Tools
Alanine Amino Transferase
Introduction
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
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
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
- 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.
- ALT activity has a diurnal variation; the nadir value is at 4:00 hr, and the peak value is at 16:00 hr.[20]
- 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]
- 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.
- 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]
- 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
- Depending on the region, alcoholic hepatitis and non-alcoholic fatty liver disease (NAFLD) are considered the most common cause of abnormally high ALT levels.
- Non-alcoholic steatohepatitis (NASH)
- Chronic hepatitis B or C
- Autoimmune hepatitis
- Alpha-1 antitrypsin deficiency
- Drug-associated, occupational exposure, or herbal supplement-induced liver injury
- Hemochromatosis
- Wilson disease
- Celiac disease
- Ischemic hepatitis,
- Budd-Chiari syndrome,
- Vascular disease
- Genetically-related conditions affecting the liver[26]
Pathophysiology
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]
- Serum bilirubin
- Serum alanine aminotransferase (ALT)
- Serum aspartate transaminase (AST)
- Serum alkaline phosphatase (ALP)
- Serum gamma-glutamyltransferase (GGT)
- Prothrombin time or an International Normalized ratio (INR)
- 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]
References
Sakagishi Y. [Alanine aminotransferase (ALT)]. Nihon rinsho. Japanese journal of clinical medicine. 1995 May:53(5):1146-50 [PubMed PMID: 7602770]
Level 3 (low-level) evidenceSenior JR. Alanine aminotransferase: a clinical and regulatory tool for detecting liver injury-past, present, and future. Clinical pharmacology and therapeutics. 2012 Sep:92(3):332-9. doi: 10.1038/clpt.2012.108. Epub 2012 Aug 8 [PubMed PMID: 22871997]
Sherman KE. Alanine aminotransferase in clinical practice. A review. Archives of internal medicine. 1991 Feb:151(2):260-5 [PubMed PMID: 1992953]
Dufour DR. Alanine aminotransferase: is it healthy to be "normal"? Hepatology (Baltimore, Md.). 2009 Dec:50(6):1699-701. doi: 10.1002/hep.23358. Epub [PubMed PMID: 19937679]
Yip TC, Wong VW, Wong GL. Alanine Aminotransferase Level: The Road to Normal in 2021. Hepatology communications. 2021 Nov:5(11):1807-1809. doi: 10.1002/hep4.1788. Epub [PubMed PMID: 34719129]
Liu Z, Que S, Xu J, Peng T. Alanine aminotransferase-old biomarker and new concept: a review. International journal of medical sciences. 2014:11(9):925-35. doi: 10.7150/ijms.8951. Epub 2014 Jun 26 [PubMed PMID: 25013373]
Kaplan MM. Alanine aminotransferase levels: what's normal? Annals of internal medicine. 2002 Jul 2:137(1):49-51 [PubMed PMID: 12093245]
Woreta TA, Alqahtani SA. Evaluation of abnormal liver tests. The Medical clinics of North America. 2014 Jan:98(1):1-16. doi: 10.1016/j.mcna.2013.09.005. Epub 2013 Oct 28 [PubMed PMID: 24266911]
Parola M, Pinzani M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Molecular aspects of medicine. 2019 Feb:65():37-55. doi: 10.1016/j.mam.2018.09.002. Epub 2018 Sep 13 [PubMed PMID: 30213667]
Calvaruso V, Craxì A. Implication of normal liver enzymes in liver disease. Journal of viral hepatitis. 2009 Aug:16(8):529-36. doi: 10.1111/j.1365-2893.2009.01150.x. Epub 2009 Jul 28 [PubMed PMID: 19656288]
Oren R. Serum liver enzymes--should we count on them? Liver international : official journal of the International Association for the Study of the Liver. 2014 Feb:34(2):171-3. doi: 10.1111/liv.12366. Epub [PubMed PMID: 24164713]
Kalra A, Yetiskul E, Wehrle CJ, Tuma F. Physiology, Liver. StatPearls. 2023 Jan:(): [PubMed PMID: 30571059]
