Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[28,29] Extremely high levels of beta-hCG are associated with infantile choriocarcinoma of the liver.
The incidence of hepatoblastoma is increased 1,000 to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome (BWS).[30,31] Hepatoblastoma is also increased in hemihypertophy, an overgrowth syndrome caused by the same epigenetic changes in chromosome 11p15.5 that cause many cases of BWS, but in a genetically mosaic fashion.[31,33] BWS can be caused by either genetic mutations and be familial, or much more commonly, by epigenetic changes and be sporadic. Either mechanism can be associated with an increased incidence of embryonal tumors including Wilms tumor and hepatoblastoma. The gene dosage and ensuing increase in expression of insulin-like growth factor 2 (IGF 2) has been implicated in the macrosomia and embryonal tumors in BWS and hemihypertrophy.[31,34] When sporadic, the types of embryonal tumors associated with BWS have frequently also undergone somatic changes in the BWS locus and IGF 2.[35,36] All children with BWS or isolated hemihypertrophy should be screened regularly by ultrasound to detect abdominal malignancies at an early stage. Screening using AFP levels has helped in the early detection of hepatoblastoma in children with BWS or hemihypertrophy. Other somatic overgrowth syndromes, such as Simpson-Golabi-Behmel syndrome, may also be associated with hepatoblastoma.
Familial adenomatous polyposis
There is an association between hepatoblastoma and familial adenomatous polyposis (FAP); children in families that carry the APC gene are at an 800-fold increased risk for hepatoblastoma. However, hepatoblastoma occurs in less than 1% of FAP family members, so ultrasound and AFP screening for hepatoblastoma in members of families with FAP is controversial.[39,40,41] The predisposition to hepatoblastoma may be limited to a specific subset of APC mutations. It has been recommended that all children with hepatoblastoma be examined for congenital hypertrophy of the retinal pigment epithelium, a marker of APC mutation carriers in 70% of polyposis families. In the absence of APC germline mutations, childhood hepatoblastomas do not have somatic mutations in the APC gene; however, they frequently have mutations in the beta-catenin gene, the function of which is closely related to APC.
Hepatitis B and hepatitis C infection
Hepatocellular carcinoma is associated with hepatitis B and hepatitis C infection,[44,45,46] especially in children with perinatally acquired hepatitis B virus. Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia. Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Mutations in the met/hepatocyte growth factor receptor gene occur in childhood hepatocellular carcinoma, and this could be the mechanism that results in a shortened incubation period. Several specific types of nonviral liver injury and cirrhosis are associated with hepatocellular carcinoma in children including tyrosinemia and biliary cirrhosis. Hepatocellular carcinoma may also arise in very young children with mutations in the bile salt export pump ABCB11, which causes progressive familial hepatic cholestasis.