High-calorie diet may worsen Wilson disease

A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.

If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.

“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.

“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.

The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”

Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.

“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.

 

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.

A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.

If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.

“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.

“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.

The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”

Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.

“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.

 

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.

A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.

If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.

“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.

“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.

The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”

Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.

“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.

 

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.