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Alanine Amino Transferase

Editor: Samy A. Azer Updated: 12/10/2022 11:49:37 AM


The liver has a central and critical biochemical role in the metabolism, digestion, detoxification, and elimination of substances from the body.[1] All blood from the intestinal tract initially passes through the liver, where products derived from the digestion of food are processed, transformed, and (in some cases) stored.[2] These include amino acids, carbohydrates, fatty acids, cholesterol, lipids, vitamins, and minerals, respectively.

Most major plasma proteins (except immunoglobulins [Igs] and the von Willebrand factor) are mainly or exclusively synthesized in the liver. The liver responds to multiple hormonal and neural stimuli to regulate blood glucose concentrations.[3] Not only does it extract glucose from the blood to generate energy, but it also stores dietary glucose as glycogen for later use. The liver is also the major site for gluconeogenesis, which is critical for maintaining blood glucose concentration in the fasting state.[4] The liver is central in lipid metabolism; it extracts and processes dietary lipids and is the principal site of cholesterol, triglyceride, and lipoprotein synthesis.[5] Another major liver function is the synthesis of bile acids from cholesterol, with the secretion of these compounds into the bile, which facilitates the absorption of dietary fat and fat-soluble vitamins.[6]

The liver is also the primary site of metabolism of both endogenous substances and exogenous compounds (e.g., drugs and toxins). This process, known as biotransformation, converts lipophilic substances to hydrophilic ones for subsequent elimination.[5] The liver is a major site of catabolism of hormones and thus participates in regulating plasma hormone concentrations.[6] The liver is also involved in hormone synthesis, producing such hormones as insulin-like growth factor 1, angiotensinogen, hepcidin, thrombopoietin, erythropoietin, and the prohormone 25-OH vitamin D. Many of these hepatic functions can be assessed by laboratory procedures to gain insight into the integrity of the liver.[1]

As a large organ, the liver shares with many other organs the ability to perform its functions with extensive reserve capacity. Individuals with liver disease often maintain normal function despite extensive liver damage. In such cases, liver disease may be recognized only using tests that detect injury.[2] Most commonly, this is accomplished by measuring the plasma activities of enzymes found within liver cells, which are released in specific patterns with different forms of injury.[7] Chronic liver injury often involves fibrosis in the liver; markers of the fibrotic process might indicate the degree of injury.[8] Chronic damage is often due to chronic inflammation; cytokines alter the pattern of liver protein production, which allows the detection of inflammation (although not necessarily that involving the liver).[9] Some proteins are produced in increased amounts with liver regeneration and neoplasia; such markers may be useful in detecting liver cell proliferation.[10]

This review focuses on the significance of the hepatic enzyme ALT in assessing hepatic injury and malfunction. ALT is aggregated primarily in the cytosol of hepatocytes and consists of 496 amino acids, and has a half-life of approximately 47 hours.[11] ALT is detectable in serum at low concentrations (typically <30 IU/L). However, any process that leads to loss of hepatocyte membrane integrity or necrosis results in the release of ALT in high concentrations in the plasma.[2]

Therefore, the elevation of serum ALT concentration is a sensitive but not specific measure of hepatocellular injury, as the degree of elevation can not determine the exact cause.[1] The most common causes are alcohol-induced liver injury, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic hepatitis B or C, autoimmune hepatitis, and drug or herbal supplement-induced liver injury.[4] Other causes include hemochromatosis, vascular disease, acute viral hepatitis, and genetic disorders affecting the liver.[7]

Etiology and Epidemiology

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Etiology and Epidemiology

The liver transaminases, mainly alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are aggregated in the cytosol of hepatocytes. These enzymes are normally detectable in the serum at low concentrations, typically <30 IU/L.[12][13] However, any process that leads to loss of hepatocyte membrane integrity or necrosis results in the release of these enzymes into the blood, where the elevated concentrations can be measured.[14] Elevation in transaminases is frequent in primary care medicine, affecting an estimated 10 to 30% of the U.S. population. Less than 5% of patients with elevated transaminases will have severe liver conditions.[15] 

Increases in alanine transaminase (ALT) alone affects 8.9% of the U.S. population.[16] Several physiological and risk factors may contribute to the serum levels of these enzymes, including age, sex, body mass index, pubertal age, elevated levels of triglycerides, insulin resistance, and blood glucose level.[17][18]

