MASLD · normal liver enzymes

MASLD in Primary Care: Screening When Liver Enzymes Look Normal

MASLD is under-read in primary care: ultrasound detects liver fat only once more than 30% of liver cells are involved, and the routine panel can read normal. GGT, read as a trend inside the reference interval, belongs in the metabolic workup of every patient who meets the definition.

The definition now requires liver fat plus a cardiometabolic risk factor. That places the condition squarely in the metabolic visit, where the routine panel and the ultrasound both under-read it.

MASLD, metabolic dysfunction-associated steatotic liver disease, is now defined by hepatic steatosis plus at least one of five cardiometabolic risk factors, a nomenclature adopted through a Delphi process with 236 panelists from 56 countries. The definition moves the condition into the metabolic visit. The video above, The Alcohol You Never Drank, covers Chapter 5 of The Angry Gut by Dr. Gurpreet Singh Padda, MD, MBA, MHP, and Ami Michelle Grimes, which treats the liver as downstream of the first brain: the gut delivers, the liver filters, and the routine workup reads the filter rather than the stream.

Dr. Padda describes closing visits for years with an instruction to lose weight and counting it as management. The evidence below is why that sentence is not a plan for a patient who has already lost and regained the weight more than once.

Why do normal liver enzymes and a clean ultrasound miss MASLD?

There are three structural blind spots. Ultrasound detects steatosis only once more than 30% of hepatocytes are involved, and British guidance states that a raised GGT with metabolic risk factors may indicate fatty liver despite a normal scan. ALT, the enzyme most clinicians follow, came out null for cardiovascular mortality at 0.87 in a dose-response synthesis of 23 studies and 1,067,922 participants, where GGT predicted it at 1.62. And peripheral blood is sampled after first-pass hepatic clearance: in elective abdominal surgery, portal blood was endotoxin-positive in 97% of patients and systemic blood in 4 of 34.

The same guideline is explicit about the trade-off of adding GGT to a first-line panel: abnormal results rise from roughly 15% to roughly 30%. They retained it anyway, because the trial cited against GGT had excluded patients with fatty liver or alcohol-related disease, the groups behind 90% of liver deaths. Specificity was traded for sensitivity in exactly the population a metabolic practice sees.

What does a GGT inside the normal range mean?

GGT behaves as a redox gauge: the ectoenzyme degrades extracellular glutathione to supply cysteine for antioxidant synthesis, and stressed cells upregulate it. Its prognostic signal starts inside the reference interval. In 9,687,066 Korean adults followed a median 8.3 years, the top tertile carried hazard ratios of 1.33 for all-cause and 1.29 for cardiovascular mortality after adjustment for alcohol, BMI and other liver enzymes, and the high tertile for women began at 21 IU/L. In 3,500 non-diabetic British men aged 60 to 79, the top quartile predicted incident diabetes at 3.68 after BMI adjustment and 2.69 after adding insulin resistance. Restricted to never-drinkers in seven pooled Japanese cohorts, the hazard per standard deviation of GGT was 1.81 for coronary death in women and 1.43 for cardiovascular death in men.

The limits are part of the interpretation. GGT is nonspecific, with obesity its commonest cause. It added little to established cardiovascular prediction in pooled British surveys. Mendelian randomization found no causal effect on diabetes (odds ratio 0.88) or coronary disease (1.08). The clinical use follows from those limits: GGT is a trajectory marker of oxidative load in a patient with steatosis, not a target to lower for its own sake and not a substitute for a risk score.

Gut delivery, insulin and the patient trials exclude

The mechanistic case centers on portal delivery. In bariatric surgery patients, portal ethanol was a median 187-fold higher than fasting systemic blood and rose from no steatosis through steatosis to steatohepatitis; blocking alcohol dehydrogenase raised systemic ethanol 15-fold after a meal in fatty liver. Pediatric and murine work places part of the effect in clearance, with reduced hepatic alcohol dehydrogenase activity linked to insulin resistance. Pooled blood endotoxin was higher in simple steatosis (standardized difference 0.86) and steatohepatitis (0.81) independent of BMI. No clinical study has yet tested the causal chain, and in adolescents endotoxin markers tracked total body fat (r = 0.64) rather than histology.

Two biological drivers, gut-derived endotoxin and ethanol on one side and insulin-resistant hepatic handling on the other, converge on the same organ. The third driver is economic: subsidized sweetener in most packaged food supplies the substrate for fermentation. The less obvious point for screening is that the liver responds to what is delivered, not only to how much is eaten. Inulin raised hepatic fat from 20.9% to 26.8% over six weeks in a small trial, while four months of resistant starch lowered intrahepatic triglyceride 9.08%, or 5.89% after adjustment for weight loss. In the largest synbiotic trial, weight loss alone moved liver fat. Both findings can hold at once, and body weight captures neither.