Knell AJ. Liver function and failure: the evolution of liver physiology. Journal of the Royal College of Physicians of London. 1980 Jul:14(3):205-8 [PubMed PMID: 7009850]
Oh RC, Hustead TR, Ali SM, Pantsari MW. Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. American family physician. 2017 Dec 1:96(11):709-715 [PubMed PMID: 29431403]
Ioannou GN, Boyko EJ, Lee SP. The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999-2002. The American journal of gastroenterology. 2006 Jan:101(1):76-82 [PubMed PMID: 16405537]
Level 2 (mid-level) evidenceClark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. The American journal of gastroenterology. 2003 May:98(5):960-7 [PubMed PMID: 12809815]
Level 2 (mid-level) evidenceBussler S, Vogel M, Pietzner D, Harms K, Buzek T, Penke M, Händel N, Körner A, Baumann U, Kiess W, Flemming G. New pediatric percentiles of liver enzyme serum levels (alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase): Effects of age, sex, body mass index, and pubertal stage. Hepatology (Baltimore, Md.). 2018 Oct:68(4):1319-1330. doi: 10.1002/hep.29542. Epub 2018 May 16 [PubMed PMID: 28926121]
Chen KW, Meng FC, Shih YL, Su FY, Lin YP, Lin F, Lin JW, Chang WK, Lee CJ, Li YH, Hsieh CB, Lin GM. Sex-Specific Association between Metabolic Abnormalities and Elevated Alanine Aminotransferase Levels in a Military Cohort: The CHIEF Study. International journal of environmental research and public health. 2018 Mar 19:15(3):. doi: 10.3390/ijerph15030545. Epub 2018 Mar 19 [PubMed PMID: 29562671]
Leibowitz A, Klin Y, Gruenbaum BF, Gruenbaum SE, Kuts R, Dubilet M, Ohayon S, Boyko M, Sheiner E, Shapira Y, Zlotnik A. Effects of strong physical exercise on blood glutamate and its metabolite 2-ketoglutarate levels in healthy volunteers. Acta neurobiologiae experimentalis. 2012:72(4):385-96 [PubMed PMID: 23377269]
Ruhl CE, Everhart JE. Diurnal variation in serum alanine aminotransferase activity in the US population. Journal of clinical gastroenterology. 2013 Feb:47(2):165-73. doi: 10.1097/MCG.0b013e31826df40a. Epub [PubMed PMID: 23164687]
Level 2 (mid-level) evidenceMera JR, Dickson B, Feldman M. Influence of gender on the ratio of serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) in patients with and without hyperbilirubinemia. Digestive diseases and sciences. 2008 Mar:53(3):799-802 [PubMed PMID: 17717745]
Qu HQ, Li Q, Grove ML, Lu Y, Pan JJ, Rentfro AR, Bickel PE, Fallon MB, Hanis CL, Boerwinkle E, McCormick JB, Fisher-Hoch SP. Population-based risk factors for elevated alanine aminotransferase in a South Texas Mexican-American population. Archives of medical research. 2012 Aug:43(6):482-8. doi: 10.1016/j.arcmed.2012.08.005. Epub 2012 Sep 5 [PubMed PMID: 22959976]
Wang S, Song J, Yang Y, Zhang Y, Chawla NV, Ma J, Wang H. Interaction between obesity and the Hypoxia Inducible Factor 3 Alpha Subunit rs3826795 polymorphism in relation with plasma alanine aminotransferase. BMC medical genetics. 2017 Jul 28:18(1):80. doi: 10.1186/s12881-017-0437-0. Epub 2017 Jul 28 [PubMed PMID: 28754107]
Bekkelund SI, Jorde R. Alanine Aminotransferase and Body Composition in Obese Men and Women. Disease markers. 2019:2019():1695874. doi: 10.1155/2019/1695874. Epub 2019 Aug 26 [PubMed PMID: 31534560]
Sohn W, Jun DW, Kwak MJ, Park Q, Lee KN, Lee HL, Lee OY, Yoon BC, Choi HS. Upper limit of normal serum alanine and aspartate aminotransferase levels in Korea. Journal of gastroenterology and hepatology. 2013 Mar:28(3):522-9. doi: 10.1111/j.1440-1746.2012.07143.x. Epub [PubMed PMID: 22497339]
Level 2 (mid-level) evidenceLudwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clinic proceedings. 1980 Jul:55(7):434-8 [PubMed PMID: 7382552]
