Alanine Aminotransferase 1
Introduction
Section titled “Introduction”Background
Section titled “Background”Alanine aminotransferase (ALT), also known as serum glutamic-pyruvic transaminase (SGPT), is an enzyme that plays a critical role in amino acid metabolism. While found in various tissues throughout the body,_ALT1_ (encoded by the _GPT_ gene) is particularly concentrated in the liver. Its presence in the bloodstream is often measured as a key indicator of liver health.
Biological Basis
Section titled “Biological Basis”The _GPT_gene provides instructions for making alanine aminotransferase 1, a cytoplasmic enzyme. This enzyme catalyzes a reversible reaction where an amino group is transferred from L-alanine to α-ketoglutarate, resulting in the formation of pyruvate and L-glutamate. This process is essential for converting amino acids into energy sources and for the synthesis of glucose, especially during fasting._ALT1_is a crucial component of the glucose-alanine cycle, a pathway that helps transport ammonia from muscles to the liver for detoxification.
Clinical Relevance
Section titled “Clinical Relevance”Measuring serum _ALT1_levels is a common diagnostic procedure in medical practice. It is primarily used to evaluate liver function and to detect potential liver damage or disease. Elevated_ALT1_levels in the blood can indicate injury to liver cells, which may be caused by various conditions such as viral hepatitis, fatty liver disease (both alcoholic and non-alcoholic), adverse drug reactions, cirrhosis, and other liver disorders. Monitoring_ALT1_ levels assists healthcare professionals in diagnosing, assessing the prognosis of, and managing liver-related conditions. It is also often included in routine blood tests and can be used to track the liver’s response to certain medications.
Social Importance
Section titled “Social Importance”The routine testing of _ALT1_levels holds significant social importance due to the widespread impact of liver diseases. Liver conditions represent a major global public health challenge, contributing substantially to illness and mortality. Early detection of liver damage through_ALT1_screening can facilitate timely medical interventions, potentially preventing the progression to more severe outcomes like liver failure or liver cancer. This diagnostic tool contributes to public health by enabling early diagnosis, guiding necessary lifestyle changes, and informing effective treatment strategies, ultimately improving patient well-being and reducing the overall burden of liver disease on healthcare systems.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Many genome-wide association studies, despite involving large cohorts, may still have insufficient statistical power to reliably detect genetic associations with modest effect sizes, potentially leading to false negative findings. This limitation suggests that a significant number of genuine genetic influences on traits might remain undiscovered without even larger sample sizes and improved statistical methods for gene discovery Genome-wide association studies have identified multiple genetic loci associated with plasma liver enzyme levels, highlighting the polygenic nature of these traits. [1]These studies often reveal common variants that contribute to individual differences in metabolic profiles and disease susceptibility.
Variants in genes related to the immune system and tissue integrity, such as complement factors and basement membrane components, can indirectly impact liver health. For instance, *rs7539005 * in the CFH gene (Complement Factor H) and *rs609061 * in the C2 gene (Complement Component 2) are associated with components of the complement system, a crucial part of innate immunity. The complement system’s activity can influence inflammatory responses, which, when dysregulated, contribute to liver damage and elevated ALT levels. [2] Similarly, *rs61833496 * within the NID1 gene (Nidogen 1) is associated with a protein essential for the structure and integrity of the basement membrane, a specialized extracellular matrix that supports tissues like the liver. Variations here could affect liver architecture and its resilience to stress, potentially influencing ALT release.
Other variants affect genes involved in fundamental cellular processes such as gene transcription and metabolic regulation. The variant *rs35267984 * in MED16 (Mediator Complex Subunit 16) is linked to a component of the Mediator complex, which acts as a bridge between gene-specific regulatory proteins and the RNA polymerase II enzyme, thereby controlling gene expression. [3] Changes in MED16 function could alter the expression of genes critical for liver metabolism or detoxification pathways, indirectly impacting ALT levels. Likewise, *rs140972619 * in DEPTOR (DEP Domain Containing MTOR-Interacting Protein) is associated with a negative regulator of the mTOR pathway, a central hub for cell growth, metabolism, and autophagy. Dysregulation of mTOR signaling can lead to metabolic disorders and liver dysfunction, influencing ALT. [4] The variant *rs149243713 * in YLPM1 (YLP Motif Containing 1), while less extensively characterized, may also play a role in cellular processes that contribute to metabolic health and, consequently, liver enzyme regulation.
