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. 2013 Dec;145(6):1271-9.e1-3.
doi: 10.1053/j.gastro.2013.08.036. Epub 2013 Aug 21.

Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis

M Shadab Siddiqui  1 , Richard K Sterling, Velimir A Luketic, Puneet Puri, R Todd Stravitz, Iliana Bouneva, Sherry Boyett, Michael Fuchs, Carol Sargeant, G Russell Warnick, Shahrzad Grami, Arun J Sanyal
Affiliations

Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis

M Shadab Siddiqui et al. Gastroenterology. 2013 Dec.

Abstract

Background & aims: Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low-normal and high-normal levels of ALT and an extended panel of cardiovascular risk factors among individuals with no known diseases in a primary care setting.

Methods: We performed a retrospective analysis of data collected from 6442 asymptomatic patients at wellness visits to a primary care setting in central Virginia from 2010 through 2011. Serum levels of ALT were compared with levels of lipids and lipoproteins, as well as metabolic, inflammatory, and coagulation-related factors associated with risk for cardiovascular disease.

Results: Serum levels of ALT were higher than 40 IU/L in 12% of subjects, and in the high-normal range (19-40 IU/L in women and 31-40 IU/L in men) in 25% of subjects. ALT level was associated with the apolipoprotein B level, concentration and particle size of very-low-density lipoproteins, concentration of low-density lipoprotein (LDL) particles (LDL-P), and percentages of small dense LDL (sdLDL) and sdLDL-cholesterol (sdLDL-C) (P < .0001 for all). A high-normal level of ALT was associated with higher levels of LDL-C, LDL-P, sdLDL-C, and sdLDL particles (P < .001 for all). These effects were independent of age, body mass index, and hyperinsulinemia. Increasing levels of ALT and fasting hyperinsulinemia (>12 μU/mL) synergized with increasing levels of triglycerides, very-low-density lipoprotein particles, LDL-P, sdLDL-C, and percentage of sdLDL-C. Levels of APOA1, high-density lipoprotein-cholesterol, and high-density lipoprotein-class 2 were associated inversely with serum level of ALT (P < .0001 for all).

Conclusions: In an analysis of asymptomatic individuals, increased serum levels of ALT (even high-normal levels) are associated with markers of cardiovascular disease.

Keywords: ALT; Atherosclerosis; BMI; HDL; HDL(INC); HDL-C; HDL2-C; Health Diagnostic Laboratories; Heart Disease; LDL; LDL-C; LDL-P; NAFLD; NASH; TSH; VLDL; VLDL-P; alanine aminotransferase; apoA; apoB; apolipoprotein A; apolipoprotein B; body mass index; high-density lipoprotein; high-density lipoprotein cholesterol; high-density lipoprotein subclass II cholesterol; low-density lipoprotein; low-density lipoprotein cholesterol; low-density lipoprotein particles; nonalcoholic fatty liver disease; sdLDL; small dense low-density lipoprotein; thyroid-stimulating hormone; very-low-density lipoprotein; very-low-density lipoprotein particle.

