Surjan Rodrigo Cañada T, de Lima Thais M, de Souza Heraldo P, Machado Marcel Cerqueira C, Ardengh José C
Surgery, Hospital 9 de Julho, São Paulo, BRA.
Clinical Emergencies Laboratory LIM 51, University of São Paulo, São Paulo, BRA.
Cureus. 2023 Jan 13;15(1):e33750. doi: 10.7759/cureus.33750. eCollection 2023 Jan.
Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma. The mechanism involved in hyperammonemia in patients with fibrolamellar carcinoma was unclear until a possible physiopathological pathway was recently proposed. An ornithine transcarboxylase dysfunction was suggested as a result of increased ornithine decarboxylase activity induced by c-Myc overexpression. This c-Myc overexpression resulted from Aurora kinase A overexpression derived from the activity of a chimeric kinase that is the final transcript of a deletion in chromosome 19, common to all fibrolamellar carcinomas. We performed the analysis of the expression of all enzymes involved and tested for the mutation in chromosome 19 in fresh frozen samples of fibrolamellar hepatocellular carcinoma, non-tumor liver, and hepatic adenomatosis. The specific DNAJB-PRKACA fusion protein that results from the recurrent mutation on chromosome 19 common to all fibrolamellar carcinoma was detected only in the fibrolamellar carcinoma sample. Fibrolamellar carcinoma and adenomyomatosis samples presented increased expression of Aurora kinase A, c-MYC, and ornithine decarboxylase when compared to normal liver, while ornithine transcarbamylase was decreased. The proposed physiopathological pathway is correct and that overexpression of c-Myc may also be responsible for hyperammonemia in patients with other types of rapidly growing hepatomas. This gives further evidence to apply new and adequate treatment to this severe complication.
高氨血症性脑病是一种与纤维板层型肝细胞癌相关的潜在致命疾病。在一种可能的生理病理途径最近被提出之前，纤维板层型癌患者高氨血症的发病机制尚不清楚。有人提出，c-Myc过表达诱导鸟氨酸脱羧酶活性增加，导致鸟氨酸转羧酶功能障碍。这种c-Myc过表达源于Aurora激酶A过表达，而Aurora激酶A过表达源自一种嵌合激酶的活性，该嵌合激酶是19号染色体缺失的最终转录产物，在所有纤维板层型癌中都很常见。我们对纤维板层型肝细胞癌、非肿瘤肝脏和肝腺瘤病的新鲜冷冻样本中所有相关酶的表达进行了分析，并检测了19号染色体的突变情况。仅在纤维板层型癌样本中检测到了由所有纤维板层型癌共有的19号染色体反复突变产生的特异性DNAJB-PRKACA融合蛋白。与正常肝脏相比，纤维板层型癌和腺肌瘤病样本中Aurora激酶A、c-MYC和鸟氨酸脱羧酶的表达增加，而鸟氨酸转氨甲酰酶减少。所提出的生理病理途径是正确的，c-Myc过表达也可能是其他类型快速生长肝癌患者高氨血症的原因。这为针对这种严重并发症应用新的适当治疗方法提供了进一步的证据。
