Low LDL-C and high HDL-C levels are associated with elevated serum transaminases amongst adults in the United States: a cross-sectional study

Abstract

Background: Dyslipidemia, typically recognized as high serum triglyceride, high low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels, are associated with nonalcoholic fatty liver disease (NAFLD). However, low LDL-C levels could result from defects in lipoprotein metabolism or impaired liver synthetic function, and may serve as ab initio markers for unrecognized liver diseases. Whether such relationships exist in the general population has not been investigated. We hypothesized that despite common conception that low LDL-C is desirable, it might be associated with elevated liver enzymes due to metabolic liver diseases.

Methods and findings: We examined the associations between alanine aminotransferase (ALT), aspartate aminotransferase (AST) and major components of serum lipid profiles in a nationally representative sample of 23,073 individuals, who had no chronic viral hepatitis and were not taking lipid-lowering medications, from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010. ALT and AST exhibited non-linear U-shaped associations with LDL-C and HDL-C, but not with triglyceride. After adjusting for potential confounders, individuals with LDL-C less than 40 and 41-70 mg/dL were associated with 4.2 (95% CI 1.5-11.7, p = 0.007) and 1.6 (95% CI 1.1-2.5, p = 0.03) times higher odds of abnormal liver enzymes respectively, when compared with those with LDL-C values 71-100 mg/dL (reference group). Surprisingly, those with HDL-C levels above 100 mg/dL was associated with 3.2 (95% CI 2.1-5.0, p<0.001) times higher odds of abnormal liver enzymes, compared with HDL-C values of 61-80 mg/dL.

Conclusions: Both low LDL-C and high HDL-C, often viewed as desirable, were associated with significantly higher odds of elevated transaminases in the general U.S. adult population. Our findings underscore an underestimated biological link between lipoprotein metabolism and liver diseases, and raise a potential need for liver evaluation among over 10 million people with particularly low LDL-C or high HDL-C in the United States.

Figure 1. Description of eligible study participants.

A total of 30,752 individuals aged 20 years or older were identified from NHANES from 1999 to 2010. Two separate datasets were generated for fasting and nonfasting lab values. In each dataset, participants with evidence of viral hepatitis B or C, currently taking lipid lowering medications, or missing lipoprotein, transaminase, or covariate measurements were excluded. This resulted in a nonfasting dataset of 23,073 observations and fasting dataset of 10,106 observations.

Figure 2. Association curves between ALT, AST and LDL-C, HDL-C and triglyceride.

The relationship between ALT, AST and LDL-C, HDL-C and triglycerides were modeled with unadjusted restricted cubic spline models. Evenly distributed conventional lipid profile cutoff points were chosen as knots in generating the model, with LDL-C at 40, 70, 100, 130, 160 mg/dL; HDL-C at 20, 30, 40, 60, 80, 100 mg/dL, and triglyceride at 50, 100, 150, 200, 250 mg/dL. Sample weights were taken into consideration during the modeling to represent the association in the general US population.