High-calorie diet may worsen Wilson disease

Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.

“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”

Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.

“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H₂O₂. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”

To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.

“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.

The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.

SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.