Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease

Abstract

BaCKgRoUND aND aIMS: Whether glycemic control, as opposed to diabetes status, is associated with the severity of NAFLD is open for study. We aimed to evaluate whether degree of glycemic control in the years preceding liver biopsy predicts the histological severity of NASH.appRoaCH aND ReSUltS: Using the Duke NAFLD Clinical Database, we examined patients with biopsy-proven NAFLD/NASH (n = 713) and the association of liver injury with glycemic control as measured by hemoglobin A1c (HbA1c). The study cohort was predominantly female (59%) and White (84%) with median (interquartile range) age of 50 (42, 58) years; 49% had diabetes (n = 348). Generalized linear regression models adjusted for age, sex, race, diabetes, body mass index, and hyperlipidemia were used to assess the association between mean HbA1c over the year preceding liver biopsy and severity of histological features of NAFLD/NASH. Histological features were graded and staged according to the NASH Clinical Research Network system. Group-based trajectory analysis was used to examine patients with at least three HbA1c (n = 298) measures over 5 years preceding clinically indicated liver biopsy. Higher mean HbA1c was associated with higher grade of steatosis and ballooned hepatocytes, but not lobular inflammation. Every 1% increase in mean HbA1c was associated with 15% higher odds of increased fibrosis stage (OR, 1.15; 95% CI, 1.01, 1.31). As compared with good glycemic control, moderate control was significantly associated with increased severity of ballooned hepatocytes (OR, 1.74; 95% CI, 1.01, 3.01; P = 0.048) and hepatic fibrosis (HF; OR, 4.59; 95% CI, 2.33, 9.06; P < 0.01).CoNClUSIoNS: Glycemic control predicts severity of ballooned hepatocytes and HF in NAFLD/NASH, and thus optimizing glycemic control may be a means of modifying risk of NASH-related fibrosis progression. (Hepatology 2021;0:1-14). NAFLD is a growing epidemic, affecting 1 in 4 persons worldwide (1,2) and ~60% of patients with type 2 diabetes (T2D). (3,4) The term NAFLD encompasses a disease spectrum with isolated steatosis on the most benign end, to NASH characterized by steatosis, inflammation, and ballooned hepatocytes, with or without fibrosis. (5) NASH increases the risk of fibrosis progression to cirrhosis with risk of hepatic decompensation and HCC, making NASH

High frequency and long persistency of ballooning hepatocyte were associated with glucose intolerance in patients with severe obesity

“…Thus, hepatocyte ballooning is considered a key finding regarding insulin resistance in the liver. This finding was proved by another research of observational study for NASH patients with or without insulin resistance 9 .…”

“…Still, the mechanism by which the liver affects glucose metabolism following weight reduction by metabolic surgery remains unknown in patients with persistent glucose intolerance or T2DM. Histological findings of the liver are associated with present metabolic status and may predict the clinical course after metabolic surgery since the liver is the central organ of metabolism 9 . Histological findings associated with a functional cure for glucose metabolism or those associated with persistent glucose intolerance and/or insulin resistance can, therefore, be used to establish appropriate therapeutic strategies for patients after metabolic surgery.…”

Underrecognition of Nonalcoholic Fatty Liver Disease in Poorly Controlled Diabetes: A Call to Action in Diabetes Care

“…Our data demonstrate a decrease in AST levels with worsening glycemic control, as well as a correlated decline in FIB-4 scores. Since higher HbA1c has been associated with more severe fibrosis on liver biopsy [ 9 , 27 ] (ie, the gold standard for diagnosing fibrosis), our data suggest that the performance of FIB-4 may vary by glycemic control. While evidence so far suggests good accuracy of FIB-4 in well-controlled T2DM populations, it is important to note that its specificity may be high in T2DM (97%), but sensitivity can be as low as 22% [ 25 ].…”

“…T2DM also leads to a substantial increase in the risk of NAFLD complications, including a 2-fold increase in hepatocellular carcinoma and liver-related mortality risk [ 7 , 8 ]. Recent evidence also suggests that beyond the presence of T2DM, glycemic control may be linked to greater severity of liver fibrosis in NAFLD [ 9 ]. Therefore, individuals with poor glycemic control may be at particular risk of progressive NAFLD and poor liver outcomes.…”

The Importance of Glycemic Equipoise in NASH

“…In this issue, Alexopoulos et al ( 3 ) aimed to examine the association between glycemic control and histological severity of NASH. In this retrospective analysis of 713 patients from the Duke NAFLD Clinical Database, they found that higher hemoglobin A1c (HbA1c) was associated with higher grades of steatosis, hepatocyte ballooning (HB), and fibrosis.…”