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Alanine Amino Transferase


Alanine Amino Transferase

Article Author:
Kevin Moriles
Article Editor:
Samy Azer
Updated:
7/5/2020 6:10:15 PM
For CME on this topic:
Alanine Amino Transferase CME
PubMed Link:
Alanine Amino Transferase

Introduction

In humans, the liver is an organ involved in various processes critical for life. The liver secrets bile produces plasma proteins such as albumin tightly regulates the composition of blood plasma controls the flow of energy and nutrients in tissues, involved in detoxification processes, and the excretion of waste products. Because of these vital functions in the human body, it is essential to assess hepatic injury and malfunction accurately. Evaluating elevations in the serum hepatic enzymes and correlating the results with the medical history and physical examination can assist in delineating the differential diagnosis. Among these hepatic enzymes, transaminases, mainly alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

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. ALT is normally 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.

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. The most common causes are alcohol-induced liver injury, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH), chronic hepatitis B or C, autoimmune hepatitis, and drug or herbal supplement-induced liver injury. Other causes include hemochromatosis, vascular disease, acute viral hepatitis, and genetic disorders affecting the liver.

Etiology and Epidemiology

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.[1][2][3] However, any process that leads to loss of hepatocyte membrane integrity or necrosis results in the release of AST and ALT in higher concentrations in the serum.[4] 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.[5] Increases in alanine transaminase (ALT) alone affects 8.9% of the U.S. population.[6] Several physiological and risk factors may contribute to the serum levels of these enzymes include age, sex, body mass index, and pubertal age, elevated levels of triglycerides, insulin resistance, and blood glucose level.[7][8]

First - 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.[9] 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 at 16:00 hr.[10]
  3. ALT is higher in males compared to females. This gender-based differences in ALT level are possibly related to hormonal differences between males and females.[11]
  4. Ethnicity affects ALT levels. Research shows that Mexican-Americans have a higher prevalence of ALT elevation compared to other ethnicities.[12] 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.[13] 
  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.[14] They found body mass index to be the most determining factor for ALT, and gender was the most influencing factor for AST.[15] 

Second - 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[16]

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 phosphate, also known as vitamin B6.[17] 

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. 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.[18][19]

Specimen Requirements and Procedure

Hepatic function panels evaluate for alanine aminotransferase (ALT) through the use of blood samples. The quality of blood specimens is vital to decrease the occurrence of laboratory errors, prevent diagnosis delay, and ensure a proper diagnosis. 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.[20]

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. Blood specimens that have fibrin strands or clots present 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. 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 are usable.[20]

Diagnostic Tests

A panel of laboratory tests to assess the liver functions, also known as the liver function test, is commonly used in clinical practice. The liver function test comprises the following[20]:

  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

Patients are instructed to avoid certain medications and foods before a hepatic function panel to ensure the integrity of blood specimens. A trained healthcare provider will disinfect 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 associated with them.

According to the International Standard ISO 6710, the light green cap contains lithium-heparin and used for the hepatic function panel.[20] After the specimen is collected and fulfill the requirements, they go for testing.

Interfering Factors

ALT levels can increase due to certain drugs, which should be avoided before testing. Drug hepatotoxicity can be nonidiosyncratic (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.[21][22][23] Hepatitis E infection can masquerade drug-induced liver injury in 3% to 13% of the cases.[24] Tacrine, a medication indicated for Alzheimer 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.[25] 

Up to 5% of patients on statin medications were found to develop elevations in ALT.[26] 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.[27] Elevation of serum ALT and AST has been reported in patients taking these medications isoniazid, pyrazinamide, rifampicin, ibuprofen, or dapsone.[28] The website maintained by the National Institute of Diabetes and Digestive Diseases (NIDDK) is a valuable resource to clinicians and researchers interested in liver hepatotoxicity and other drugs that can causes increases in serum ALT. As stated earlier, periods of intense exercise should be avoided before testing, as it can also increase alanine transaminase levels.[29]

Results, Reporting, Critical Findings

Results of a hepatitis panel should correlate with the initial findings in a complete history and physical examination. A thorough review should include important questions regarding the patient’s age, past medical history (diabetes, obesity, hyperlipidemia, inflammatory bowel disease, celiac sprue, thyroid disorders, autoimmune hepatitis, and 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).

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.[30] 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.[30]

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. In the workup for elevated transaminase levels, repeat liver enzymes are typically not necessary.[31]

  • 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. Although there are specific hepatic diseases that 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. It is common to see increases in both AST and ALT serum levels concomitantly. 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.[32]

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.[31] 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. Hepatitis serology labs should also be ordered to confirm the diagnosis and the type of viral hepatitis.

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.[33] 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.[33] In the evaluation of 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.[32] In paracetamol toxicity, the levels of serum ALT are usually higher than 1,000 U/L.[32] Therefore, paracetamol toxicity should be among the differential diagnosis of patients presenting with acute liver failure.[32] 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, and dapsone.[21][22][23]

Non-alcoholic fatty liver disease (NAFLD) should merit consideration among the most common cause of abnormally elevated ALT levels in asymptomatic patients. NAFLD is the accumulation of fat 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. NAFLD is usually associated with higher ALT and GGT levels in patients with impaired glucose tolerance or type 2 diabetes mellitus. Risk factors for NAFLD include morbid obesity, hyperglycemia, hypertriglyceridemia, hypertension, and decreased insulin sensitivity. 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.[32][34]

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.[35] Later, the usefulness of this ratio has been 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, and 1.5 to <2.0 in acute viral hepatitis, and >1.0 in fibrosis and cirrhosis. However, many laboratories do not include this ratio in their reports because it is not specific, and AST can be affected by hemolysis. The ratio is affected by the number of days post-exposure and the severity of the disease. Another important 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.[36]

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 the practice of collecting blood samples, educate participants on the risks, and addressing common errors that occur can increase lab safety.

Healthcare workers should demonstrate a degree of competency before working with patients. Personal protective equipment and antiseptics should be utilized by healthcare workers 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. The use of a sharps container can decrease the risk of a needle-stick injury from occurring.[20]

Enhancing Healthcare Team Outcomes

Multi-disciplinary rounds are a time in which medical and other health providers can collaborate and work together to enhance patients' healthcare outcomes. Clinicians may review the significance of the hepatic function test panel in correlation with the medical history and physical examination of each patient to early detect any drug-induced hepatic injury 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.[37]


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