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Figures

Figure 1
Figure 1
Serum ALT levels are directly related to very low density lipoprotein (VLDL) size (Figure 1A), % small dense LDL cholesterol (sdLDL-C) (Figure 1B), and desmosterol:cholesterol ratio (Figure 1D) in an apparently healthy population. Percent sdLDL-C is directly related to VLDL size (Figure 1C). Percent sdLDL-C and LDL-particle concentrations (LDL-P) increase from lean to overweight to obese cohorts (P <.001) (Figure 1D & 1E). Although % sdLDL-C and LDL-P were similar between overweight and obese individuals with normal ALT, they increased dramatically in those with elevated ALT (P <.01). (*P <.05 between normal and elevated ALT). All data represented as means ± S.E.M. Elevated ALT is defined as > 19 U/L in women and >31 U/L in women.
Figure 1
Figure 1
Serum ALT levels are directly related to very low density lipoprotein (VLDL) size (Figure 1A), % small dense LDL cholesterol (sdLDL-C) (Figure 1B), and desmosterol:cholesterol ratio (Figure 1D) in an apparently healthy population. Percent sdLDL-C is directly related to VLDL size (Figure 1C). Percent sdLDL-C and LDL-particle concentrations (LDL-P) increase from lean to overweight to obese cohorts (P <.001) (Figure 1D & 1E). Although % sdLDL-C and LDL-P were similar between overweight and obese individuals with normal ALT, they increased dramatically in those with elevated ALT (P <.01). (*P <.05 between normal and elevated ALT). All data represented as means ± S.E.M. Elevated ALT is defined as > 19 U/L in women and >31 U/L in women.
Figure 1
Figure 1
Serum ALT levels are directly related to very low density lipoprotein (VLDL) size (Figure 1A), % small dense LDL cholesterol (sdLDL-C) (Figure 1B), and desmosterol:cholesterol ratio (Figure 1D) in an apparently healthy population. Percent sdLDL-C is directly related to VLDL size (Figure 1C). Percent sdLDL-C and LDL-particle concentrations (LDL-P) increase from lean to overweight to obese cohorts (P <.001) (Figure 1D & 1E). Although % sdLDL-C and LDL-P were similar between overweight and obese individuals with normal ALT, they increased dramatically in those with elevated ALT (P <.01). (*P <.05 between normal and elevated ALT). All data represented as means ± S.E.M. Elevated ALT is defined as > 19 U/L in women and >31 U/L in women.
Figure 1
Figure 1
Serum ALT levels are directly related to very low density lipoprotein (VLDL) size (Figure 1A), % small dense LDL cholesterol (sdLDL-C) (Figure 1B), and desmosterol:cholesterol ratio (Figure 1D) in an apparently healthy population. Percent sdLDL-C is directly related to VLDL size (Figure 1C). Percent sdLDL-C and LDL-particle concentrations (LDL-P) increase from lean to overweight to obese cohorts (P <.001) (Figure 1D & 1E). Although % sdLDL-C and LDL-P were similar between overweight and obese individuals with normal ALT, they increased dramatically in those with elevated ALT (P <.01). (*P <.05 between normal and elevated ALT). All data represented as means ± S.E.M. Elevated ALT is defined as > 19 U/L in women and >31 U/L in women.
Figure 1
Figure 1
Serum ALT levels are directly related to very low density lipoprotein (VLDL) size (Figure 1A), % small dense LDL cholesterol (sdLDL-C) (Figure 1B), and desmosterol:cholesterol ratio (Figure 1D) in an apparently healthy population. Percent sdLDL-C is directly related to VLDL size (Figure 1C). Percent sdLDL-C and LDL-particle concentrations (LDL-P) increase from lean to overweight to obese cohorts (P <.001) (Figure 1D & 1E). Although % sdLDL-C and LDL-P were similar between overweight and obese individuals with normal ALT, they increased dramatically in those with elevated ALT (P <.01). (*P <.05 between normal and elevated ALT). All data represented as means ± S.E.M. Elevated ALT is defined as > 19 U/L in women and >31 U/L in women.
Figure 1
Figure 1
Serum ALT levels are directly related to very low density lipoprotein (VLDL) size (Figure 1A), % small dense LDL cholesterol (sdLDL-C) (Figure 1B), and desmosterol:cholesterol ratio (Figure 1D) in an apparently healthy population. Percent sdLDL-C is directly related to VLDL size (Figure 1C). Percent sdLDL-C and LDL-particle concentrations (LDL-P) increase from lean to overweight to obese cohorts (P <.001) (Figure 1D & 1E). Although % sdLDL-C and LDL-P were similar between overweight and obese individuals with normal ALT, they increased dramatically in those with elevated ALT (P <.01). (*P <.05 between normal and elevated ALT). All data represented as means ± S.E.M. Elevated ALT is defined as > 19 U/L in women and >31 U/L in women.
Figure 2
Figure 2
Liver fat score progressively increase from lowest ALT quartile (Q1) to the highest ALT quartile (Q4) (Figure 1A). LDL particle concentration (Figure 2B), % small dense LDL cholesterol (Figure 2C), VLDL size (Figure 2D), and small density LDL-cholesterol (Figure 2E) are increased in individuals with elevated liver fat across the three ALT groups. HDL-subclass 2 cholesterol (Figure 2F) is lower in individuals with increased liver fat scores. Low-normal (Low-Nml) ALT defined as ALT < 19 U/L in women and < 31 U/L in men, elevated ALT is defined as ALT > 40 U/L and high-normal (High-Nml) is any ALT values between these two groups. All data represented as means ± S.E.M. (*P <.001 between normal and increased liver fat)