Variants in genes with roles in extracellular matrix dynamics and non-coding RNA function also contribute to the genetic landscape of liver enzyme regulation. For example, *rs116913826 * in HPSE2(Heparanase 2) is associated with a gene related to enzymes that modify heparan sulfate, a key component of the extracellular matrix. Alterations in extracellular matrix remodeling can impact liver fibrosis and inflammation, both of which affect ALT levels.[5] Additionally, the locus *rs564871187 * spanning RPL29P19 (a ribosomal protein pseudogene) and LINC02947 (a long intergenic non-coding RNA) suggests that variations in non-coding regions can influence gene expression through regulatory mechanisms. Such regulatory changes can subtly alter liver cell function and contribute to variations in ALT concentrations. [6]
Finally, genetic variations affecting DNA replication, cell structure, and mitochondrial function can also modulate liver enzyme levels. The locus *rs56205242 * encompasses POLA2 (DNA Polymerase Alpha 2, Accessory Subunit) and CDC42EP2 (CDC42 Effector Protein 2). POLA2 is crucial for DNA replication and repair, vital for liver regeneration, while CDC42EP2 is involved in cell cytoskeleton organization, impacting cell shape and motility. [7] Variations in these genes could influence the liver’s capacity for repair or its cellular integrity, affecting the release of ALT into the bloodstream. Similarly, *rs140705291 * within the region of RNU6-756P (a small nuclear RNA pseudogene) and TMEM65 (Transmembrane Protein 65) is relevant. TMEM65 is a mitochondrial protein, and mitochondrial dysfunction is a known contributor to various liver diseases and elevated ALT. [8] These genetic associations underscore the complex and multifaceted genetic architecture underlying ALT levels and liver health.
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Definition and Biological Significance of Alanine Aminotransferase 1
Section titled “Definition and Biological Significance of Alanine Aminotransferase 1”Alanine aminotransferase 1, commonly abbreviated as ALT, is a critical enzyme primarily found in the liver, playing a central role in amino acid metabolism. As a plasma liver enzyme, ALT facilitates the transfer of an amino group from alanine to α-ketoglutarate, producing pyruvate and glutamate.[1]This enzymatic activity is essential for various metabolic pathways, including gluconeogenesis. Elevated levels of ALT in the blood are widely recognized as a key indicator for identifying patients with liver diseases, monitoring disease progression and severity, and detecting drug-induced liver injury.[1]Beyond its role in liver health, ALT levels also hold significant epidemiological importance, serving as prospective risk factors for conditions such as type 2 diabetes, cardiovascular disease, and overall mortality.[1]
Clinical Measurement and Diagnostic Thresholds
Section titled “Clinical Measurement and Diagnostic Thresholds”The measurement of alanine aminotransferase 1 levels is a standard component of clinical liver-enzyme tests, which are routinely performed to assess liver function and health. These tests involve drawing blood samples, typically after an overnight fast, to ensure accurate baseline measurements.[5] While specific methodologies for ALT measurement are not detailed, related liver enzymes like gamma-glutamyl transferase (GGT) are measured using spectrophotometry, suggesting similar enzymatic assay techniques are employed for ALT. [7] Diagnostic criteria for elevated ALT are typically defined by upper limits of normal, which can vary by demographic factors; for instance, levels above 36 U/L in females and 60 U/L in males have been used as thresholds in some studies. [1] Deviations from these normal ranges, which are often established by clinical biochemistry units, prompt further investigation into potential liver dysfunction or other associated health risks. [2]
Genetic and Environmental Influences on ALT Levels
Section titled “Genetic and Environmental Influences on ALT Levels”Plasma levels of alanine aminotransferase 1 are influenced by a complex interplay of both environmental and genetic factors. Research indicates a notable heritability for ALT, estimated to be around 33%, highlighting a significant genetic component in determining an individual’s enzyme levels.[1] Genome-wide association studies have identified specific genetic loci associated with variations in ALT levels, including regions on chromosome 10 (encompassing genes like CPN1, ERLIN1, and CHUK) and chromosome 22 (involving PNPLA3 and SAMM50). [1] Particularly, variants within the PNPLA3 gene, such as rs738409 (Ile148Met) and rs2294918 (Lys434Glu), have been linked to altered ALT levels, with carriers of specific genotypes, like homozygous GG for rs2281135 , showing an increased risk of elevated ALT. [1] These genetic associations suggest that mechanisms such as cis- or trans-transcriptional effects or altered protein function contribute to the observed variations, providing valuable insights for interpreting liver enzyme tests and identifying candidate genes for various liver diseases. [1]
History and Epidemiology
Section titled “History and Epidemiology”Evolution of Clinical and Epidemiological Understanding
Section titled “Evolution of Clinical and Epidemiological Understanding”Alanine aminotransferase (ALT) levels have long been a cornerstone in clinical diagnostics, widely employed to identify individuals with liver diseases, monitor disease progression and treatment efficacy, and detect drug-induced liver injury.[1]Beyond its direct role in assessing liver health, the epidemiological significance of plasma ALT levels extends substantially, as research has identified them as prospective risk factors for critical health outcomes. Studies have shown that elevated ALT levels are associated with an increased risk of developing type 2 diabetes, cardiovascular disease, and all-cause mortality across various large cohorts.[1] This recognition broadened the understanding of ALT from a mere liver enzyme marker to an important indicator of broader metabolic and systemic health, influencing how these tests are interpreted in a wider epidemiological context.