Akuyam SA, Abubakar A, Lawal N, Yusuf R, Aminu SM, Hassan A, Musa A, Bello AK, Yahaya IA, Okafor PA. Assessment of biochemical liver function tests in relation to age among steady state sickle cell anemia patients. Nigerian journal of clinical practice. 2017 Nov:20(11):1428-1433. doi: 10.4103/njcp.njcp_14_17. Epub [PubMed PMID: 29303127]
Mukherjee T, Hanes J, Tews I, Ealick SE, Begley TP. Pyridoxal phosphate: biosynthesis and catabolism. Biochimica et biophysica acta. 2011 Nov:1814(11):1585-96. doi: 10.1016/j.bbapap.2011.06.018. Epub 2011 Jul 8 [PubMed PMID: 21767669]
di Salvo ML, Contestabile R, Safo MK. Vitamin B(6) salvage enzymes: mechanism, structure and regulation. Biochimica et biophysica acta. 2011 Nov:1814(11):1597-608. doi: 10.1016/j.bbapap.2010.12.006. Epub 2010 Dec 20 [PubMed PMID: 21182989]
Vanderlinde RE. Review of pyridoxal phosphate and the transaminases in liver disease. Annals of clinical and laboratory science. 1986 Mar-Apr:16(2):79-93 [PubMed PMID: 3008634]
Tutor-Crespo MJ, Hermida J, Tutor JC. Activation of serum aminotransferases by pyridoxal-5' -phosphate in epileptic patients treated with anticonvulsant drugs. Clinical biochemistry. 2004 Aug:37(8):714-7 [PubMed PMID: 15302618]
Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2005 Feb 1:172(3):367-79 [PubMed PMID: 15684121]
Córdoba J, O'Riordan K, Dupuis J, Borensztajin J, Blei AT. Diurnal variation of serum alanine transaminase activity in chronic liver disease. Hepatology (Baltimore, Md.). 1998 Dec:28(6):1724-5 [PubMed PMID: 9890798]
Level 3 (low-level) evidenceLukicheva TI, Men'shikov VV. [The preanalytical stage of under measuring of concentration of catalytic activity of enzymes: the characteristics and tasks of standardization]. Klinicheskaia laboratornaia diagnostika. 2012 Jun:(6):9-12 [PubMed PMID: 22946217]
Magnette A, Chatelain M, Chatelain B, Ten Cate H, Mullier F. Pre-analytical issues in the haemostasis laboratory: guidance for the clinical laboratories. Thrombosis journal. 2016:14():49. doi: 10.1186/s12959-016-0123-z. Epub 2016 Dec 12 [PubMed PMID: 27999475]
Plebani M. Errors in clinical laboratories or errors in laboratory medicine? Clinical chemistry and laboratory medicine. 2006:44(6):750-9 [PubMed PMID: 16729864]
Lee NY. Types and Frequencies of Pre-Analytical Errors in the Clinical Laboratory at the University Hospital of Korea. Clinical laboratory. 2019 Sep 1:65(9):. doi: 10.7754/Clin.Lab.2019.190512. Epub [PubMed PMID: 31532088]
Najat D. Prevalence of Pre-Analytical Errors in Clinical Chemistry Diagnostic Labs in Sulaimani City of Iraqi Kurdistan. PloS one. 2017:12(1):e0170211. doi: 10.1371/journal.pone.0170211. Epub 2017 Jan 20 [PubMed PMID: 28107395]
Level 2 (mid-level) evidencePlebani M. The detection and prevention of errors in laboratory medicine. Annals of clinical biochemistry. 2010 Mar:47(Pt 2):101-10. doi: 10.1258/acb.2009.009222. Epub 2009 Dec 1 [PubMed PMID: 19952034]
Lippi G, von Meyer A, Cadamuro J, Simundic AM. Blood sample quality. Diagnosis (Berlin, Germany). 2019 Mar 26:6(1):25-31. doi: 10.1515/dx-2018-0018. Epub [PubMed PMID: 29794250]
Level 2 (mid-level) evidenceMaire I. [Determination of the activity of alanine aminotransferase]. Revue francaise de transfusion et d'hemobiologie : bulletin de la Societe nationale de transfusion sanguine. 1990 Mar:33(2):101-9 [PubMed PMID: 2200419]
Mäntele W, Deniz E. UV-VIS absorption spectroscopy: Lambert-Beer reloaded. Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy. 2017 Feb 15:173():965-968. doi: 10.1016/j.saa.2016.09.037. Epub 2016 Sep 21 [PubMed PMID: 27727137]
Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clinic proceedings. 2014 Jan:89(1):95-106. doi: 10.1016/j.mayocp.2013.09.016. Epub [PubMed PMID: 24388027]
Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, González-Grande R, Pizarro A, Durán JA, Jiménez M, Rodrigo L, Romero-Gomez M, Navarro JM, Planas R, Costa J, Borras A, Soler A, Salmerón J, Martin-Vivaldi R, Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005 Aug:129(2):512-21 [PubMed PMID: 16083708]
Level 2 (mid-level) evidenceSgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, Lenoir C, Lemoine A, Hillon P. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology (Baltimore, Md.). 2002 Aug:36(2):451-5 [PubMed PMID: 12143055]
Davern TJ, Chalasani N, Fontana RJ, Hayashi PH, Protiva P, Kleiner DE, Engle RE, Nguyen H, Emerson SU, Purcell RH, Tillmann HL, Gu J, Serrano J, Hoofnagle JH, Drug-Induced Liver Injury Network (DILIN). Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology. 2011 Nov:141(5):1665-72.e1-9. doi: 10.1053/j.gastro.2011.07.051. Epub 2011 Aug 16 [PubMed PMID: 21855518]
Level 2 (mid-level) evidenceLewis JH. The adaptive response (drug tolerance) helps to prevent drug-induced liver injury. Gastroenterology & hepatology. 2012 May:8(5):333-6 [PubMed PMID: 22933867]
Devarbhavi H. An Update on Drug-induced Liver Injury. Journal of clinical and experimental hepatology. 2012 Sep:2(3):247-59. doi: 10.1016/j.jceh.2012.05.002. Epub 2012 Sep 21 [PubMed PMID: 25755441]
Telles-Correia D, Barbosa A, Cortez-Pinto H, Campos C, Rocha NB, Machado S. Psychotropic drugs and liver disease: A critical review of pharmacokinetics and liver toxicity. World journal of gastrointestinal pharmacology and therapeutics. 2017 Feb 6:8(1):26-38. doi: 10.4292/wjgpt.v8.i1.26. Epub [PubMed PMID: 28217372]
Purkins L, Love ER, Eve MD, Wooldridge CL, Cowan C, Smart TS, Johnson PJ, Rapeport WG. The influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a Phase I unit. British journal of clinical pharmacology. 2004 Feb:57(2):199-208 [PubMed PMID: 14748819]
Level 1 (high-level) evidenceHall P, Cash J. What is the real function of the liver 'function' tests? The Ulster medical journal. 2012 Jan:81(1):30-6 [PubMed PMID: 23536736]
Agrawal S, Dhiman RK, Limdi JK. Evaluation of abnormal liver function tests. Postgraduate medical journal. 2016 Apr:92(1086):223-34. doi: 10.1136/postgradmedj-2015-133715. Epub 2016 Feb 3 [PubMed PMID: 26842972]
Malakouti M, Kataria A, Ali SK, Schenker S. Elevated Liver Enzymes in Asymptomatic Patients - What Should I Do? Journal of clinical and translational hepatology. 2017 Dec 28:5(4):394-403. doi: 10.14218/JCTH.2017.00027. Epub 2017 Sep 21 [PubMed PMID: 29226106]
Gowda S, Desai PB, Hull VV, Math AA, Vernekar SN, Kulkarni SS. A review on laboratory liver function tests. The Pan African medical journal. 2009 Nov 22:3():17 [PubMed PMID: 21532726]
Peralta C, Jiménez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. Journal of hepatology. 2013 Nov:59(5):1094-106. doi: 10.1016/j.jhep.2013.06.017. Epub 2013 Jun 25 [PubMed PMID: 23811302]
Level 3 (low-level) evidenceGalvin Z, McDonough A, Ryan J, Stewart S. Blood alanine aminotransferase levels }1,000 IU/l - causes and outcomes. Clinical medicine (London, England). 2015 Jun:15(3):244-7. doi: 10.7861/clinmedicine.15-3-244. Epub [PubMed PMID: 26031973]
Abutaleb A, Kottilil S. Hepatitis A: Epidemiology, Natural History, Unusual Clinical Manifestations, and Prevention. Gastroenterology clinics of North America. 2020 Jun:49(2):191-199. doi: 10.1016/j.gtc.2020.01.002. Epub 2020 Mar 29 [PubMed PMID: 32389358]
Seto DS. Viral hepatitis. Pediatric clinics of North America. 1979 May:26(2):305-14 [PubMed PMID: 379776]
Schwarz KB, Balistreri W. Viral hepatitis. Journal of pediatric gastroenterology and nutrition. 2002:35 Suppl 1():S29-32 [PubMed PMID: 12151818]
Ryder SD, Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system: Acute hepatitis. BMJ (Clinical research ed.). 2001 Jan 20:322(7279):151-3 [PubMed PMID: 11159575]