Physiological Factors

  1. Extreme physical exertion can induce a reversible elevation in serum ALT, approximately 2 to 2.2-fold higher than the normal limit.[19] While the source of elevated ALT in these individuals could be non-hepatic, it is likely released from the exercising skeletal muscles.
  2. ALT activity has a diurnal variation; the nadir value is at 4:00 hr, and the peak value is at 16:00 hr.[20]
  3. ALT is higher in males compared to females. These gender-based differences in ALT levels are possibly related to hormonal differences between males and females.[21]
  4. Ethnicity affects ALT levels. Research shows that Mexican Americans have a higher ALT elevation prevalence than other ethnicities.[22] This finding could be related to higher incidences of metabolic syndrome, a major cause of elevated ALT in Mexican Americans.
  5. Research has found no overall association between the hypoxia-inducible factor 3 alpha subunit (HIF3A) rs3826795 polymorphism and ALT. However, a significant interaction between obesity and rs3826795 concerning ALT was found - rs382695 G-allele number elevation of ALT significantly only in obese children but not in non-obese children.[23]
  6. In another study, Bekkelund, and Jorde, found that serum ALT was associated with body fat mass index in men. ALT was associated with lean mass index in men and women in the overweight and obese population.[24] They found body mass index to be the most determining factor for ALT, and gender was the most influencing factor for AST.[25]

Pathological Causes

  1. Depending on the region, alcoholic hepatitis and non-alcoholic fatty liver disease (NAFLD) are considered the most common cause of abnormally high ALT levels.
  2. Non-alcoholic steatohepatitis (NASH)
  3. Chronic hepatitis B or C
  4. Autoimmune hepatitis
  5. Alpha-1 antitrypsin deficiency
  6. Drug-associated, occupational exposure, or herbal supplement-induced liver injury
  7. Hemochromatosis
  8. Wilson disease
  9. Celiac disease
  10. Ischemic hepatitis,
  11. Budd-Chiari syndrome,
  12. Vascular disease
  13. Genetically-related conditions affecting the liver[26]


ALT enzyme catalyzes the transfer of amino groups from the L-alanine to alpha-ketoglutarate, and the conversion products are L-glutamate and pyruvate. The process is critical in the liver in the tricarboxylic acid (TCA) cycle. Pyruvate can be used in the citric acid cycle to produce cellular energy. The coenzyme needed for this reaction is pyridoxal 5'-phosphate, also known as vitamin B6.[27]

The pyridoxal 5'-phosphate (P-5′-P)  is bound to the inactive apoenzyme and serves as a true prosthetic group. The pyridoxal 5'-phosphate attached to the apoenzyme accepts the amino group from the first substrate, aspartate or alanine, to form enzyme-bound pyridoxamine-5′-phosphate and the first reaction product, oxaloacetate or pyruvate, respectively.[28] The coenzyme in the amino form then transfers its amino group to the second substrate, 2-oxoglutarate, to form the second product, glutamate. The pyridoxal 5'-phosphate (P-5′-P)  is thus regenerated.[29]

Both coenzyme-deficient apoenzymes and holoenzymes may be present in serum.[30] Therefore, the addition of P-5′-P under measurement conditions that allow recombination with the enzymes usually produces an increase in aminotransferase activity. For clinical assays, in accordance with the principle that all factors affecting the rate of reaction must be optimized and controlled, the addition of P-5′-P in aminotransferase methods is recommended to ensure that all enzymatic activity is measured.[31]

ALT is found ubiquitously throughout the human body, in the kidney, myocardium, skeletal muscle, brain, pancreas, spleen, and lung. More specifically, the highest tissue concentration of ALT activity is in the cytosol of hepatocytes. The activity of ALT in hepatocytes is approximately 3000 times higher than that of serum ALT activity.[32] Therefore, in patients with acute or chronic hepatocellular injury, the release of ALT from dying or damaged hepatocytes results in increased serum ALT levels. The half-life of ALT is approximately 47 hours in circulation.[33]

Specimen Requirements and Procedure

According to the International Standard ISO 6710, the light green cap contains lithium-heparin and is used for the hepatic function panel.[34] A trained healthcare provider will disinfect the skin and wrap an elastic strap around the arm to visualize a vein. Blood will be drawn and put into a sample container. The sample must be placed in the correctly colored cap, as the various color caps have a particular additive.[35]