Genetic Influences and Population-Based Discoveries
Section titled “Genetic Influences and Population-Based Discoveries”The understanding of ALT levels has evolved to incorporate the significant role of genetic variation, with studies estimating the heritability of plasma ALT at approximately 33%. [1] Landmark genome-wide association studies (GWAS) have been instrumental in uncovering specific genetic loci that influence these levels in diverse populations. For instance, a comprehensive study involving 7,715 individuals across three populations, with replication in an additional three cohorts, identified two key loci associated with plasma ALT levels: one encompassing CPN1-ERLIN1-CHUK on chromosome 10 and another involving PNPLA3-SAMM50 on chromosome 22. [1] These discoveries offer valuable insights into the genetic architecture underlying ALT regulation, providing candidate genes for various liver diseases of viral, metabolic, autoimmune, or toxic origin, and enhancing the interpretation of liver enzyme tests in both clinical and epidemiological settings. [1]
Alanine Aminotransferase 1: Biological Background
Section titled “Alanine Aminotransferase 1: Biological Background”Alanine aminotransferase (ALT) is an enzyme widely recognized for its crucial role in amino acid metabolism and its diagnostic utility in clinical settings. Plasma levels of ALT are routinely assessed as part of liver enzyme tests, which serve as primary indicators for identifying and monitoring liver diseases, as well as detecting drug-induced liver injury.[1]Beyond its direct association with liver health, ALT levels also hold significant epidemiological importance, demonstrating correlations with broader health outcomes such as an increased risk for type 2 diabetes, cardiovascular disease, and all-cause mortality.[1] The levels of this enzyme in the plasma are influenced by a combination of environmental factors and genetic predispositions, with genetic factors contributing an estimated heritability of 33% to circulating ALT levels. [1]
Genetic Regulation and Molecular Mechanisms
Section titled “Genetic Regulation and Molecular Mechanisms”Genetic studies have shed light on specific genomic regions that influence plasma ALT levels, highlighting the complex regulatory networks involved. Genome-wide association studies (GWAS) have identified two prominent loci associated with ALT levels: one encompassing CPN1-ERLIN1-CHUK on chromosome 10 and another involving PNPLA3-SAMM50 on chromosome 22. [1] These genetic associations suggest that variations within these regions can impact ALT levels through various mechanisms, including cis- or trans-transcriptional effects, where genetic variants alter the expression levels of nearby or distant genes. [1] Additionally, missense variations within the functional domains of encoded proteins can lead to protein dysfunction, or other yet-to-be-identified pathways may contribute to the observed effects. [1] The process of alternative splicing, where different messenger RNA (mRNA) transcripts are produced from a single gene, is another mechanism by which genetic variants can modify protein structure and function .
