Low LDL-C and High HDL-C Levels Are Associated with Elevated Serum Transaminases amongst Adults in the United States: A Cross-sectional Study

PLOS ONE, Dec 2019

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.

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Low LDL-C and High HDL-C Levels Are Associated with Elevated Serum Transaminases amongst Adults in the United States: A Cross-sectional Study

Tsugawa Y (2014) Low LDL-C and High HDL-C Levels Are Associated with Elevated Serum Transaminases amongst Adults in the United States: A Cross-sectional Study. PLoS ONE 9(1): e85366. doi:10.1371/journal.pone.0085366 Low LDL-C and High HDL-C Levels Are Associated with Elevated Serum Transaminases amongst Adults in the United States: A Cross-sectional Study Zhenghui Gordon Jiang 0 Kenneth Mukamal 0 Elliot Tapper 0 Simon C. Robson 0 Yusuke Tsugawa 0 0 1 Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , Massachusetts, United States of America, 2 Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , Massachusetts, United States of America, 3 Harvard University Interfaculty Initiative in Health Policy, Harvard University , Cambridge, Massachusetts , United States of America 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. - Competing Interests: The authors have declared that no competing interests exist. Measurement of triglyceride and cholesterol concentrations among different lipoproteins as part of the serum lipid panel is a routine part of cardiovascular disease risk stratification. It is rarely considered a useful screening tool for the evaluation of liver diseases, yet there is reason to think otherwise. The liver is the central hub for lipid metabolism and controls the production and clearance of serum lipoproteins [1,2]. Hence, liver disease is likely to be intimately related to serum lipid levels. Dyslipidemia typically refers to elevated LDL-C or triglyceride or low HDL-C, a pattern that is associated with cardiovascular risk and is also frequently seen in nonalcoholic fatty liver disease (NAFLD) [3,4]. NAFLD, a spectrum of disease ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis, is the most common form of chronic liver disease and the most likely cause of elevated transaminases in otherwise healthy individuals [4,5]. Up to 3346% of the US population may have NAFLD, among whom 3% eventually develop endstage liver disease [68]. Hepatic steatosis, the critical first hit of NAFLD, fundamentally results from imbalanced intrahepatic lipid homeostasis leading to triglyceride accumulation [9]. Insulin resistance, as seen in metabolic syndrome, a common cause of dyslipidemia, is thought to be a primary driver of NAFLD [6,7,10,11]. In population-based epidemiological studies, factors associated with elevated ALT include higher age, male gender, high waist circumference, high triglyceride level, and biomarkers consistent with insulin resistance [4]. However, steatosis does not always concord with dyslipidemia. Two classic examples are abetalipoproteinemia and familial hypobetalipoproteinemia (FHBL), genetic conditions characterized by inadequate assembly and secr (...truncated)


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Zhenghui Gordon Jiang, Kenneth Mukamal, Elliot Tapper, Simon C. Robson, Yusuke Tsugawa. Low LDL-C and High HDL-C Levels Are Associated with Elevated Serum Transaminases amongst Adults in the United States: A Cross-sectional Study, PLOS ONE, 2014, 1, DOI: 10.1371/journal.pone.0085366