ALT and AST: Alanine Aminotransferase and Aspartate Aminotransferase: Diagnostic Significance and Clinical Insights
Authors: Payal Bhandari M.D., Amer Džanković, Madison Granados
Contributors: Vivi Chador, Hailey Chin, Nigella Umali Ruguian
Key Insights
The liver, known as the body’s “chemical factory,” is essential for metabolism, detoxification, energy, blood clotting, and immune function. Liver function tests, including ALT, AST, alkaline phosphatase, albumin, bilirubin, and GGT, assess liver health1,2.
ALT is specific to the liver, while AST is also found in the heart, muscles, brain, and lungs3.Elevated levels indicate liver damage, often caused by medications, steroids, creatine supplements4, or substances like alcohol and tobacco, which can harm liver function over time5. Conditions like hepatitis, NAFLD, and steatohepatitis may go unnoticed until severe stages like cirrhosis.
ALT and AST tests are crucial for detecting liver damage, guiding treatment, and advancing research.
What are ALT and AST?
Enzymes are proteins that speed up metabolic processes like tissue building, substance transport, and chemical reactions. Alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT) are key enzymes involved in amino acid metabolism2. Enzymes bind to specific molecules, or substrates, reducing the energy required for reactions. Without them, essential processes like digestion, DNA replication, and muscle or nerve function would be too slow to sustain life. Despite their varied roles, enzymes share chemical features critical to their function.
Amino Acids are the Building Blocks of Protein
Proteins are made of amino acids, the building blocks of life. Each amino acid has an amino group (-NH2), carboxyl group (-COOH), and unique side chain (R). Of the 20 amino acids essential for protein synthesis, some must be obtained from food. Amino acids link via peptide bonds into chains, with their sequence determining protein shape and function. Even minor changes can impact function, causing diseases or enhancing activity.5, 6,7
Figure 1: The amino acids.
Protein Metabolism and Synthesis
Figure 2: Protein cannot be stored and is broken into amino acids for new proteins, nonessential amino acids, and nitrogen compounds. Excess protein converts to glycogen or fat for energy or metabolic pathways.
Role of AST and ALT in the Body
The body usually gets energy (ATP) from glucose in food. However, during long periods without eating, intense exercise, insulin deficiency (like in diabetes), or when the brain needs extra energy, the body breaks down fats and proteins into amino acids, lactate, and glycerol for fuel. This process, called ketogenesis, happens mainly in the liver and partly in the kidneys and small intestine. Because the brain can’t use fat directly for energy, the glycerol from fats must be turned into glucose through a process called gluconeogenesis.
Harvesting Energy (ATP) After A Meal
Food is digested in the small intestine, releasing glucose, fatty acids (FAs), and amino acids (AAs) into the blood. Insulin moves glucose to tissues for energy (ATP), while excess nutrients are processed in the liver. Glucose is stored as glycogen or converted into FAs and AAs. FAs form triacylglycerol (TAG), stored or released as VLDL. Proteins and AAs are used for energy, protein synthesis, or glucose production, with toxic byproducts detoxified.
Harvesting Energy During Short-Term Fasting, Intense Exercise, and Emotional Intensity
Gluconeogenesis reduces oxaloacetate in liver cells, blocking acetyl-CoA from entering the Krebs cycle. To compensate, glucagon and epinephrine lower insulin and activate lipoprotein lipase (LPL), which breaks down glycogen and fats. This releases acetyl-CoA, converted into acetoacetate for energy (ATP) or beta-hydroxybutyrate. Some acetoacetate becomes acetone, exhaled through the lungs .
Harvesting Energy During Prolonged Fasting
During starvation or intense exercise, the body shifts to alternative energy sources. The liver releases VLDL cholesterol, fat tissue breaks down fatty acids and glycerol for ketones, and muscles break down proteins, releasing lactate and alanine. The liver converts these into glucose through gluconeogenesis, involving lactate oxidation to pyruvate and cycles through oxaloacetate and malate.
Figure 3: Circadian rhythm genes regulate liver glucose and ketone production for energy. During fasting or exercise, ketones stabilize blood sugar, improve insulin sensitivity, and reduce reliance on carbs, lowering hunger, anxiety, inflammation, and stress hormones.
The Synthesis and Metabolism of Amino Acids
Amino acids break down into intermediates for the Krebs Cycle to produce energy. Glucogenic amino acids form pyruvate, while ketogenic ones produce acetyl-CoA and ketones. Non-essential amino acids are made through protein breakdown, transamination, and nitrogen removal (deamination) 6, 11.
