Enzymes are here and there but they shouldn’t be everywhere!
Part 1: ALT:AST Ratio

By Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

Alanine aminotransferase (ALT)) and aspartate aminotransferase (AST) are enzymes that participate in gluconeogenesis by transferring amino groups to alpha-ketoglutaric acid from alanine (to produce pyruvic acid) or from aspartic acid (to produce oxaloacetic acid). They are often called “liver enzymes” though they are found in other tissues.

ALT is found in high concentrations in the liver and lower concentrations in the brain, intestines, muscle, adipose tissue, and prostate. Elevated serum levels of ALT tend to be more specific to liver injury than other tissue injury.[i]

AST is found in the liver, muscle, brain, kidneys, pancreas, lungs, and white and red blood cells. Increased release of both enzymes into the bloodstream is a sign of tissue damage which can eventually lead to loss of function.[ii]

In this first part of our 2-part series on the ratios of ALT and AST we will be diving into the ALT:AST ratio and discussing the types of conditions that are associated with an elevated ratio. Part 2 will focus on the AST:ALT ratio!

ALT:AST ratio

An increasing ratio of ALT to AST is associated with the closely related disorders of insulin resistance, metabolic syndrome, non-alcoholic fatty liver disease, and cardiovascular disease.[iii] [iv] Research strongly suggests that the ratio may be used as a marker of metabolic health. A health survey of 16,371 adults revealed that increasing ALT:AST ratios correlated with impaired fasting glucose, insulin resistance/HOMA-IR, undiagnosed type 2 diabetes, and declining metabolic health.[v]

Insulin resistance

The presence of insulin resistance should be assessed in view of its role in metabolic syndrome, diabetes, cardiovascular disease, dyslipidemia, and hypertension and extensive research is warranted.

An increased ratio of ALT to AST is independently associated with insulin resistance (IR) and considered a primary marker for the disorder. Researchers in a large cross-sectional study of 8398 adults suggested a cut-off point for ALT:AST of 0.80 in non-centrally obese individuals and 0.78 in the centrally obese for identifying IR.[vi]

Insulin resistance[vii]

  • Insulin resistance is identified as an impaired biologic response to insulin stimulation of target tissues, primarily the liver, muscle, and adipose tissue.
  • Insulin resistance impairs glucose disposal, resulting in a compensatory increase in beta-cell insulin production and hyperinsulinemia.
  • The metabolic consequences of insulin resistance can result in hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperuricemia, elevated inflammatory markers, endothelial dysfunction, and a prothrombic state.
  • Progression of insulin resistance can lead to metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus.
  • Screening for insulin resistance can be achieved by calculating the homeostatic model assessment- insulin resistance (HOMA-IR): fasting insulin (μU/ml) x fasting glucose (mmol/l) /22.5.[viii]

In a cross-sectional study of 587 male and 755 female adults, increased risk of insulin resistance was identified by an increasing ratio of ALT to AST in both overweight (BMI greater than 25) and normal weight individuals (BMI less than 25).[ix] The study identified insulin resistance in overweight subjects with an ALT:AST ratio greater than or equal to 1.02. Insulin resistance was identified in normal weight individuals with an ALT:AST ratio of 0.82 or greater, a level associated with a 1.91-fold increase in insulin resistance. The ALT:AST ratio was a better predictor of insulin resistance than blood pressure, low HDL, or ALT and AST alone. The study defined insulin resistance as a HOMA-IR value of 2.5 or greater.

Cardiovascular disease

Cardiovascular disease, insulin resistance, and other metabolic disorders are closely linked, and assessment of the ALT:AST ratio can help confirm this morbid relationship. The ratio of ALT to AST was calculated in 1063 patients with proven coronary artery disease. Research revealed that an ALT:AST ratio of 1.1 was “strongly and significantly” able to predict adverse cardiovascular events in those CAD patients with insulin resistance (defined by a HOMA-R of greater than 2.5).[x]

Metabolic syndrome

The phenomenon of metabolic syndrome is characterized by insulin resistance, glucose intolerance, atherogenic dyslipidemia, hypertension, abdominal obesity, inflammation, and a prothrombotic state and represents a cluster of metabolic abnormalities. Use of the ALT:AST ratio can help identify those at risk for, or in the throes of, metabolic syndrome. A ratio of greater than 1 was observed in 60 adults with established metabolic syndrome.[xi]

The ALT:AST ratio may even help identify those with metabolic syndrome in its “silent” stage. A cross-sectional examination of 1643 male and 1764 female subjects revealed significantly higher ratios of ALT to AST in those identified as having metabolic syndrome. Elevated ALT:AST ratios in both males and females diagnosed with metabolic syndrome significantly correlated with greater waist circumference as well. [xii] The study also confirmed a close association of metabolic syndrome with non-alcoholic fatty liver disease, another metabolic abnormality associated with elevated ALT:AST ratios.

Non-alcoholic liver disease (NAFLD)

The health of the liver is closely tied to blood glucose regulation and insulin resistance, as the liver is responsible for clearing insulin from the bloodstream.[xiii] It comes as no surprise that insulin resistance in turn is closely tied to NAFLD. An increased ALT:AST ratio is considered a surrogate marker for non-alcoholic fatty liver disease, an all-too-common phenomenon associated with accumulation of fat in the liver (hepatosteatosis).[xiv]

The strong association between ALT:AST ratio and NAFLD is evident even in children and adolescents. Those with an ALT:AST ratio of greater than 0.98 had a 2.19-fold greater risk of NAFLD. Low-grade NAFLD was characterized by an ALT:AST ratio of 1.07 while a ratio higher than 1.46 was associated with higher grade NAFLD. Individuals with NAFLD were heavier with a greater waist circumference and had significantly higher blood pressure and dyslipidemia.[xv]

