1A1 gene was found to be associated with neonatal hyperbilirubinemia in western people. However, the high allele-frequency of Gly71Arg, but not promoter polymorphism, in UGT1A1 gene was found to be responsible for neonatal hyperbilirubinemia in Japanese, Koreans and Taiwanese studies. We will discuss the impacts of various feeding modes on neonatal jaundice and provide information concerning that whether there are interactions between genetic polymorphism of UGT1A1 gene and breastfeeding itself, or the fasting effect, in affecting circulating bilirubin levels in the first week of life based on study from single medical center in Taiwan.

Biliary atresia (BA) is an infantile obliterative cholangiopathy of unknown etiology. It is the most common pediatric liver disease leading to liver transplant. Research efforts of the Biliary Atresia Research Consortium (BARC)(a multi-center consortium funded by the National Institute of Health in the United States) have focused on attempts to understand etiologic factors and determinants of outcome. There are three major types of BA (Group I – no anomalies; Group II – major anomalies without splenic malformation; Group III – splenic malformation). These three groups differ as to certain clinical and demographic features, suggesting different etiologies for the three groups. There has been progress in the investigations of etiologies (viral, autoimmune, genetic) from both animal and human studies. The rotavirus (RV) mouse model has been particularly helpful and has shown that administration of rhesus RV to newborn Balb C mice results in an immune mediated attack against the biliary system involving both cellular and humoral immunity. Gamma interferon is also a key inflammatory factor since gamma interferon knockout mice do not develop BA when given RV. RV does result in a productive infection of human cholangiocytes with release of IL-8, a neutrophil chemoattractant. BARC has also investigated clinical determinants of outcome. Bilirubin at 3 months post Kasai is predictive of clinical outcome at two years and age <45 days at Kasai,is the best determinant of neurocognitive outcome at 2 years.

Given the intense inflammatory infiltrate in the periportal area, there have been anecdotal experiences and single center small pilot studies of the effects of corticosteroids suggesting a beneficial effect. However a large scale, placebo controlled prospective multicenter European trial failed to confirm this.  BARC is currently performing a similar trial – results should be available 2011.

The three best strategies to improve outcome are believed to be 1) Improving early diagnosis by methods such as the Japanese stool color card given to all newborn mothers 2)Understanding etiology so as to improve early diagnosis and rational therapy for the various etiologies and 3)Designing effective antifibrotic therapies which would have broad application regardless of etiology.

Cholestasis is a common manifestation of inherited or acquired liver diseases in pediatric patients. Recent advances in understanding the molecular mechanisms of bile transport and physiology have facilitated the diagnosis of many cholestatic liver diseases previously thought to be idiopathic. Highly diverse etiologies and overlapping symptoms make the diagnosis of pediatric cholestasis challenging.

The primary etiologies of intrahepatic cholestasis include infectious diseases, inherited liver transport disorders, metabolic disorders, ductal-plate malformations, chromosome anomalies and endocrine disorders. Ischemia, drugs and parental nutrition have also been indicated as secondary causes of intrahepatic cholestasis. Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by early onset cholestasis, progressive liver cirrhosis and hepatic failure during the first or second decade of life. Within this group, three types of genetic defects have been identified. Characterized by low serum GGT levels, PFIC-1 and -2 are caused by mutations in the ATP8B1 (FIC1) and ABCB11 (BSEP) genes, respectively. PFIC-3 is characterized by high serum GGT levels and is caused by genetic mutations in ABCB4 (MDR3). Inborn errors of bile acid synthesis result in a deficiency of primary bile acids and abnormal bile acid metabolites, resulting in progressive intrahepatic cholestasis and low serum bile-acid levels. The above-mentioned genetic disorders are also responsible for minor forms of cholestatic liver diseases in adults: benign recurrent intra-hepatic cholestasis, drug-related cholestasis, intrahepatic cholesatsis of pregnancy, and cholesterol gall-bladder stones.

Aberrant ductal formation during the development of the liver contributes to unique forms of intrahepatic cholestasis. Alagille syndrome is an autosomal dominant disorder caused by JAG1 or NOTCH2 mutations. Intrahepatic ductal paucity, peripheral pulmonary artery stenosis, and other organic anomalies are characteristic of this syndrome. Other forms of ductal plate malformation can also cause intrahepatic cholestasis and fibrocystic diseases of the liver and kidney.  

A recently discovered neonatal cholestatic disorder caused by citrin deficiency (NICCD) was found to be more prevalent in Asian countries. Common mutations, including 1638ins23 and 85del4 in the SLC25A13 gene were found in Asian patients. Heterozygous carriers of these mutations are prevalent in the normal population. Cholestasis is resolved during the first year of life in most patients. Occasionally, some patients are affected by adult-onset type II citrullinemia (CTLN2).

The treatment for intrahepatic cholestasis includes nutritional therapy and choleretic agents. Donor shortage and higher surgical risks for infants pose challenges for patients in need of liver transplantation. Nuclear receptors are being investigated as potential therapeutic agents for intrahepatic cholestasis. Hepatocyte transplantation is also under experimental investigation.

In conclusion, neonatal and infantile cholestasis is a common disorder with highly diverse etiologies, making the diagnosis a challenge for clinicians. Research is been carried out to improve diagnosis and treatment, as well as to elucidate the etiology of cryptogenic diseases

Orthotopic liver transplantation (OLT) is the treatment option for patients with end stage liver disease and is widely accepted in many Asian countries. The results of OLT is excellent with long term survival rate of well above 80%. The quality of life after OLT is extremely good and the vast majority of the recipients are able to function normally without much limitation to their daily activities.

Organ shortage is a major problem in OLT and many of the patients expired before a donor organ is available. As such, surgical techniques using split liver and living donors are important advances in recent years. The surgical outcome of these two procedures is comparable to those using cadaveric grafts.

Organ rejection is always a problem in transplantation. In fact the success of OLT is greatly enhanced by the discovery of anti-rejection medications such as cyclosporine and tacrolimus. However these medications are known to have a number of serious complications including renal toxicity. A number of newer drugs which are less nephrotoxic are now available.

Infection is an important issue in OLT. There are a number of risk factors which include pre-transplant malnutrition, poor immune function in patients with end stage liver disease and the operation itself. Immediately after the operation, the recipient is usually intubated with many invasive intravenous lines and drainage tubes. The use of anti-rejection drugs also suppresses their immune function. Other than bacterial infection, viral infection and fungal infections are particularly problematic among the recipients. The use of prophylactic gancyclovir has greatly reduced the rates of symptomatic cytomegalovirus (CMV) infection.  Risk factors for fungal infections include multiple operations, CMV infection, prolonged antibiotics usage and multiple rejections.

Hepatitis B infection had been a contraindication for OLT. However, patients with hepatitis B infection are suitable for OLT in recent years because it is possible to control viral replication with the use of nucleoside analog, hyperimmune gammaglobulin and vaccination.

In recent years, OLT is a treatment option for patients with liver cancer, provided that the cancer is confined to the liver and not more than certain acceptable size.

In children, Ebstein Barr virus and Herpes infections are common. These infections are associated with post-transplant lymphoproliferative disease (PTLD). Fortunately in many patients, the PTLD would improve if the immunosuppressants are reduced in time. Monoclonal antibodies can be used to treat PTLD and the outcome is satisfactory.