In the Journals

FGF21 protein may predict severity of NASH in obesity, diabetes

Measurement of fibroblast growth factor 21, a protein widely expressed in the liver, may predict the severity of nonalcoholic steatohepatitis in adults with obesity or type 2 diabetes, according to findings published in The Journal of Clinical Endocrinology & Metabolism.

Kenneth Cusi

“Plasma fibroblast growth factor 21 (FGF21) correlates with severe steatohepatitis in patients with nonalcoholic steatohepatitis (NASH), and in particular, fibrosis, the most important feature that determines the progression of disease,” Kenneth Cusi, MD, FACP, FACE, professor of medicine and chief of the division of endocrinology, diabetes and metabolism at the University of Florida and Endocrine Today Editorial Board member, said in an interview. “We also saw that, as patients become more insulin resistant in muscle and adipose tissue, they had higher levels of FGF21. This protein could potentially identify those at the highest risk for disease progression.”

In a cross-sectional study, Cusi and colleagues analyzed data from 187 patients with a BMI greater than 25 kg/m² recruited from the general population of San Antonio (80% with obesity). All patients underwent a 2-hour oral glucose tolerance test to diagnose or confirm prediabetes or type 2 diabetes. Researchers assessed insulin resistance via euglycemic-hyperinsulinemic clamp, intrahepatic triglycerides via liver magnetic resonance spectoscropy and fasting plasma FGF21 levels. Participants with nonalcoholic fatty liver disease (NAFLD) also underwent a liver biopsy (n = 146). Researchers stratified patients by three groups: No NAFLD (n = 41; mean age, 55 years; 68% men; 51% with type 2 diabetes), patients with isolated steatosis or borderline NASH (n = 52; mean age, 48 years; 73% men; 54% with type 2 diabetes) and patients with NASH (n = 94; mean age, 50 years; 73% men; 54% with type 2 diabetes).

Researchers found that plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (P = .006) and skeletal muscle (P = .007), but not with liver insulin sensitivity. Patients with NASH had higher FGF21 levels than those without NASH (mean, 453 pg/mL vs. 341 pg/mL; P = .03) or no NAFLD (mean, 325 pg/mL; P = .02). The observed between-group differences in FGF21 levels were independent of obesity, the researchers noted, as patients with and without NASH had a comparable BMI (mean, 34.8 kg/m² vs. 33.8 kg/m², respectively).

“Of note, plasma FGF21 levels also correlated with visceral fat on MRI, but not with total body fat as measured by DXA, confirming that factors beyond total adiposity play a role in the control of FGF21 metabolism,” the researchers wrote.

Additionally, plasma FGF21 increased with the severity of necroinflammation (P = .02) and with worsening fibrosis (P < .001) but not with worsening steatosis (P = .6), according to researchers.

“We don’t really understand what the mechanism is that leads to NASH in two individuals with similar risk factors, like obesity and diabetes,” Cusi said. “These findings imply that plasma FGF21 does have a significant role in the pathogenesis of the disease.”

Cusi, who called the findings intriguing, said it is still premature to suggest routinely measuring plasma FGF21 in patients with obesity and NASH, and more studies are needed to strengthen the observed association. He added that several studies are ongoing assessing the effectiveness of FGF21 analogues in patients with obesity and NASH.

“Studies on the correlation between liver fat and FGF21 have been mixed,” Cusi said. “What makes this study unique is the large number of people who underwent gold-standard measurements of liver fat and insulin resistance, with most also undergoing a liver biopsy.”

Cusi noted that type 2 diabetes appears to worsen the course of NAFLD; the most recent American Diabetes Association’s Standards of Medical Care in Diabetes states physicians should screen for fibrosis in patients with diabetes and steatosis or with elevated liver enzyme levels.

“Practitioners need to be thinking more about the potential presence of NASH in their patients with obesity and diabetes,” Cusi said. – by Regina Schaffer

For more information:

Kenneth Cusi, MD, FACP, FACE, can be reached at University of Florida College of Medicine, 1600 SW Archer Road, Room H-2, Gainesville, FL 32610; email: Kenneth.cusi@medicine.ufl.edu.

Disclosures: Cusi reports he has received researcher support from Cirius, Inventiva, Janssen, Novartis, Novo Nordisk and Zydus, and serves as a consultant for Bristol-Myers Squibb, Coherus, Deuterex, Eli Lilly, Janssen, Novo Nordisk, Pfizer, Poxel, Sanofi and Tobira Therapeutics.