Who should be tested for MASLD?

• Adults meeting the MASLD definition, or with an incidental echogenic liver on imaging done for another reason.
• Patients whose GGT rises across serial panels while staying inside the reference interval.
• Normal-BMI patients with features of insulin resistance, including South Asian patients who are thin outside and fat inside.
• Patients repeatedly counseled to lose weight with no measurement of what changed.

Written selection criteria make that list reproducible across clinicians.

What the measurements add, and what a finding changes

Measura [Cardiometabolic and Autonomic Health Analysis] does not image the liver; confirming steatosis stays with radiology. What it measures is the terrain that decides risk:

• Laboratory panels that read GGT serially beside glucose, insulin and lipids, turning a single in-range value into a trajectory.
• Bioimpedance body composition, which separates fat and muscle compartments and exposes the normal-BMI phenotype that weight-based counseling misses.
• Arterial stiffness and endothelial function, because the mortality signal attached to GGT is largely cardiovascular.

A finding changes management when it relocates the patient. Steatosis with a rising GGT and abnormal vascular measures belongs in active cardiovascular prevention rather than a weight handout. Adverse body composition at normal BMI reframes counseling around insulin and dietary delivery, with lifestyle work prescribed as treatment and its physiological rationale documented. Measurement repeated on a schedule shows whether the terrain moved, which no single panel can.

Workflow and documentation

Build eligibility into standing orders so testing does not depend on who remembers. Findings recorded at the annual wellness visit, beside the cognitive and fall screening already structured there (see cognitive assessment and fall prevention), support the measures discussed in HEDIS and value-based care. The patient version, written for someone holding an echogenic ultrasound report, is what an echogenic liver means. The barrier upstream of the portal vein is covered in metabolic endotoxemia screening, and every cohort cited here is set out with its limits in the Chapter 5 companion. The same unrecognized liver disease can surface as confusion in older patients, which is why screening for cirrhosis in dementia belongs in the cognitive workup.

Frequently asked questions

Does a normal ultrasound exclude MASLD?

No. Ultrasound becomes sensitive to steatosis only once more than 30% of hepatocytes carry fat, so milder disease scans clean. British guidance notes that a raised GGT in a patient with metabolic risk factors may still reflect fatty liver behind a normal scan. The measurement rationale is expanded in clinical rationale.

How should an in-range GGT be interpreted?

As a position on a risk gradient rather than a pass. Pooled cohorts show cardiovascular mortality rising within the reference interval, at 1.10 per 10 U/L across 527,589 participants. Because GGT is nonspecific and not causal by Mendelian randomization, serial values read in context carry more information than any single reading. Reading trends is covered in interpreting the report.

Should suspected gut-derived ethanol prompt testing for auto-brewery syndrome?

Not routinely. The portal ethanol finding describes concentrations cleared on first pass, not intoxication. Auto-brewery syndrome is rare, its literature covers 165 patients across case reports and series, and a single blood alcohol reading does not establish it. The practical target is the metabolic terrain that governs delivery and clearance. Common physician questions are collected in physician questions.

Does Measura image the liver?

No. Ultrasound and other liver imaging are performed elsewhere. Measura measures the laboratory, body composition and vascular picture around steatosis and returns findings to the ordering physician, who retains diagnosis and treatment. How the protocol is introduced into a practice is described in onboarding the Measura protocol.

How often should these measures be repeated?

The evidence summarized here sets no fixed interval. The clinical logic is trajectory: GGT, insulin measures, body composition and vascular function repeated at planned visits show whether changes in dietary delivery and insulin resistance are moving the terrain. Documenting the interval in advance keeps follow-up consistent. Between-visit structures are discussed in chronic care and between-visit monitoring.

What is the difference between NAFLD and MASLD?

The difference is the definition. MASLD, metabolic dysfunction-associated steatotic liver disease, is the name set by the new fatty liver disease nomenclature, adopted through a Delphi process with 236 panelists from 56 countries. It requires liver fat plus at least one of five cardiometabolic risk factors. That ties the diagnosis to metabolism and places it in the metabolic visit, where the routine panel and the ultrasound both under-read it.

Can you have fatty liver with normal liver enzymes?

Yes. The routine panel can read normal while fat sits in the liver. ALT, the enzyme most clinicians follow, did not predict cardiovascular death in a synthesis of 23 studies, while GGT did. Blood drawn from the arm is also sampled after the liver has already filtered what the gut delivered. GGT, read as a trend inside the reference interval, belongs in the workup of anyone who meets the MASLD definition.

Does fatty liver go away?

Liver fat moves, and what reaches the liver matters as much as how much is eaten. In the trials cited here, four months of resistant starch lowered liver triglyceride by 9.08%, or 5.89% after adjusting for weight loss, while inulin raised liver fat from 20.9% to 26.8% over six weeks. Weight loss alone also moved liver fat. Repeating the measurements on a schedule shows whether the terrain is changing.