Glutamic acid/glutamate (Glu), glutamine (Gln), and alanine (Ala) are the most abundant amino acids in the body and an integral part of human cells and bacterial cell walls.11 They play unique roles in protein metabolism, cell signaling, harvesting energy, and nitrogen homeostasis. Glu and Gln are the primary sources of ammonium production in cells.
Glu is most abundant in the liver, kidneys, and muscles. It is the brain’s main excitatory chemical, helping neurons and astrocytes send signals to communicate. Glu plays a key role in learning, memory, and adapting connections in the brain.
The small intestine metabolizes 90% of Glu into amino acids like alanine, proline, aspartate, and citrulline12, leaving little Glu in the blood after meals13.
Glu cannot cross the blood-brain barrier and is converted in the brain to GABA, an inhibitory neurotransmitter that regulates neural activity, sleep, mood, pain relief, and blood pressure15,16,17
Aspartate/aspartic acid is a powerful antioxidant in the nervous, endocrine, and reproductive systems.18 It supports the synthesis and release of hormones like glucocorticoids, prolactin, oxytocin, and steroids.19
ALT and AST are essential for amino acid conversion and metabolite production. AST produces oxaloacetate and glutamate, which support energy production in the Krebs cycle. ALT deaminates alanine, creating pyruvate, which is used to make glucose through gluconeogenesis. ALT helps regulate blood sugar, especially during fasting and intense exercise.
Degradation of Toxic Nitrogen
In the liver, toxic amino groups (-NH2) from amino acid metabolism are converted to ammonia, then to less toxic urea with carbon dioxide released. About 40-50% of urea is excreted by the kidneys in urine, and 10% is eliminated through sweat, stool, and breath20. The remaining urea is either stored as fat in the liver, abdomen, and muscles or accumulates in the blood, causing cell damage.
Figure 4: The toxic amino group derived from metabolizing amino acids are broken into the urea, ammonia, and carbon dioxide, and subsequently either excreted in the urine and during exhalation, or recycled in the liver.
Regulation of AST and ALT Synthesis
Hormonal Regulation:
Hormones such as insulin and glucagon can influence the synthesis of AST and ALT. For example, glucagon stimulates gluconeogenesis, which can upregulate ALT activity in the liver.
Nutritional Status:
Amino acid levels and nutritional status influence enzyme activity. During fasting or starvation, the body boosts gluconeogenesis, which increases ALT activity.
Cellular Stress and Damage:
Cell stress or damage increases AST and ALT production. When liver cells are damaged, these enzymes are released into the blood, raising transaminase levels detectable in tests.
Clinical Significance of Monitoring AST and ALT Levels
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of abnormal transaminase levels and metabolic issues. There is no effective drug to treat this widespread condition. Figure 6 shows that poor liver function is linked to reduced blood flow to the digestive organs, slowing digestion and causing gut bacteria imbalance (dysbiosis). Gut microbiota aids in digestion, nutrient absorption, and waste removal.
Figure 5: Healthy gut microbiota support digestion, nutrient absorption, and waste removal. Dysbiosis disrupts metabolism, increases harmful pathogens, and weakens immune responses177.
Dysbiosis allows undigested food into the bloodstream, thickening blood, reducing oxygen (hypoxia), and causing cell death, inflammation, and ROS. It lowers RBC production, prompting kidneys to release erythropoietin, while WBCs clear debris, form clots, and create vessels. This leads to atherosclerosis, disrupting energy and linking elevated transaminase to inflammation, autoimmune disorders, and organ damage.
Elevated AST and ALT indicate liver, bile duct, or gallbladder dysfunction and may affect the heart, pancreas, or kidneys. Changes in bilirubin and alkaline phosphatase can reveal metabolic issues. ALT is more specific to liver disorders, and the AST/ALT ratio aids diagnosis25.
ALT Elevation is Greater Than Elevated or Normal AST
In acute liver inflammation, ALT and AST levels can rise significantly due to infection, medications, or stress. Mild elevations (2-3 times normal) often result from protein metabolism issues. NAFLD, the leading cause of elevated ALT-to-AST ratios globally26, includes steatosis, NASH, fibrosis, and cirrhosis. It is linked to fat storage, insulin resistance, and diabetes27,28,29. Abdominal fat is a stronger predictor of elevated ALT than body weight, as shown in studies with over 17,000 participants. 30,31,32,33,34,35,36,37
Elevated AST Alone
Elevated AST levels alone suggest increased glutamate and aspartate processing, leading to higher levels of these amino acids in the blood and triggering an immune response.