After the specimen is collected and fulfills the requirements, they go for testing. Hepatic function panels evaluate for alanine aminotransferase (ALT) through the use of blood samples. The quality of blood specimens is vital to decrease laboratory errors, prevent diagnosis delay, and ensure a proper diagnosis.[36] All specimens should undergo measurement of the hemolysis index, as hemolyzed blood is considered unsuitable for testing. The inappropriate quality or sample volume contributes to approximately 80 to 90% of laboratory errors.[37]

A hemolysis index assesses the sample at specific wavelengths to determine the potential concentration of cell-free hemoglobin and ensure quality. If the hemolysis index is unavailable, then a visual inspection should be conducted instead.[38] Blood specimens with fibrin strands or clots should not be used for testing. Recommendations include that blood tubes filled at less than 90% of their nominal volume should not be used for testing to maintain specimen integrity.[39] Only in emergent situations that require the evaluation of prothrombin time and fibrinogen assay that blood coagulation tubes filled to 70% of their nominal volume usable.[40]

Diagnostic Tests

A panel of laboratory tests to assess liver functions, also known as the liver function test, is commonly used in clinical practice. The liver function test comprises the following:[40]

  1. Serum bilirubin
  2. Serum alanine aminotransferase (ALT)
  3. Serum aspartate transaminase (AST)
  4. Serum alkaline phosphatase (ALP)
  5. Serum gamma-glutamyltransferase (GGT)
  6. Prothrombin time or an International Normalized ratio (INR)
  7. Serum albumin

Testing Procedures

The liver function tests are performed on semi-automatic or fully automated analyzers which are based on the principle of photometry. Photometry is the measurement of light absorbed in the ultraviolet (UV) to visible (VIS) to infrared (IR) range. This measurement determines the amount of an analyte in a solution or liquid. Photometers utilize a specific light source and detectors that convert light passed through a sample solution into a proportional electrical signal. These detectors may be photodiodes, photoresistors, or photomultipliers.[41] Photometry uses Beer–Lambert’s law to calculate coefficients obtained from the transmittance measurement. A correlation between absorbance and analyte concentration is then established by a test-specific calibration function to achieve highly accurate measurements.[42]

Interfering Factors

Patients are instructed to avoid certain medications and foods before a hepatic function panel to ensure the integrity of blood specimens.[43] Drug hepatotoxicity can be non-idiosyncratic (predictable) or idiosyncratic (unpredictable). Also, drug-associated hepatotoxicity can classify as immune-mediated and non-immune-mediated. The incidence of drug-induced liver injury is 19 cases per 100,000 persons. The most common drug causing drug-induced liver injury is amoxicillin/clavulanate.[44][45] Hepatitis E infection can masquerade drug-induced liver injury in 3% to 13% of the cases.[46] Tacrine, a medication for Alzheimer's disease, was withdrawn from the market because of significant liver injury. This medication caused elevations of ALT levels that trended as high as 20 times the normal reference level.[47] 

Up to 5% of patients on statin medications were found to develop elevations in ALT.[48] Ceftriaxone, phenytoin, carbamazepine, cotrimoxazole, and allopurinol have been reported to cause liver injury. Also, tricyclic antidepressants, imipramine, and amitriptyline have links to transient elevations in ALT.[49] Elevation of serum ALT and AST has been reported in patients taking these medications isoniazid, pyrazinamide, rifampicin, ibuprofen, or dapsone.[50] The website maintained by the National Institute of Diabetes and Digestive Diseases (NIDDK) is a valuable resource for clinicians and researchers interested in liver hepatotoxicity and other drugs that can cause increases in serum ALT. As stated earlier, periods of intense exercise should be avoided before testing, as it can also increase alanine transaminase levels.[51]

Results, Reporting, and Critical Findings

The results of a hepatitis panel should correlate with the initial findings in a complete history and physical examination. A thorough review should include essential questions regarding the patient’s age, past medical history (diabetes, obesity, hyperlipidemia, inflammatory bowel disease, celiac sprue, thyroid disorders, autoimmune hepatitis, acquired muscle disorders, alcohol consumption, medication use, toxin exposure, and family history of genetic liver conditions (Wilson’s disease, alpha-1-antitrypsin deficiency, hereditary hemochromatosis).[32]