References

• Rinella, M. E., Lazarus, J. V., Ratziu, V., Francque, S. M., Sanyal, A. J., Kanwal, F., Romero, D., Abdelmalek, M. F., Anstee, Q. M., Arab, J. P., Arrese, M., Bataller, R., Beuers, U., Boursier, J., Bugianesi, E., Byrne, C. D., Castro Narro, G. E., Chowdhury, A., Cortez-Pinto, H., … Newsome, P. N. (2023). A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology, 78(6), 1966-1986. https://doi.org/10.1097/HEP.0000000000000520
• Newsome, P. N., Cramb, R., Davison, S. M., Dillon, J. F., Foulerton, M., Godfrey, E. M., Hall, R., Harrower, U., Hudson, M., Langford, A., Mackie, A., Mitchell-Thain, R., Sennett, K., Sheron, N. C., Verne, J., Walmsley, M., & Yeoman, A. (2018). Guidelines on the management of abnormal liver blood tests. Gut, 67(1), 6-19. https://doi.org/10.1136/gutjnl-2017-314924
• Rahmani, J., Miri, A., Namjoo, I., Zamaninour, N., Maljaei, M. B., Zhou, J. B., Shokouhi Nasab Kermani, R., Kord Varkaneh, H., Fatahi, S., & Zhang, Y. (2019). Elevated liver enzymes and cardiovascular mortality: a systematic review and dose-response meta-analysis of more than one million participants. European Journal of Gastroenterology & Hepatology, 31(5), 555–562. https://doi.org/10.1097/MEG.0000000000001353
• Jacob, A. I., Goldberg, P. K., Bloom, N., Degenshein, G. A., & Kozinn, P. J. (1977). Endotoxin and bacteria in portal blood. Gastroenterology, 72(6), 1268–1270. https://pubmed.ncbi.nlm.nih.gov/858472/
• Cho, E. J., Jeong, S.-M., Chung, G. E., Yoo, J.-J., Cho, Y., Lee, K.-N., Shin, D. W., Kim, Y. J., Yoon, J.-H., Han, K., & Yu, S. J. (2023). Gamma-glutamyl transferase and risk of all-cause and disease-specific mortality: a nationwide cohort study. Scientific Reports, 13(1), 1751. https://doi.org/10.1038/s41598-022-25970-0
• Wannamethee, S. G., Shaper, A. G., Lennon, L., & Whincup, P. H. (2005). Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care, 28(12), 2913-2918. https://doi.org/10.2337/diacare.28.12.2913
• Li, Y., Iso, H., Cui, R., Murakami, Y., Yatsuya, H., Miura, K., Nagasawa, S.-Y., Ueshima, H., & Okamura, T. (2016). Serum gamma-glutamyltransferase and mortality due to cardiovascular disease in Japanese men and women. Journal of Atherosclerosis and Thrombosis, 23(7), 792-799. https://doi.org/10.5551/jat.32698
• Liu, J., Au Yeung, S. L., Lin, S. L., Leung, G. M., & Schooling, C. M. (2016). Liver enzymes and risk of ischemic heart disease and type 2 diabetes mellitus: A Mendelian randomization study. Scientific Reports, 6, 38813. https://doi.org/10.1038/srep38813
• Meijnikman, A. S., Davids, M., Herrema, H., Aydin, O., Tremaroli, V., Rios-Morales, M., Levels, H., Bruin, S., de Brauw, M., Verheij, J., Kemper, M., Holleboom, A. G., Tushuizen, M. E., Schwartz, T. W., Nielsen, J., Brandjes, D., Dallinga-Thie, G. M., Havik, S. R., Ackermans, M. T., … Nieuwdorp, M. (2022). Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nature Medicine, 28(10), 2100–2106. https://doi.org/10.1038/s41591-022-02016-6
• Ni, Y., Qian, L., Siliceo, S. L., Long, X., Nychas, E., Liu, Y., Ismaiah, M. J., Leung, H., Zhang, L., Gao, Q., Wu, Q., Zhang, Y., Jia, X., Liu, S., Yuan, R., Zhou, L., Wang, X., Li, Q., Zhao, Y., … Jia, W. (2023). Resistant starch decreases intrahepatic triglycerides in patients with NAFLD via gut microbiome alterations. Cell Metabolism, 35(9), 1530-1547.e8. https://doi.org/10.1016/j.cmet.2023.08.002

Related reading

• Metabolic Endotoxemia: What to Measure When Zonulin Cannot
• Intrinsic Factor Antibody: Screening for Autoimmune Gastritis
• Laboratory Panels

Medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP, medical director of Measura. Last reviewed September 12, 2026.