The role of liver fat and insulin resistance as determinants of plasma aminotransferase elevation in nonalcoholic fatty liver disease

Abstract

Plasma aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are usually increased in patients with nonalcoholic fatty liver disease (NAFLD). However, the factors behind their elevation remain unclear. The aim of this study was to assess the role of insulin resistance (IR) and liver triglyceride content in relation to histology in patients with NAFLD/nonalcoholic steatohepatitis (NASH) with normal or elevated ALT levels. To this end, we enrolled 440 patients, divided into three groups: no NAFLD (n 5 60); NAFLD with normal ALT (n 5 165); and NAFLD with elevated ALT (n 5 215). We measured: (1) liver fat by proton magnetic resonance spectroscopy ( 1 H-MRS); (2) severity of liver disease by biopsy (n 5 293); and (3) insulin sensitivity in liver, muscle, and adipose tissue by a euglycemic hyperinsulinemic clamp with 3-3 H-glucose. Patients with NAFLD and elevated ALT, even when well matched for body mass index to those with normal ALT, had worse adipose tissue insulin resistance (ATIR; P < 0.0001), higher liver triglyceride content (P < 0.0001), and lower plasma adiponectin (P < 0.05), but no differences in hepatic insulin resistance. Similar results were found when only patients with NASH were compared: both ATIR (P < 0.0001) and liver triglyceride content by 1 H-MRS (P < 0.0001) were worse in NASH with elevated ALT. Consistent with the 1 H-MRS data, steatosis on liver biopsy was also significantly increased in patients with NASH and elevated ALT levels (P < 0.0001). However, and most important, there were no differences in inflammation (P 5 0.62), ballooning (P 5 0.13), or fibrosis (P 5 0.12). Conclusion: In patients with NAFLD or NASH, ATIR (but not HIR) and liver triglyceride content are major factors in the elevation of plasma aminotransferase levels. Patients with normal versus elevated ALT had similar severity of NASH, suggesting that plasma aminotransferase levels are misleading parameters for guiding clinical management. (HEPATOLOGY 2015;61:153-160)

Plasma Thyroid Hormone Concentration is Associated with Hepatic Triglyceride Content in Patients with Type 2 Diabetes

“…We observed a trend toward lower plasma alanine and aspartate aminotransferases with increasing plasma free T4. These results are in accordance with previous reports,21 and emphasize results from our own laboratory suggesting that plasma alanine and aspartate aminotransferases are a better reflection of the severity of hepatic triglyceride accumulation rather than of other histological parameters such as inflammation, ballooning, or fibrosis 22. The fact that plasma free T4 levels were significantly correlated with acetyl and butyrylcarnitine (independently of hepatic triglyceride content) supports the role of free T4 in modulating β-oxidation in patients with NAFLD.…”

Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis

“…The apparent lack of differences in ALT concentrations between groups found in the present study might have resulted from the lack of impaired overall glucose tolerance and the rather early signs of impairments of insulin signaling. Indeed, recent studies suggest that insulin resistance in adipose tissue, high liver TG content, and low plasma adiponectin are major factors in the elevation of plasma aminotransferase concentrations in patients with NAFLD, whereas hepatic insulin resistance seems to be of lesser importance in this respect (27). Here, in livers of WSD-fed mice, mRNA expression of Insr, Irs1, and Irs2 was similar to controls, suggesting that insulin signaling was not yet altered.…”

Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups

“…Most T2DM patients with NAFLD have normal serum liver enzymes, which is not reassuring given that NASH, advanced fibrosis and even cirrhosis may be found in such "normal" liver enzymes individuals. 4,89,112 Accordingly, NAFLD prevalence is much higher (76%) than previously believed in overweight/obese T2DM patients with normal serum aminotransferases, and that 56% of these patients had histologically-proven NASH. 113 Collectively, these studies imply that the "normal" range of serum liver enzymes needs to be lowered to capture more NAFLD cases.…”