A review of systems should also include signs and symptoms of chronic liver disease such as jaundice, ascites, peripheral edema, hepatosplenomegaly, gynecomastia, testicular hypotrophy, muscle wasting, encephalopathy, pruritus, and gastrointestinal bleeding.[52] Other tests that help determine the cause of elevated transaminase levels found on a hepatitis panel include fasting lipid levels, hemoglobin A1C level, fasting glucose, complete blood count with platelets, a complete metabolic panel, iron studies, hepatitis C antibody, and hepatitis B surface antigen testing.[53]

A hepatitis panel’s reference ranges can fluctuate amongst different laboratories. Reported values also can vary depending on gender, body mass index, and past medical history. Repeated liver enzymes are typically unnecessary in the workup for elevated transaminase levels.[54]

  • Normal serum alanine aminotransferase (ALT) is 7-56 U/L.
  • Normal serum aspartate aminotransferase (AST) is 0 to 35 U/L.
  • Normal serum alkaline phosphatase (ALP) is 41 to 133 U/L.
  • Normal serum gamma-glutamyl transferase (GGT) is 9 to 85 U/L.
  • Normal serum total bilirubin is 0 to 1.2 mg/dL.
  • Normal albumin is 40 to 60 g/L.

Clinical Significance

It is essential to consider that any liver cell injury can cause an increase in ALT serum levels.[55] Although specific hepatic diseases are associated with an elevation in ALT levels, there is no correlation between the absolute peak of the ALT elevation and the magnitude of hepatic injury.[54] It is common to see a concomitant increase in both AST and ALT serum levels. ALT levels greater than 1000 U/L should consider acute ischemic liver injury, severe drug-induced liver injury, or acute viral hepatitis. Other causes include common bile duct stones and hepatitis E infection.[56]

Viral hepatitis is liver inflammation from hepatitis A, B, C, D, and E. Acute hepatitis A, in comparison with both Hepatitis C and B, is associated with higher increases in serum ALT and AST levels, reaching the levels of 3000 to 4000 IU/L for each. The diagnosis of chronic hepatitis will have elevations in ALT levels for greater than six months.[54] Common clinical signs of viral hepatitis include jaundice, anorexia, fatigue, vomiting, fever, nausea, and hepatomegaly. The risk factors for viral hepatitis include travel to areas where hepatitis is endemic, multiple sexual partners, occupational exposure to chemicals and hepatotoxicants, and intravenous drug use.[57] Hepatitis serology labs should also be ordered to confirm the diagnosis and the type of viral hepatitis.[58]

The most efficient aminotransferase threshold for diagnosing acute liver injury lies at seven times the URL (sensitivity and specificity >95%).[59] In acute viral hepatitis, peak values of transaminase activity occur between the 7th and 12th days; activities then gradually decrease, reaching physiologic concentrations by the 3rd to 5th week if recovery is uneventful.[57] Peak activities bear no relationship to prognosis andmay fall with the worsening of the patient’s condition, perhaps because of a lack of further functional hepatocytes to continue enzyme release.

The persistence of increased ALT for longer than six months after an episode of acute hepatitis is used to diagnose chronic hepatitis.[60] Most patients with chronic hepatitis have a maximum ALT of fewer than seven times the URL. ALT may be persistently normal in 15% to 50% of patients with chronic hepatitis C, but the likelihood of continuously normal ALT decreases with an increasing number of measurements.[61] In patients with acute hepatitis C, ALT should be measured periodically over the next 1 to 2 years to determine if it becomes and stays normal.[62]

Ischemic liver injury, also known as ischemic hepatitis, occurs when there is an acute reduction in blood perfusion to the liver, leading to necrosis of hepatic centrilobular cells on histology.[63] The occurrence of hepatic damage is higher in septic shock, where a decrease in blood perfusion to the liver is due to infection. A recent study revealed the incidence of abnormally elevated ALT was more sensitive to the diagnosis of ischemic hepatitis due to septic or hypovolemic shock.[64] In evaluating septic shock as a potential cause for ischemic liver injury, serum lactate, serum CRP, blood counts, D-dimer levels, and blood cultures should be measured. 

