Home
JournalsCollections
For Authors For Reviewers For Editorial Board Members
Article Processing Charges Open Access
Ethics Advertising Policy
Editorial Policy Resource Center
Company Information Contact Us
OPEN ACCESS

Pediatric Hepatocellular Carcinoma: Metabolic Causes and Possible Prevention

  • Hakim Rahmoune1,2,*,
  • Nada Boutrid1,2,
  • Mounira Amrane2 and
  • Belkacem Bioud1,2
Journal of Exploratory Research in Pharmacology   2019;4(2):19-20

doi: 10.14218/JERP.2019.00002

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Rahmoune H, Boutrid N, Amrane M, Bioud B. Pediatric Hepatocellular Carcinoma: Metabolic Causes and Possible Prevention. J Explor Res Pharmacol. 2019;4(2):19-20. doi: 10.14218/JERP.2019.00002.

Dear Editor,

Hepatocellular carcinoma is a devastating malignancy in childhood. We highlight some specific aspects in the pediatric population, especially involving metabolic diseases like tyrosinemia type 1.

Pediatric hepatocellular carcinoma is the second most common malignant liver cancer and differs from the adult form in its etiologies, biological behavior, and low frequency of cirrhosis.1,2 The main pediatric causes of hepatocellular carcinoma are hepatitis B virus infection and genetic/metabolic disorders, such as hepatorenal tyrosinemia, familial progressive intrahepatic cholestasis, glycogen storage diseases, and Alagille’s syndrome.2

The age that hepatocellular carcinoma typically affects children is 10–14 years (median), and it is often metastatic or locally advanced at diagnosis. However, due to mass immunization against hepatitis B virus, the epidemiologic and clinical profiles of pediatric hepatocellular carcinoma are shifting; younger patients with congenital and metabolic liver disease now make up the major portion of patients with hepatocellular carcinoma.3 Thus, management of any predisposing liver disease is highly recommended for preventing and detecting hepatocellular carcinoma.2,4

Currently, the most important metabolic disorder leading to hepatocellular carcinoma is tyrosinemia type I (hepatorenal tyrosinemia), an autosomal recessive condition resulting in hepatic failure with renal and neurological comorbidities and long-term risks for hepatic carcinoma.5 In fact, due to the enzyme deficiency (fumarylacetoacetate hydrolase deficiency) in hepatorenal tyrosinemia, the substrate fumarylacetoacetate accumulates. This accumulating fumarylacetoacetate and its precursor, maleylacetoacetate, is mutagenic and causes chromosomal instability, cell cycle arrest, and apoptosis, leading first to liver cirrhosis and later on to hepatocellular carcinoma.6 The molecular basis of the pathogenic liver process in hepatorenal tyrosinemia is still unclear. Multiple signaling pathways involved in cell proliferation, differentiation, and cancer have been found to be rapidly deregulated in hepatorenal tyrosinemia-model mice. The p21 and mTOR pathways, critical regulators of proliferation and tumorigenesis, have also been found to be dysregulated.7

Interestingly, an effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione exists.5–7 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione prevents the development of hepatocellular carcinoma when started early but fails to stop this malignancy if prescribed at a later stage, stressing the importance of a prompt diagnosis and management of hepatorenal tyrosinemia.8 Prior to the availability of 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione for the treatment of hepatorenal tyrosinemia, the only definitive therapy of liver damage was transplantation. Nowadays, hepatic grafting is reserved for hepatorenal tyrosinemia pediatric cases with severe liver failure who fail to respond to 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione therapy or those with documented evidence of malignant changes.9–10

Declarations

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Conceptualization (HR, MA), writing the original draft (HR, NB), review and editing (HR, BN, BB).

References

  1. Forner A, Da Fonseca LG, Díaz-González Á, Sanduzzi-Zamparelli M, Reig M, Bruix J. Controversies in the management of hepatocellular carcinoma. JHEP Reports 2019;1:17-29 View Article PubMed/NCBI
  2. Khanna R, Verma SK. Pediatric hepatocellular carcinoma. World J Gastroenterol 2018;24:3980 View Article PubMed/NCBI
  3. Palaniappan K, Borkar VV, Safwan M, Vij M, Govil S, Shanmugam N. Pediatric hepatocellular carcinoma in a developing country: Is the etiology changing?. Pediatr Transplant 2016;20:898-903 View Article PubMed/NCBI
  4. Weeda VB, Aronson DC, Verheij J, Lamers WH. Is hepatocellular carcinoma the same disease in children and adults? Comparison of histology, molecular background, and treatment in pediatric and adult patients. Pediatr Blood Cancer 2019;66:e27475 View Article PubMed/NCBI
  5. Chinsky JM, Singh R, Ficicioglu C, Van Karnebeek CD, Grompe M, Mitchell G. Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations. Genet Med 2017;19:1380 View Article PubMed/NCBI
  6. van Ginkel WG, Pennings JP, van Spronsen FJ. Liver cancer in tyrosinemia type 1. Adv Exp Med Biol 2017;959:101-109 View Article PubMed/NCBI
  7. Tanguay RM, Angileri F, Vogel A. Hereditary Tyrosinemia. Cham: Springer; 2017, 49-64 View Article PubMed/NCBI
  8. van Ginkel WG, Pennings JP, van Spronsen FJ. Hereditary Tyrosinemia. Cham: Springer; 2017, 101-109 View Article PubMed/NCBI
  9. Sniderman King L, Trahms C, Scott CR. Tyrosinemia type I. 2006 Jul 24 [Updated 2017 May 25, cited 2019 May 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1515/ View Article PubMed/NCBI
  10. Bartlett DC, Lloyd C, McKiernan PJ, Newsome PN. Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function. J Inherit Metab Dis 2014;37:745-752 View Article PubMed/NCBI