Liver Enzymes Explained: Understanding AST, ALT, ALP & GGT
1. Introduction
When liver cells are stressed, inflamed, or injured, they leak measurable enzymes into the bloodstream, these act like silent biochemical signals that often reveal trouble long before symptoms appear.
Among these, ALT, AST, and GGT are the most widely used indicators of hepatocellular injury and metabolic dysfunction. Yet their interpretation is far from straightforward: mild elevations can reflect reversible metabolic stress, while normal values can sometimes mask progressive disease.
In this chapter, we break down what these enzymes truly represent, why they rise, how they differ, and how to interpret them in the specific context of MASLD, MASH, and metabolic injury to the liver.
2. Alanine Aminotransferase (ALT/SGPT)
ALT is an enzyme found primarily in liver cells. Its release into the bloodstream indicates hepatocellular injury.
ALT is like an alarm that goes off when liver cells are damaged. When liver cells are injured or dying, they release ALT into your bloodstream. Think of it as checking for leaks in a water pipe, if you see water where it shouldn’t be, you know there’s damage somewhere. For fatty liver disease, even mildly elevated ALT (higher than 30 for men or 19 for women) can be significant, even though older reference ranges might still call this “normal.”
Normal Ranges:
- Traditional: 10-40 IU/L (males), 10-35 IU/L (females)
- Optimized for MASLD detection: 30 IU/L (males), 19 IU/L (females) (Prati et al., 2002)
Clinical Significance:
ALT is considered the most specific marker for liver injury. In MASLD, ALT elevation typically ranges from 1.5 to 5 times the upper limit of normal. Studies have shown that using lower, more sensitive cut-offs significantly increases the detection of biopsy-proven NAFLD (Kunde et al., 2005).
Importantly, ALT can be normal even in patients with significant MASLD/MASH, particularly in those with advanced fibrosis where the AST:ALT ratio begins to reverse (Kwo et al., 2017).
The recent American College of Gastroenterology guidelines suggest that true healthy normal ALT levels range from 29-33 IU/L for males and 19-25 IU/L for females, emphasizing that even modest elevations above these levels warrant assessment (Kwo et al., 2017).
3. Aspartate Aminotransferase (AST/SGOT)
AST is found in liver cells as well as heart, muscle, kidney, and brain tissue. While less specific for liver disease than ALT, it provides important diagnostic information when considered alongside ALT.
Normal Ranges:
- 10-40 IU/L (males)
- 10-35 IU/L (females)
Values exceeding 1,000 IU/L suggest acute liver injury from causes such as drug-induced liver injury, viral hepatitis, or ischemic hepatitis (Kwo et al., 2017).
4. ALT/AST ratio
The ratio of serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT), commonly called the De Ritis ratio, is a long-standing, inexpensive biochemical index used to help characterise hepatocellular injury.
Its interpretive value rests on basic biochemical differences: ALT is predominantly a cytosolic enzyme concentrated in hepatocytes and is relatively liver-specific, whereas AST exists in both cytosolic and mitochondrial isoforms and is also abundant in heart, skeletal muscle, kidney and other tissues. Because mitochondrial injury and extra-hepatic sources preferentially increase AST, the AST/ALT ratio integrates information about the location and severity of cellular damage and about the likelihood of non-hepatic contributions to transaminase elevations (Botros et al. (2013)).
4.1 Typical clinical patterns and supporting evidence
The AST:ALT ratio provides valuable diagnostic clues. In MASLD/NASH, the ratio is typically <1 (ALT higher than AST), while in alcoholic liver disease, the ratio is usually >2 (Mofrad et al., 2003).
As NASH progresses to cirrhosis, the AST:ALT ratio often increases above 1 due to declining ALT levels and maintained or elevated AST (due to mitochondrial injury).
AST/ALT < 1 (ALT predominance). This pattern, ALT higher than AST, frequently appears in metabolic-associated liver disease and early hepatocellular injury, where cytosolic hepatocyte stress (e.g., lipotoxicity, insulin resistance) predominates and ALT leaks more readily into plasma (Forlano et al. (2021)). Large cohort analyses and population studies also show that a comparatively higher ALT (or higher ALT/AST ratio) associates with incident NAFLD in many settings (Zou et al. (2020); Xuan et al. (2024)).
AST/ALT ≈ 1. When AST and ALT are similar, the finding is nonspecific: it may represent mixed or transitional disease (for example evolving fibrosis), subacute injuries, or simply sampling at a time when kinetics of release/clearance produce similar values. Alone it does not reliably distinguish etiology or stage. Composite fibrosis scores or imaging are required for staging. (Forlano et al. (2021)).
AST/ALT > 1: (AST predominance) and especially ≥ 2. A ratio ≥ 2:1 has classic association with alcoholic liver injury: preferential mitochondrial damage with release of mitochondrial AST and relative suppression of ALT synthesis (in part due to pyridoxal-5′-phosphate deficiency) produces a disproportionately high AST (Sorbi et al. (1999); Botros et al. (2013)). However, AST/ALT ≥ 2 is specific but not highly sensitive for alcohol-related hepatitis, and elevated AST from non-hepatic sources (e.g., muscle injury) can also produce high ratios; therefore the ratio should not be interpreted in isolation.
