Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency

Institute of Liver Studies, King's College Hospital, London, UK.
Hepatology (Impact Factor: 11.06). 08/2006; 44(2):478-86. DOI: 10.1002/hep.21287
Source: PubMed


Hepatocellular carcinoma (HCC) is rare in young children. We attempted to see if immunohistochemical and mutational-analysis studies could demonstrate that deficiency of the canalicular bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholestasis (PFIC)--or "neonatal hepatitis" suggesting PFIC--that was associated with HCC in young children. We studied 11 cases of pediatric HCC in the setting of PFIC or "neonatal hepatitis" suggesting PFIC. Archival liver were retrieved and immunostained for BSEP. Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents. Among the 11 nonrelated children studied aged 13-52 months at diagnosis of HCC, 9 (and a full sibling, with neonatal hepatitis suggesting PFIC, of a tenth from whom liver was not available) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not. Mutations in ABCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (n = 7). These mutations were confirmed in the parents (n = 14). With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated in all 5 parents in whom leukocyte DNA could be studied. Thirteen different mutations were found. In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized risk for HCC in young children. Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutation in ABCB11.

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Available from: Giorgina Mieli-Vergani, Dec 01, 2014
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    • "Pathogenesis is based on a defect in hepatic metabolism, perhaps a defect in transport, formation or excretion of primary bile acids where children are unable to drain bile from the liver even though the large bile ducts are open [35]. Hepatocellular carcinoma may develop in PFIC type II at a very early age [11] [22]; even toddlers have been affected. The disease is typically progressive, leading to fulminant liver failure and death in childhood in the absence of liver transplantation [34]. "
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    ABSTRACT: Progressive familial intrahepatic cholestasis refers to a heterogenous group of autosomal recessive disorders in which children develop severe intrahepatic cholestasis progressing to biliary cirrhosis and chronic liver failure, usually during the first decade of life. The clinical features include jaundice, hepatomegaly, splenomegaly, growth retardation and severe pruritus. The laboratory tests demonstrate elevated bilirubin, bile acids and liver function enzymes. The only curative treatment of progressive familial intrahepatic cholestasis is liver transplantation.This article presents the medical and dental history along with a comprehensive dental management and prognosis of a 6 years old male patient with progressive familial intrahepatic cholestasis type I and liver cirrhosis 5 years post living related liver transplant in Riyadh, Saudi Arabia. The patient demonstrated improved oral hygiene performance during the course of treatment, and continued to demonstrate a low caries rate up to 7 months following treatment. Based upon the apparent success of the preventive programme, the patient was judged to have a very good prognosis.
    Full-text · Article · Jan 2013
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    • "Other hereditary liver diseases have been associated with increased risk of HCC development, such as autoimmune hepatitis (RR 23) [69], porphyria (RR 5–36) [70, 71], α1-antitrypsin deficiency (RR 5) [72], progressive familial intrahepatic cholestasis (RR 3.7) [73, 74], glycogen storage disease type 1 (von Gierke disease) (RR unk.) [75], hereditary tyrosinemia type I (RR unk.) [76–78], Wilson's disease (RR unk.) [79], Niemann-Pick disease (RR unk.) [80], Gaucher disease (RR unk.) [81], and hereditary telangieatasias (RR unk.) [82, 83], but these associations are poorly studied due to the rarity of the disease processes. "
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    ABSTRACT: Hereditary etiologies of pancreatic and hepatobiliary cancers are increasingly recognized. An estimated >10% of pancreatic and increasing number of hepatobiliary cancers are hereditary. The cumulative risk of hereditary pancreatic cancer ranges from measurable but negligible in cystic fibrosis to a sobering 70% in cases of hereditary pancreatitis. Candidates for pancreatic cancer surveillance are those with a risk pancreatic cancer estimated to be >10-fold that of the normal population. Screening for pancreatic cancer in high-risk individuals is typically performed by endoscopic ultrasound and should begin at least 10 years prior to the age of the youngest affected relative. Disease states known to be associated with increased risk of hepatocellular cancer include hereditary hemochromatosis, autoimmune hepatitis, porphyria, and α1-antitrypsin deficiency, with relative risks as high as 36-fold. Although much less is known about hereditary bile-duct cancers, Muir-Torre syndrome and bile salt export pump deficiency are diseases whose association with hereditary carcinogenesis is under investigation.
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    • "While in most ways the clinical features of PFIC-2 are similar to PFIC-1 (FIC1 disease due to mutations in ATP8B1), it is uniquely associated with substantially increased risk of hepatobiliary cancer. Early presentation of hepatocellular carcinoma (HCC) was reported in 10 children with BSEP disease [2], and cholangiocarcinoma, a very rare cancer in children, was reported in 2 cases [3]. In a large survey of families with severe BSEP disease, 15% of patients developed HCC or cholangiocarcinoma [1]. "
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    ABSTRACT: BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer. A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 x 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat. Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.
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