Elevated ALT Level Alone
Sudden weight loss and prolonged fasting can raise ALT levels mildly (2–3 times normal), while starvation, such as in anorexia nervosa, can increase them significantly (4–30 times normal)38. Low RBC and hemoglobin levels reduce oxygen delivery (hypoxia), causing RBC destruction (hemolysis) and releasing toxic byproducts processed by the liver and spleen. Excess hemolysis increases bilirubin processing, often leading to gallstones. A study found ALT levels at 82.5 IU/L in cholecystitis patients without gallstones and 95 IU/L in those with gallstones39. Gallstone-induced pancreatic inflammation raised ALT to about 200 IU/L42.Excess bilirubin can cross the blood-brain barrier, damaging nerve cells and affecting vision, speech, cognition, hormones, and electrolyte balance35, 43,44, 45, 46, 47.
AST Elevation Is Greater Than Elevated or Normal ALT
The primary causes of higher AST levels in comparison to the ALT levels include, but are not limited to, the following:
Alcohol can damage genes for enzymes like alcohol dehydrogenase, aldehyde dehydrogenase, and cytochrome P450 2E1, leading to higher acetaldehyde and estrogen levels in tissues and blood48,49,50. Acetaldehyde harms liver cell structure and function, causing:
Decreased metabolism of amino acids and synthesis of many proteins (such as hemoglobin and red blood cells)
Dysregulated gluconeogenesis and ketogenesis, and increased fat storage51
Dysregulated hormonal and energy homeostasis
Accelerated red blood cell (RBC) destruction, elevating reactive oxygen species (ROS), altering metabolic pathways, damaging cells in various organs, and increasing AST and ALT levels.
Chronic liver dysfunction and disease is characterized by moderate-to-severe scar tissue deposition that alters its structure and function.86
Figure 6: Liver dysfunction triggers inflammation, diverting nutrients from organ functions to toxin removal. Chronic inflammation causes structural damage, scarring, clotting, and liver failure.
Copper is essential for protein metabolism and is stored mainly in bones and muscles54. Wilson disease, an autosomal recessive disorder, causes excess copper to build up in the blood due to a gene mutation56,57,58. Copper toxicity can result from uncoated cookware, contaminated water, or exposure to sources like pesticides and burn creams. Foods rich in copper include animal products, nuts, seeds, and spinach. Low copper intake increases absorption, making accidental exposure more harmful53.
Figure 7: Dietary copper (Cu) is absorbed in the small intestine and transported to the liver, where 85 to 95 percent is bound to the protein ceruloplasmin. 50 percent of copper is stored in the gallbladder as bile, while the remaining is loosely bound to albumin and other small molecules and excreted into the stomach.55 Excess consumption of copper-rich foods (such as animal products) can lead to liver damage and cause excess free copper ions into the circulation.58
Figure 8: Excess free copper ions in the circulation can damage the structure, function, and genetic code of various organs, decrease red blood cell production, and alter skin pigmentation 56,57,58.
Depressed AST and ALT Levels
Low AST and ALT levels usually indicate good liver function. However, in advanced liver disease (e.g., cirrhosis), they may reflect depleted liver function. Chronic medication use, malnutrition, and frequent nicotine or alcohol use can also lower transaminase levels.
Prevalence and Statistics Regarding Abnormal AST and ALT Levels
Abnormal ALT and AST levels indicate disrupted protein metabolism, leading to toxic free nitrogen, increased reactive oxygen species (ROS), cell damage, and altered metabolic pathways.
Liver disease is rising globally and in the U.S., where it was the 8th leading cause of death in 201661. NAFLD, now the leading cause of liver-related deaths, surpasses viral causes. Diagnosed through imaging or histology, NAFLD results from the liver’s inability to process excess fat and protein. Its severe form, NASH, causes liver cell injury, increasing risks of complications and organ failure. Between 1988 and 2002, ALT levels doubled to 8.9% and AST to 4.9%, with NAFLD prevalence in the U.S. matching the global rate of 25.24%62, 63.
NAFLD and abnormal ALT/AST levels are influenced by socioeconomic, ethnic, and genetic factors. Hispanic Americans have higher NAFLD risks, with 33% prevalence in Mexican Americans compared to 16% in Dominicans and 18% in Puerto Ricans. A mutation in the PNPLA3 gene, which produces adiponutrin, is a key genetic risk factor65.
Although genetics cannot be changed, healthier lifestyle choices, including diet and exercise, can significantly improve liver health and reduce disease risks.
Conclusion
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are vital enzymes for amino acid metabolism, protein and glucose production, and energy balance. Monitoring these enzymes can reveal hidden health issues. Abnormal levels may result from dehydration, poor diet, medications, or genetic mutations. Improving liver, heart, and brain health requires better diet, exercise, hydration, and medication management. The rise in obesity and NAFLD, both linked to abnormal ALT/AST, underscores the importance of prevention to reduce risks of chronic diseases like heart attack, stroke, and dementia.
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