Changes with advancing fibrosis/cirrhosis. In advanced chronic liver disease or cirrhosis, ALT levels may decline because of loss of viable hepatocytes while AST (including mitochondrial AST released from damaged cells and possibly from non-hepatic sources) may remain relatively higher, producing a higher AST/ALT ratio even when absolute enzyme levels are normal or only mildly elevated (Botros et al. (2013); Forlano et al. (2021)).
While ALT is found mainly in the liver, AST is found in many organs including the heart and muscles. Doctors look at the ratio between AST and ALT to help figure out what’s causing liver problems. If you have fatty liver disease, your ALT is usually higher than your AST. But if you drink too much alcohol, your AST becomes much higher than your ALT. As fatty liver disease gets worse and turns into cirrhosis, the pattern can flip again—this is like watching how the damage to your liver changes over time.
4.2 Evidence from contemporary cohorts
Longitudinal and large cross-sectional studies have re-examined the ratio in metabolic-associated disease. Zou et al. (2020) reported that higher ALT/AST (equivalently lower AST/ALT) predicted incident NAFLD over five years among >12,000 nonobese Chinese adults; the association persisted after multivariable adjustment and showed nonlinear/saturation effects.
Xuan et al. (2024) found in a large U.S. cross-sectional NHANES analysis that higher ALT/AST associated with greater odds of NAFLD and with markers of both steatosis and fibrosis, and in ROC comparisons the ALT/AST ratio outperformed single enzymes alone for detecting NAFLD. These population studies emphasise that the relative pattern of transaminases contains epidemiologic signal for metabolic steatosis, but they do not transform AST/ALT into a reliable fibrosis test—noninvasive fibrosis indices (FIB-4, APRI) and elastography generally outperform the simple ratio for staging fibrotic disease (Forlano et al. (2021)).
4.3 Major limitations and pitfalls
Extra-hepatic AST sources. Because AST exists in skeletal and cardiac muscle as well as liver, muscle injury, strenuous exercise, myocardial injury, or hemolysis can raise AST disproportionately and falsely elevate the AST/ALT ratio. Clinical context and additional tests (CK, troponin, hemolysis markers) are essential to exclude non-hepatic causes.
Timing and enzyme kinetics. AST and ALT differ in subcellular location and clearance; timing of blood sampling relative to the insult affects the ratio. Acute mitochondrial injury (e.g., severe alcohol-related hepatocellular necrosis) can transiently raise AST more than ALT early after injury.
Advanced disease paradox. In advanced fibrosis/cirrhosis reduced ALT production from lost hepatocyte mass can raise the AST/ALT ratio despite less active hepatocellular necrosism so a rising ratio may sometimes reflect chronicity rather than worsening active inflammation.
Population heterogeneity. Studies vary by age, sex, BMI, comorbidities and ethnicity; the diagnostic performance (sensitivity/specificity) of any ratio threshold differs across cohorts (Zou et al. (2020); Xuan et al. (2024)).
4.4 Practical recommendations
Use the AST/ALT ratio as one interpretive element: it is most useful to (a) raise suspicion for alcoholic versus non-alcoholic etiologies when AST/ALT ≥ 2 and clinical history supports alcohol exposure, and (b) contribute to initial risk stratification for metabolic steatosis where ALT predominance is present. Do not use the ratio alone to stage fibrosis or to exclude significant disease; combine it with clinical history, GGT, platelet count, validated noninvasive fibrosis scores (FIB-4, APRI) and imaging (ultrasound/TE) as indicated (Forlano et al. (2021); Botros et al. (2013)).
5. Gamma-Glutamyl Transferase (GGT)
GGT is an enzyme found on cell membranes, particularly abundant in the bile ducts. It catalyzes the transfer of gamma-glutamyl groups between molecules.
Normal Range:
- 0-50 IU/L (may vary by laboratory)
Clinical Significance: GGT is highly sensitive for liver and biliary disease but lacks specificity, as it can be elevated by alcohol consumption, medications (phenytoin, phenobarbital), and metabolic syndrome (Lee et al 2006).
In NAFLD/MASLD patients, GGT levels may be elevated 2-3 times above the upper limit of normal (Kwo et al., 2017). GGT is particularly useful when elevated alongside alkaline phosphatase, as this pattern suggests cholestatic liver disease. Studies have shown that even GGT levels within the “normal” range are significantly associated with BMI, waist circumference, HOMA-IR, triglycerides, and HDL cholesterol after adjustment for BMI (Kunde et al., 2005).
In lay person’s terms, GGT is especially high in the tubes that carry bile from your liver to your intestines. It’s very sensitive, it goes up with almost any kind of liver problem, but it’s not specific, meaning it can’t tell you exactly what’s wrong. Think of it as a general “check engine” light rather than a specific diagnostic. It’s particularly useful when high along with another enzyme called alkaline phosphatase, as this combination suggests bile flow problems. GGT also responds strongly to alcohol, making it useful for detecting alcohol use.