It is imperative to identify NAFLD early as it is closely related to oxidative stress, endothelial dysfunction, adverse cardiovascular events, and metabolic syndrome.[xvi]  Evaluation of the ALT:AST ratio can be a significant predictor for hepatosteatosis/NAFLD in individuals with chronic hepatitis C infection as well.[xvii]

An optimal ratio of ALT to AST may reflect metabolic health and absence of liver disease. However, an extremely low ALT:AST may be due to extremely low ALT levels which are in turn associated with frailty and aging.[xviii]

Condition

ALT:AST ratio

Increased risk of insulin resistance (IR) in centrally obese individuals Greater than 0.78
Increased risk of IR in NON-centrally obese individuals Greater than 0.8
1.91-fold increased risk of IR in normal weight individuals 0.82 or greater
Increased risk of IR in overweight individuals 1.02 or greater
Increased risk of CVD events in CAD patients with IR 1.1
Increased risk of metabolic syndrome 1 or greater
2.19-fold increased risk of NAFLD 0.98 or greater
Increased risk of low-grade NAFLD 1.07
Increased risk of high-grade NAFLD Greater than 1.46

References

[i] Liu Z, Que S, Xu J, Peng T. Alanine aminotransferase-old biomarker and new concept: a review. Int J Med Sci. 2014 Jun 26;11(9):925-35. [R]

[ii] Lala V, Goyal A, Bansal P, Minter DA. Liver Function Tests. 2020 Mar 27. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 [R].

[iii] Sg, R., Dhamija, R., Gurtoo, A., & Singh, R. (2017). Correlation Of Alt/ast Ratio With Insulin Resistance In Metabolic Syndrome. International Journal of Advanced Research, 5(3), 1677-1684. [R]

[iv] Vonbank, A., Saely, C., Rein, P et al. (2016). The alanine aminotransferase/aspartate aminotransferase ratio predicts future cardiovascular events in patients with established coronary artery disease and homa insulin resistance. Atherosclerosis, 252, e64-e65.   [R]

[v] Kwon SS, Lee SG. A High Alanine Aminotransferase/Aspartate Aminotransferase Ratio Determines Insulin Resistance and Metabolically Healthy/Unhealthy Obesity in a General Adult Population in Korea: The Korean National Health and Nutritional Examination Survey 2007-2010. Exp Clin Endocrinol Diabetes. 2019 Oct;127(10):677-684. [R]

[vi] Zhao L, Cheng J, Chen Y, et al. Serum alanine aminotransferase/aspartate aminotransferase ratio is one of the best markers of insulin resistance in the Chinese population. Nutr Metab (Lond). 2017 Oct 10;14:64. [R]

[vii] Freeman AM, Pennings N. Insulin Resistance. 2019 Dec 26. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 [R]

[viii] Sg, R., Dhamija, R., Gurtoo, A., & Singh, R. (2017). Correlation Of Alt/ast Ratio With Insulin Resistance In Metabolic Syndrome. International Journal of Advanced Research, 5(3), 1677-1684. [R]

[ix] Kawamoto R, Kohara K, Kusunoki T, et al. Alanine aminotransferase/aspartate aminotransferase ratio is the best surrogate marker for insulin resistance in non-obese Japanese adults. Cardiovasc Diabetol. 2012 Oct 1;11:117. [R]

[x] Vonbank, A., Saely, C., Rein, P et al. (2016). The alanine aminotransferase/aspartate aminotransferase ratio predicts future cardiovascular events in patients with established coronary artery disease and homa insulin resistance. Atherosclerosis, 252, e64-e65.  [R]

[xi] Sg, R., Dhamija, R., Gurtoo, A., & Singh, R. (2017). Correlation Of Alt/ast Ratio With Insulin Resistance In Metabolic Syndrome. International Journal of Advanced Research, 5(3), 1677-1684. [R]

[xii] Ohgo, H., Yokoyama, H., Hirose, Het al. (2009). Significance of ALT/AST ratio for specifying subjects with metabolic syndrome in its silent stage. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 3(1), 3-6.

[xiii] Kwon SS, Lee SG. A High Alanine Aminotransferase/Aspartate Aminotransferase Ratio Determines Insulin Resistance and Metabolically Healthy/Unhealthy Obesity in a General Adult Population in Korea: The Korean National Health and Nutritional Examination Survey 2007-2010. Exp Clin Endocrinol Diabetes. 2019 Oct;127(10):677-684. [R]

[xiv] Zhao L, Cheng J, Chen Y, et al. Serum alanine aminotransferase/aspartate aminotransferase ratio is one of the best markers of insulin resistance in the Chinese population. Nutr Metab (Lond). 2017 Oct 10;14:64. [R]

[xv] Lu CW, Lin MS, Lin YS, et al. Aminotransferase Ratio Is a Useful Index for Hepatosteatosis in Children and Adolescents: A Cross-Sectional Observational Study. Gastroenterol Nurs. 2019 Nov/Dec;42(6):486-495. [R]

[xvi] Sg, R., Dhamija, R., Gurtoo, A., & Singh, R. (2017). Correlation Of Alt/Ast Ratio With Insulin Resistance In Metabolic Syndrome. International Journal of Advanced Research, 5(3), 1677-1684. [R]

[xvii] Lin MS, Lin HS, Chung CM, et al. Serum aminotransferase ratio is independently correlated with hepatosteatosis in patients with HCV: a cross-sectional observational study. BMJ Open. 2015 Sep 14;5(9):e008797. [R]

[xviii] Liu Z, Que S, Xu J, Peng T. Alanine aminotransferase-old biomarker and new concept: a review. Int J Med Sci. 2014 Jun 26;11(9):925-35. [R]

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