Medications can account for an elevation in ALT. Paracetamol toxicity (also known as acetaminophen) has been shown in a recent study to account for almost half of the drug-induced liver injuries. In paracetamol toxicity, the levels of serum ALT are usually higher than 1,000 U/L.[56] Therefore, paracetamol toxicity should be among the differential diagnoses of patients with acute liver failure. A review of patient hepatotoxic medicines is vital in ensuring the proper diagnosis. Drugs associated with an elevation of transaminases include tacrine, imipramine, amitriptyline, isoniazid, pyrazinamide, rifampicin, ibuprofen, nimesulide, cotrimoxazole, phenytoin, dapsone.[45][43]

Non-alcoholic fatty liver disease (NAFLD) should merit consideration among the most common cause of abnormally elevated ALT levels in asymptomatic patients.[65] NAFLD is the fat accumulation within the liver in patients who do not consume alcohol. NAFLD has the potential to progress into hepatic fibrosis and cirrhosis, thus increasing liver-related morbidity and mortality.[66] NAFLD is usually associated with higher ALT and GGT levels in patients with impaired glucose tolerance or type 2 diabetes mellitus. NAFLD risk factors include morbid obesity, hyperglycemia, hypertriglyceridemia, hypertension, and decreased insulin sensitivity.[67] A NAFLD fibrosis score and radiological imaging such as CT or MRI of the liver should be considered to assess the severity and progression of NAFLD. The diagnosis of NAFLD is made with the presence of steatosis in 5% or greater of hepatocytes.[68]

In 1957, DeRitis described in a publication the ratio between AST and ALT in the diagnosis of viral hepatitis, where ALT is usually higher than AST.[69] Later, the usefulness of this ratio was highlighted in alcoholic hepatitis, where AST is mostly more elevated than ALT. Therefore, the ratio between AST and ALT is >2.0 for alcoholic hepatitis, 1.5 to <2.0 in acute viral hepatitis, and >1.0 in fibrosis and cirrhosis.[70] However, many laboratories do not include this ratio in their reports because it is not specific, and AST can be affected by hemolysis.[71] The ratio is affected by the number of days post-exposure and the severity of the disease. Another critical factor is the relatively short half-life of AST (18 hours) compared to ALT (47 hours) and the fact that gender requires consideration, and there is an intra-individual variation of both AST and ALT.[72]

Quality Control and Lab Safety

The collection of blood samples carries significant safety risks for both personnel and patient if done improperly. Structured curricula designed to standardize collecting blood samples, educate participants on the risks, and address common errors can increase lab safety.[73]

Healthcare workers should demonstrate a degree of competency before working with patients. Healthcare workers should utilize personal protective equipment and antiseptics to prevent accidental contamination of blood samples or infection. Personal protective equipment includes single-use nonsterile gloves, eye protection, and masks if there is a potential for blood exposure. Equipment such as trays or tube holders should be cleaned and disinfected if used on multiple patients. Disposal of all needles and syringes must be considered immediately after use. Using a sharps container can decrease the risk of a needle-stick injury.[40]

For non-waived tests, laboratory regulations require, at the minimum, analysis of at least two levels of control materials once every 24 hours. To ensure accurate results, laboratories can assay QC samples more frequently. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance. To minimize QC when performing tests for which manufacturers’ recommendations are less than those required by the regulatory agency (such as once per month), the labs can develop an individualized quality control plan (IQCP) that involves performing a risk assessment of potential sources of error in all phases of testing and putting in place a QC plan to reduce the likelihood of errors.[74]

Westgard multi-rules are used to evaluate the quality control runs. In case of a rule violation, proper corrective and preventive action should be taken before patient testing is performed.[75] Biological variation data suggest that an imprecision (CV) of less than 9.7%, a bias of ±11.5%, and a total error of ±27.5% for ALT is required for clinical use of its determinations. In general, the imprecision target is easily met using current aminotransferase methods.[76]

Enhancing Healthcare Team Outcomes

Multi-disciplinary and interprofessional rounds are when medical and other health providers collaborate to enhance patients' healthcare outcomes. Clinicians may review the significance of the hepatic function test panel in correlation with each patient's medical history and physical examination to detect any drug-induced hepatic injury early and build a differential diagnosis. Changes in the patient's patterns of ALT and AST over time or other liver function tests may necessitate a referral to gastroenterologists for consultation. Clinical pharmacists can also advise about potential contraindications or hepatotoxic medication interactions. The charge nurse of each floor can communicate updates on a patient's response to treatment, other recent laboratory orders, and current disposition. A multi-disciplinary approach can ensure a higher quality of care for each patient and enhance outcomes.[77]



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