Cellular Pathways and Lipid Metabolism
Section titled “Cellular Pathways and Lipid Metabolism”One of the key biomolecules implicated in the genetic regulation of ALT is the PNPLA3 (patatin-like phospholipase domain-containing protein 3), also known as ADPN. This liver-expressed transmembrane protein possesses phospholipase activity, making it integral to lipid metabolism within the cell. [1] PNPLA3 plays a dual role in energy homeostasis, being significantly upregulated during adipocyte differentiation and in response to both fasting and feeding states, thereby facilitating both energy mobilization and lipid storage in adipose tissue and the liver. [1] Elevated PNPLA3mRNA expression has been observed in the subcutaneous and visceral adipose tissue of individuals with obesity, underscoring its involvement in metabolic pathways relevant to liver function and overall lipid balance.[1]
Pathophysiological Significance and Systemic Impact
Section titled “Pathophysiological Significance and Systemic Impact”The intricate interplay between genetic factors, cellular metabolism, and tissue-specific functions profoundly impacts ALT levels and their clinical implications. For example, specific genetic variants within PNPLA3, such as the lead single nucleotide polymorphism (SNP)rs2281135 , which is in complete linkage disequilibrium with intronic SNPs rs1010022 and rs2072907 , have been linked to differences in adipose PNPLA3 mRNA expression and adipocyte lipolysis. [1] Furthermore, nonsynonymous SNPs within PNPLA3, including rs738409 (Ile148Met) and rs2294918 (Lys434Glu), are hypothesized to act as exonic splicing silencer elements, potentially influencing gene regulation. [1] Homozygous carriers of the GG genotype for rs2281135 face a 34% greater risk of having ALT levels exceeding the upper limits of normal, illustrating a direct genetic link to elevated enzyme levels. [1] These insights into the genetic and molecular underpinnings of ALT regulation are crucial for better interpreting liver enzyme tests and identifying candidate genes for various liver diseases, including those of viral, metabolic, autoimmune, or toxic origin. [1]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Role and Regulation
Section titled “Metabolic Role and Regulation”Alanine aminotransferase 1 (ALT) is a crucial liver enzyme, and its plasma levels are widely used in clinical diagnostics. The primary metabolic function of ALTinvolves the transamination of L-alanine and α-ketoglutarate to pyruvate and L-glutamate, a pivotal reaction linking amino acid and carbohydrate metabolism. Alterations inALT levels are therefore indicative of changes in hepatic metabolic processes, reflecting the liver’s overall metabolic health. [1] Beyond its direct role in liver function, plasma ALThas substantial epidemiological significance as a prospective risk factor for broader metabolic disorders such as type 2 diabetes, cardiovascular disease, and all-cause mortality, suggesting its integration into systemic metabolic regulation.[1] These associations imply that ALT levels can serve as a systemic readout, reflecting the complex interplay of various metabolic pathways and their overall homeostasis.
Genetic and Transcriptional Control
Section titled “Genetic and Transcriptional Control”The regulation of ALT levels is significantly influenced by human genetic variation, with studies estimating its heritability to be around 33%. [1] Genome-wide association studies have identified specific genetic loci associated with plasma ALT levels, notably regions on chromosome 10 encompassing CPN1-ERLIN1-CHUK and on chromosome 22 involving PNPLA3-SAMM50. [1] The mechanisms underlying these genetic associations are diverse and can involve cis- or trans-transcriptional effects, where variants influence the rate of mRNA transcription in liver or lymphoblastoid cells. [1] Furthermore, missense variations occurring within the functional domains of the proteins encoded by these genes can lead to altered protein function or stability, thereby directly impacting ALT activity and circulating levels. [1]
Systemic Integration and Pathway Crosstalk
Section titled “Systemic Integration and Pathway Crosstalk”The levels of ALTin plasma are a result of complex interactions between both genetic predispositions and various environmental factors. The enzyme’s broad epidemiological relevance, extending beyond its direct hepatic function to predict risks for type 2 diabetes and cardiovascular disease, underscores its role in broader physiological systems.[1] This suggests significant pathway crosstalk, where the metabolic state of the liver, as reflected by ALTlevels, is intricately connected to systemic energy metabolism, lipid processing, and cardiovascular health. Such systemic integration highlightsALT as a marker that reflects the emergent properties of a vast network of interconnected metabolic and regulatory pathways throughout the body.
Clinical Significance and Disease Mechanisms
Section titled “Clinical Significance and Disease Mechanisms”In clinical practice, ALT plasma levels are a standard biomarker for the diagnosis of liver diseases, for monitoring the course and severity of these conditions, and for assessing the efficacy of therapeutic interventions. [1] Dysregulation of ALT pathways is a hallmark of various liver pathologies, including those of viral, metabolic, autoimmune, or toxic origin. [1] The genetic loci identified as influencing ALT levels, such as those associated with CPN1-ERLIN1-CHUK and PNPLA3-SAMM50, are considered candidate genes that may contribute to the susceptibility or progression of these diverse liver diseases. [1]Understanding these disease-relevant mechanisms provides potential therapeutic targets for mitigating liver injury and related systemic complications.