Spearman CW, Dusheiko GM, Hellard M, Sonderup M. Hepatitis C. Lancet (London, England). 2019 Oct 19:394(10207):1451-1466. doi: 10.1016/S0140-6736(19)32320-7. Epub [PubMed PMID: 31631857]
Kaplan DE. Hepatitis C Virus. Annals of internal medicine. 2020 Sep 1:173(5):ITC33-ITC48. doi: 10.7326/AITC202009010. Epub [PubMed PMID: 32866406]
Guo G, Wu XZ, Su LJ, Yang CQ. Clinical features of ischemic hepatitis caused by shock with four different types: a retrospective study of 328 cases. International journal of clinical and experimental medicine. 2015:8(9):16670-5 [PubMed PMID: 26629201]
Level 2 (mid-level) evidenceSeeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation and pathogenesis. The American journal of medicine. 2000 Aug 1:109(2):109-13 [PubMed PMID: 10967151]
Level 2 (mid-level) evidenceSanyal D, Mukherjee P, Raychaudhuri M, Ghosh S, Mukherjee S, Chowdhury S. Profile of liver enzymes in non-alcoholic fatty liver disease in patients with impaired glucose tolerance and newly detected untreated type 2 diabetes. Indian journal of endocrinology and metabolism. 2015 Sep-Oct:19(5):597-601. doi: 10.4103/2230-8210.163172. Epub [PubMed PMID: 26425466]
Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nature medicine. 2018 Jul:24(7):908-922. doi: 10.1038/s41591-018-0104-9. Epub 2018 Jul 2 [PubMed PMID: 29967350]
Byrne CD, Targher G. NAFLD: a multisystem disease. Journal of hepatology. 2015 Apr:62(1 Suppl):S47-64. doi: 10.1016/j.jhep.2014.12.012. Epub [PubMed PMID: 25920090]
Mundi MS, Velapati S, Patel J, Kellogg TA, Abu Dayyeh BK, Hurt RT. Evolution of NAFLD and Its Management. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2020 Feb:35(1):72-84. doi: 10.1002/ncp.10449. Epub 2019 Dec 16 [PubMed PMID: 31840865]
De Ritis F, Coltorti M, Giusti G. An enzymic test for the diagnosis of viral hepatitis: the transaminase serum activities. 1957. Clinica chimica acta; international journal of clinical chemistry. 2006 Jul 23:369(2):148-52 [PubMed PMID: 16781697]
Majhi S, Baral N, Lamsal M, Mehta KD. De Ritis ratio as diagnostic marker of alcoholic liver disease. Nepal Medical College journal : NMCJ. 2006 Mar:8(1):40-2 [PubMed PMID: 16827089]
Level 2 (mid-level) evidenceWilliams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology. 1988 Sep:95(3):734-9 [PubMed PMID: 3135226]
Botros M, Sikaris KA. The de ritis ratio: the test of time. The Clinical biochemist. Reviews. 2013 Nov:34(3):117-30 [PubMed PMID: 24353357]
Kandel KP, Neupane BB, Giri B. Status of chemistry lab safety in Nepal. PloS one. 2017:12(6):e0179104. doi: 10.1371/journal.pone.0179104. Epub 2017 Jun 23 [PubMed PMID: 28644869]
Yago M, Pla C. Reference-mean-centered statistical quality control. Clinical chemistry and laboratory medicine. 2020 Aug 27:58(9):1517-1523. doi: 10.1515/cclm-2019-1034. Epub 2020 Jan 13 [PubMed PMID: 31926071]
Level 2 (mid-level) evidencePoh DKH, Lim CY, Tan RZ, Markus C, Loh TP. Internal quality control: Moving average algorithms outperform Westgard rules. Clinical biochemistry. 2021 Dec:98():63-69. doi: 10.1016/j.clinbiochem.2021.09.007. Epub 2021 Sep 14 [PubMed PMID: 34534518]
Level 2 (mid-level) evidenceBaral RM, Dhand NK, Freeman KP, Krockenberger MB, Govendir M. Biological variation and reference change values of feline plasma biochemistry analytes. Journal of feline medicine and surgery. 2014 Apr:16(4):317-25. doi: 10.1177/1098612X13508770. Epub 2013 Nov 11 [PubMed PMID: 24217705]
Level 3 (low-level) evidenceGurses AP, Xiao Y. A systematic review of the literature on multidisciplinary rounds to design information technology. Journal of the American Medical Informatics Association : JAMIA. 2006 May-Jun:13(3):267-76 [PubMed PMID: 16501176]
Level 1 (high-level) evidence