Figure 2
Figure 2
Liver fat score progressively increase from lowest ALT quartile (Q1) to the highest ALT quartile (Q4) (Figure 1A). LDL particle concentration (Figure 2B), % small dense LDL cholesterol (Figure 2C), VLDL size (Figure 2D), and small density LDL-cholesterol (Figure 2E) are increased in individuals with elevated liver fat across the three ALT groups. HDL-subclass 2 cholesterol (Figure 2F) is lower in individuals with increased liver fat scores. Low-normal (Low-Nml) ALT defined as ALT < 19 U/L in women and < 31 U/L in men, elevated ALT is defined as ALT > 40 U/L and high-normal (High-Nml) is any ALT values between these two groups. All data represented as means ± S.E.M. (*P <.001 between normal and increased liver fat)
Figure 2
Figure 2
Liver fat score progressively increase from lowest ALT quartile (Q1) to the highest ALT quartile (Q4) (Figure 1A). LDL particle concentration (Figure 2B), % small dense LDL cholesterol (Figure 2C), VLDL size (Figure 2D), and small density LDL-cholesterol (Figure 2E) are increased in individuals with elevated liver fat across the three ALT groups. HDL-subclass 2 cholesterol (Figure 2F) is lower in individuals with increased liver fat scores. Low-normal (Low-Nml) ALT defined as ALT < 19 U/L in women and < 31 U/L in men, elevated ALT is defined as ALT > 40 U/L and high-normal (High-Nml) is any ALT values between these two groups. All data represented as means ± S.E.M. (*P <.001 between normal and increased liver fat)
Figure 2
Figure 2
Liver fat score progressively increase from lowest ALT quartile (Q1) to the highest ALT quartile (Q4) (Figure 1A). LDL particle concentration (Figure 2B), % small dense LDL cholesterol (Figure 2C), VLDL size (Figure 2D), and small density LDL-cholesterol (Figure 2E) are increased in individuals with elevated liver fat across the three ALT groups. HDL-subclass 2 cholesterol (Figure 2F) is lower in individuals with increased liver fat scores. Low-normal (Low-Nml) ALT defined as ALT < 19 U/L in women and < 31 U/L in men, elevated ALT is defined as ALT > 40 U/L and high-normal (High-Nml) is any ALT values between these two groups. All data represented as means ± S.E.M. (*P <.001 between normal and increased liver fat)
Figure 2
Figure 2
Liver fat score progressively increase from lowest ALT quartile (Q1) to the highest ALT quartile (Q4) (Figure 1A). LDL particle concentration (Figure 2B), % small dense LDL cholesterol (Figure 2C), VLDL size (Figure 2D), and small density LDL-cholesterol (Figure 2E) are increased in individuals with elevated liver fat across the three ALT groups. HDL-subclass 2 cholesterol (Figure 2F) is lower in individuals with increased liver fat scores. Low-normal (Low-Nml) ALT defined as ALT < 19 U/L in women and < 31 U/L in men, elevated ALT is defined as ALT > 40 U/L and high-normal (High-Nml) is any ALT values between these two groups. All data represented as means ± S.E.M. (*P <.001 between normal and increased liver fat)
Figure 2
Figure 2
Liver fat score progressively increase from lowest ALT quartile (Q1) to the highest ALT quartile (Q4) (Figure 1A). LDL particle concentration (Figure 2B), % small dense LDL cholesterol (Figure 2C), VLDL size (Figure 2D), and small density LDL-cholesterol (Figure 2E) are increased in individuals with elevated liver fat across the three ALT groups. HDL-subclass 2 cholesterol (Figure 2F) is lower in individuals with increased liver fat scores. Low-normal (Low-Nml) ALT defined as ALT < 19 U/L in women and < 31 U/L in men, elevated ALT is defined as ALT > 40 U/L and high-normal (High-Nml) is any ALT values between these two groups. All data represented as means ± S.E.M. (*P <.001 between normal and increased liver fat)
Figure 3
Figure 3
Presence of elevated ALT was associated with worsening expanded cardiovascular profile in both individuals with normal or elevated serum insulin concentrations. There was a synergistic increase seen in serum LDL particle concentrations (LDL-P), small dense LDL cholesterol (sdLDL-C), % small dense LDL-C, and small dense LDL-particle concentrations (sdLDL-P) in individuals with both elevated insulin and elevated ALT concentrations. The increase in VLDL size was additive in individuals with elevated ALT and insulin concentrations. (*P <.001 elevated ALT vs elevated insulin; ** P <.001 elevated insulin vs. elevated insulin and elevated ALT). Elevated ALT is defined as > 19 U/L in women and >31 U/L in women.
See this image and copyright information in PMC

Comment in

  • An ALTer ego of serum ALT: is it more than a marker of liver inflammation?
    Kim D, Kim WR. Kim D, et al. Gastroenterology. 2013 Dec;145(6):1191-3. doi: 10.1053/j.gastro.2013.10.040. Epub 2013 Oct 28. Gastroenterology. 2013. PMID: 24176872 No abstract available.
  • Reply: To PMID 23973920.
    Siddiqui MS. Siddiqui MS. Gastroenterology. 2014 May;146(5):1427-8. doi: 10.1053/j.gastro.2014.03.043. Epub 2014 Mar 26. Gastroenterology. 2014. PMID: 24681172 No abstract available.
  • Liver and atherosclerosis.
    Purnak T, Efe C, Basar O. Purnak T, et al. Gastroenterology. 2014 May;146(5):1427. doi: 10.1053/j.gastro.2014.01.068. Epub 2014 Mar 26. Gastroenterology. 2014. PMID: 24681174 No abstract available.

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