Clinical Relevance
Section titled “Clinical Relevance”Diagnostic and Monitoring Utility
Section titled “Diagnostic and Monitoring Utility”Alanine aminotransferase (ALT) levels are a cornerstone in clinical diagnostics, widely employed to identify and manage liver diseases. Plasma liver-enzyme tests, including ALT, serve as critical indicators for detecting the presence of liver pathologies, monitoring the progression and severity of these conditions, and assessing the efficacy of therapeutic interventions.[1] Furthermore, ALT levels are an important biomarker for identifying drug-induced liver injury, offering clinicians a valuable tool for patient safety and medication management. These applications underscore ALT’s fundamental role in routine clinical practice for liver health assessment.
Genetic Predisposition and Risk Stratification
Section titled “Genetic Predisposition and Risk Stratification”Genetic factors significantly influence plasma ALT levels, with an estimated heritability of 33%, indicating a substantial genetic component to an individual’s ALT profile. [1] Population-based genome-wide association studies have identified specific genetic loci associated with ALT levels, including CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22. [1] These findings are pivotal for interpreting liver-enzyme tests and pinpointing candidate genes involved in various liver diseases of viral, metabolic, autoimmune, or toxic origin.
Among these, the PNPLA3 gene (also known as ADPN) is particularly notable, encoding a liver-expressed transmembrane protein with phospholipase activity that plays a role in energy mobilization and lipid storage. [1] Specific variants, such as the lead SNP rs2281135 , are in complete linkage disequilibrium with obesity-associated tagSNPs and are linked to differences inPNPLA3 mRNA expression and adipocyte lipolysis. [1] Homozygous carriers of the GG genotype for rs2281135 demonstrate a 34% increased risk of having ALT levels above the upper limit of normal, highlighting its utility in identifying high-risk individuals and potentially guiding personalized medicine approaches for managing liver health. [1] The association of these loci with both ALT and AST suggests a broader predisposition to hepatocyte dysfunction, further emphasizing their relevance in risk stratification.
Metabolic and Systemic Health Associations
Section titled “Metabolic and Systemic Health Associations”Beyond its direct role in liver disease, ALT has considerable epidemiologic significance, serving as a prospective risk factor for several systemic health conditions. Elevated ALT levels have been consistently linked in multiple large studies to an increased risk of developing type 2 diabetes, cardiovascular disease, and even all-cause mortality.[1]This extended prognostic value positions ALT as a broader indicator of metabolic health and overall systemic risk, rather than solely a liver-specific marker. Understanding these associations aids in comprehensive risk assessment, allowing for earlier identification of individuals prone to these comorbidities and informing potential prevention strategies.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs7539005 | CFH | t-SNARE domain-containing protein 1 measurement glycosyltransferase 8 domain-containing protein 1 measurement kallikrein-6 measurement OCIA domain-containing protein 1 measurement protein measurement |
| rs609061 | C2 | stabilin-2 measurement C-C motif chemokine 1 measurement cystatin-8 measurement hephaestin-like protein 1 measurement WAP four-disulfide core domain protein 5 measurement |
| rs35267984 | MED16 | interleukin-34 measurement interleukin-37 measurement interleukin-10 receptor subunit alpha measurement protein measurement C-type lectin domain family 4 member D measurement |
| rs140972619 | DEPTOR | alanine aminotransferase 1 measurement |
| rs116913826 | HPSE2 | alanine aminotransferase 1 measurement |
| rs149243713 | YLPM1 | alanine aminotransferase 1 measurement |
| rs564871187 | RPL29P19 - LINC02947 | alanine aminotransferase 1 measurement |
| rs61833496 | NID1 | alanine aminotransferase 1 measurement |
| rs56205242 | POLA2 - CDC42EP2 | alanine aminotransferase 1 measurement |
| rs140705291 | RNU6-756P - TMEM65 | alanine aminotransferase 1 measurement |
References
Section titled “References”[1] Yuan, X., et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet, vol. 83, no. 4, 2008, pp. 520-528.
[2] Wallace, C., et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, vol. 82, no. 1, 2008, pp. 139-49.
[3] Melzer, D., et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet, vol. 4, no. 5, 2008, e1000072.
[4] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 12, 2008, pp. 1421-1427.
[5] Sabatti, C., et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 40, no. 12, 2008, pp. 1394-1402.
[6] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 12, 2008, pp. 1412-21.
[7] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, suppl. 1, 2007, p. S11.
[8] Reiner, A. P., et al. “Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.”Am J Hum Genet, vol. 82, no. 5, 2008, pp. 1193-201.