Surjan RC, Santos ES, Silveira SD, Makdissi FF, Machado MA

Clin Mol Hepatol

Fibrolamellar hepatocellular carcinoma-related hyperammonemic encephalopathy: up to now and next steps

Fibrolamellar hepatocellular carcinoma (FLHCC) is indeed a rare
primary hepatic tumor that arises in non-cirrhotic livers, more
common in males (male to female ratio 1.7), with age-specific incidence
with two peaks between ages of 10–30 and 60–69 (although
being a tumor usually believed to affect mostly very young
individuals) and is associated with better 5-year survival than
conventional hepatocellular carcinoma (HCC).2 Although FLHCC
was usually referred as a subtype of HCC, recent researches have
demonstrated that FLHCC is actually an independent entity, with
distinctive molecular tumor profile, histological features and clinical
One of the most feared complications associated with FLHCC is
the development of acute onset hyperammonemic encephalopathy
(HAE), which was first reported by Sethi et al.5 in 2009, this
condition is associated with high mortality.6
High mortality was related to the ignorance of the physiopathology
of HAE in patients with FLHCC. Some authors have proposed
some explanations, such as portosystemic shunt.5,7 In 2017,
we published a new proposal of the physiopathology of this complication
of FLHCC, and initiated with the very unique mutation (a
heterozygous deletion of chromosome 19) that is responsible for
the development of the tumor. This mutation is responsbile for
overexperssion of a chimeric DNAJB1-PRKACA kinase and Aurora
Kinase A that culminate with c-Myc and ornithine decarboxylase
dysfunction and result in depletion of amino acids crucial to urea
cycle function.8 This urea cycle dysfuntion is then responsible for
the acummulation of ammonia in the bloodsteram and occurs
The importance of this finding was, once understanding that an
urea cycle disorder due to metabolites consumption was responsible
for the hyperammonemia, to guide the developement of new
medical treatment options based on a combination of ammonia
scavenger drugs (sodium benzoate and phenylbutyrate) with amino
acids supplementation (citrulline, ornithine and arginine), thus
reducing the mortality of FLHCC-related HAE and allowing complete
clinical recovery from HAE