6. Alkaline Phosphatase (ALP)
ALP is present in bile ducts and bone. Elevated ALP primarily suggests cholestatic liver disease or bone disorders.
Normal Range:
- 30-120 IU/L (varies with age, sex, and laboratory)
Clinical Significance: In liver disease, elevated ALP alongside elevated GGT indicates cholestasis (impaired bile flow). ALP alone can be elevated in bone disease, pregnancy, or adolescent growth. In MASLD, ALP may be mildly elevated but is not the primary marker of disease activity. Markedly elevated ALP (>4 times ULN) suggests primary biliary cholangitis (Lindor et al 2019), primary sclerosing cholangitis, or bile duct obstruction (Kwo et al., 2017).
ALP is found in both the bile ducts in your liver and in bones. When it’s elevated, doctors first need to figure out whether the source is liver or bone. In liver disease, high ALP usually means bile (the fluid that helps digest fats) isn’t flowing properly—imagine a blocked drain. Doctors often check GGT at the same time: if both are high, the problem is likely in the liver; if only ALP is high, it might be coming from your bones.
ALP can also be naturally higher in growing children and teenagers, or during pregnancy, these are normal situations.
7. Next Steps
Elevated Liver enzymes are probably the first indication that something is off with your liver. However, the actual issue can only be diagnosed after we look at liver function tests that we will talk about in the next section as well as the imaging tests talked about later.
Reversing high liver enzymes back to normal levels is quite possible in few months simply by interventions such as dietary changes such as Mediterranean diet and cutting out ultraprocessed food, exercise, a weight loss of 7-10% (if overweight/obese BMI) or even 3% (normal BMI).
8. References
Zou Y, Zhong L, Hu C, Sheng G. Association between the alanine aminotransferase/aspartate aminotransferase ratio and new-onset non-alcoholic fatty liver disease in a nonobese Chinese population: a population-based longitudinal study. Lipids Health Dis. 2020 Nov 25;19(1):245. doi: 10.1186/s12944-020-01419-z. https://pubmed.ncbi.nlm.nih.gov/33239040/.
Botros M, Sikaris KA. The De Ritis Ratio: The Test of Time. Clin Biochem Rev. 2013 Nov;34(3):117–130. https://pubmed.ncbi.nlm.nih.gov/24353357/.
Kunde SS, Lazenby AJ, Clements RH, Abrams GA. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology. 2005;42(3):650-656. doi:10.1002/hep.20818 https://pubmed.ncbi.nlm.nih.gov/16037946/. This study demonstrated that lowering ALT thresholds increased detection of NAFLD in obese women.
Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017;112(1):18-35. doi:10.1038/ajg.2016.517. https://pubmed.ncbi.nlm.nih.gov/27995906/. Comprehensive ACG guideline on evaluation of abnormal liver tests. Provides systematic approach to interpreting patterns of elevation (hepatocellular vs. cholestatic). Discusses when imaging and biopsy are indicated. Establishes normal ranges for all standard liver function tests.
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419. doi:10.1002/hep.30145 https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.30145. AASLD guidance on PBC diagnostic criteria including biochemical pattern of elevated ALP (often >4× ULN) with or without elevated GGT. Discusses differential diagnosis of cholestatic liver diseases including PSC, drug-induced cholestasis, and biliary obstruction.
Sorbi D, Boyum JH, Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase in alcoholic liver disease. Am J Gastroenterol. 1999 Apr;94(4):1018–1022. https://pubmed.ncbi.nlm.nih.gov/10201476/.
Forlano R, Mullish BH, Dhar A, Goldin RD, Thursz M, Manousou P. Liver function tests and metabolic-associated fatty liver disease: Changes in upper normal limits, does it really matter? World J Hepatol. 2021 Dec 27;13(12):2104–2112. doi: 10.4254/wjh.v13.i12.2104. https://pubmed.ncbi.nlm.nih.gov/35070011/.
Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1-9. doi:10.7326⁄0003-4819-137-1-200207020-00006 https://www.acpjournals.org/doi/10.7326/0003-4819-137-1-200207020-00006 This landmark study in healthy blood donors established lower ULN values for ALT that better identify liver disease.
Xuan Y, Wu D, Zhang Q, Yu Z, Yu J, Zhou D. Elevated ALT/AST ratio as a marker for NAFLD risk and severity: insights from a cross-sectional analysis in the United States. Front Endocrinol (Lausanne). 2024 Aug 26;15:1457598. doi: 10.3389/fendo.2024.1457598. https://pubmed.ncbi.nlm.nih.gov/39253584/.
Lee DH, Silventoinen K, Hu G, et al. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur Heart J. 2006;27(18):2170-2176. doi:10.1093/eurheartj/ehl086 https://pubmed.ncbi.nlm.nih.gov/16772340/. Large prospective study demonstrating that GGT levels, even within “normal” range, predict cardiovascular events independent of traditional risk factors. Shows strong association between GGT and metabolic syndrome components including BMI, triglycerides, and insulin resistance.