Measurement of fibroblast growth factor 21, a protein widely expressed in the liver, may predict the severity of nonalcoholic steatohepatitis in adults with obesity or type 2 diabetes, according to findings published in The Journal of Clinical Endocrinology & Metabolism.

Kenneth Cusi

“Plasma fibroblast growth factor 21 (FGF21) correlates with severe steatohepatitis in patients with nonalcoholic steatohepatitis (NASH), and in particular, fibrosis, the most important feature that determines the progression of disease,” Kenneth Cusi, MD, FACP, FACE, professor of medicine and chief of the division of endocrinology, diabetes and metabolism at the University of Florida and Endocrine Today Editorial Board member, said in an interview. “We also saw that, as patients become more insulin resistant in muscle and adipose tissue, they had higher levels of FGF21. This protein could potentially identify those at the highest risk for disease progression.”

In a cross-sectional study, Cusi and colleagues analyzed data from 187 patients with a BMI greater than 25 kg/m² recruited from the general population of San Antonio (80% with obesity). All patients underwent a 2-hour oral glucose tolerance test to diagnose or confirm prediabetes or type 2 diabetes. Researchers assessed insulin resistance via euglycemic-hyperinsulinemic clamp, intrahepatic triglycerides via liver magnetic resonance spectoscropy and fasting plasma FGF21 levels. Participants with nonalcoholic fatty liver disease (NAFLD) also underwent a liver biopsy (n = 146). Researchers stratified patients by three groups: No NAFLD (n = 41; mean age, 55 years; 68% men; 51% with type 2 diabetes), patients with isolated steatosis or borderline NASH (n = 52; mean age, 48 years; 73% men; 54% with type 2 diabetes) and patients with NASH (n = 94; mean age, 50 years; 73% men; 54% with type 2 diabetes).

Researchers found that plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (P = .006) and skeletal muscle (P = .007), but not with liver insulin sensitivity. Patients with NASH had higher FGF21 levels than those without NASH (mean, 453 pg/mL vs. 341 pg/mL; P = .03) or no NAFLD (mean, 325 pg/mL; P = .02). The observed between-group differences in FGF21 levels were independent of obesity, the researchers noted, as patients with and without NASH had a comparable BMI (mean, 34.8 kg/m² vs. 33.8 kg/m², respectively).

“Of note, plasma FGF21 levels also correlated with visceral fat on MRI, but not with total body fat as measured by DXA, confirming that factors beyond total adiposity play a role in the control of FGF21 metabolism,” the researchers wrote.

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Additionally, plasma FGF21 increased with the severity of necroinflammation (P = .02) and with worsening fibrosis (P < .001) but not with worsening steatosis (P = .6), according to researchers.

“We don’t really understand what the mechanism is that leads to NASH in two individuals with similar risk factors, like obesity and diabetes,” Cusi said. “These findings imply that plasma FGF21 does have a significant role in the pathogenesis of the disease.”

Cusi, who called the findings intriguing, said it is still premature to suggest routinely measuring plasma FGF21 in patients with obesity and NASH, and more studies are needed to strengthen the observed association. He added that several studies are ongoing assessing the effectiveness of FGF21 analogues in patients with obesity and NASH.

“Studies on the correlation between liver fat and FGF21 have been mixed,” Cusi said. “What makes this study unique is the large number of people who underwent gold-standard measurements of liver fat and insulin resistance, with most also undergoing a liver biopsy.”

Cusi noted that type 2 diabetes appears to worsen the course of NAFLD; the most recent American Diabetes Association’s Standards of Medical Care in Diabetes states physicians should screen for fibrosis in patients with diabetes and steatosis or with elevated liver enzyme levels.

“Practitioners need to be thinking more about the potential presence of NASH in their patients with obesity and diabetes,” Cusi said. – by Regina Schaffer

For more information:

Kenneth Cusi, MD, FACP, FACE, can be reached at University of Florida College of Medicine, 1600 SW Archer Road, Room H-2, Gainesville, FL 32610; email: Kenneth.cusi@medicine.ufl.edu.

Disclosures: Cusi reports he has received researcher support from Cirius, Inventiva, Janssen, Novartis, Novo Nordisk and Zydus, and serves as a consultant for Bristol-Myers Squibb, Coherus, Deuterex, Eli Lilly, Janssen, Novo Nordisk, Pfizer, Poxel, Sanofi and Tobira Therapeutics.