Total globulin reflects all non-albumin proteins in circulation and includes many carrier proteins and immunoglobulins (antibodies). A decreased total globulin can be seen with immune deficiency and lead poisoning. In contrast, high levels are seen with infection, inflammation, capillary permeability and vascular disorders, liver disease, and gammopathies such as multiple myeloma.
Standard Range: 1.9 - 3.70 g/dL (19.00 – 37.00 g/L)
The ODX Range: 2.40 – 2.80 g/dL (24.00 – 28.00 g/L)
Low levels of globulins can be seen in immune deficiency, antibody deficiency disorders (Pecoraro 2018), and lead exposure (Kalahasthi 2019).
High levels of globulins are associated with infection, inflammation (Yang 2018, Ye 2020), inflammatory bowel disease (Hashash 2022), increased capillary permeability, collagen vascular disease, lupus, gammopathies, multiple myeloma, liver disease (Pagana 2021), cancer, nephrotic syndrome, diabetes, rheumatoid disease (Koyama 2016), and increased all-cause mortality, especially from pulmonary causes (Juraschek 2015). A markedly elevated globulin level can also be seen with Menetrier’s disease (Hanif 2014).
Total globulin measurement in the blood accounts for all non-albumin proteins, including many transport proteins and immunoglobulins. Globulins are categorized as alpha, beta, or gamma. Alpha1 globulins include transport proteins such as thyroid- and cortisol-binding globulins; alpha2 globulins include haptoglobins, ceruloplasmin, prothrombin, and cholinesterase.
Beta1 globulins include transferrin, lipoproteins, plasminogen, and complement proteins. Gamma globulins are immunoglobulins (antibodies). Globulin levels may increase to maintain a normal total protein level when albumin is decreased or selectively lost. This may occur with collagen vascular diseases that increase capillary permeability, e.g., lupus erythematosus. Liver disease may cause low albumin followed by an increased globulin. In such cases, total protein can be normal, but the albumin:globulin ratio will decrease to 1 or less. However, gammopathies such as multiple myeloma will increase both globulin and total protein (Pagana 2021). Most globulins are produced in the liver. However, gamma globulin antibodies are produced by lymphocytes (Gropper 2021).
The total globulins measurement is also called the “gamma gap,” calculated by subtracting albumin from the total serum protein value. A review of NHANES data found that mortality risk, especially from pulmonary causes, increased as the gamma gap increased to 3.1-3.7 g/dL. Researchers note that total globulin levels of 3.8-4.1 g/dL weren’t associated with increased mortality risk until they reached 4.2 g/dL, at which level risk increased again (Juraschek 2015).
Review of data for 7.7. million life insurance applicants revealed an increasing relative mortality rate as total globulin values increased above 3.2 g/dL. The rate doubled as concentrations rose above 4.0 g/dL. Low levels below 1.9 g/dL were also associated with a slight increase in relative mortality (Fulks 2014). In individuals, 90 years old and older, 4-year all-cause mortality risk increased independently as total globulin levels increased to 2.9 g/dL or above. Researchers recognize increased globulin as a “nonspecific” marker of systemic inflammation (Yang 2018).
Elevated total globulin levels are observed in inflammatory bowel disease (IBD). A four-year follow-up of 1,767 IBD patients found that total globulin above 4 g/dL was associated with more severe disease and hospitalization. Those with higher total globulin had significantly higher CRP, ESR, and anemia, significantly lower albumin and hemoglobin, and fewer hospital-free and surgery-free days (Hashash 2022).
Decreased serum globulin levels are also detrimental and may assist in the early identification of antibody deficiency disorders. Identification of a serum globulin below 1.9 g/dL helped diagnose antibody deficiency, avoid diagnostic delays, and possibly reduce morbidity and mortality in these disorders (Pecoraro 2018). Lead poisoning is also associated with significantly lower globulin and total protein levels with a concomitant increase in the albumin:globulin ratio (Kalahasthi 2019).
Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P. Advanced Nutrition and Human Metabolism. 8th edition. Wadsworth Publishing Co Inc. 2021.
Fulks, Michael et al. “Serum globulin predicts all-cause mortality for life insurance applicants.” Journal of insurance medicine (New York, N.Y.) vol. 44,2 (2014): 93-8.
Hanif, Farina Mohammed et al. “An unusual presentation of Ménétrier's Disease.” Journal of the College of Physicians and Surgeons--Pakistan : JCPSP vol. 24 Suppl 3 (2014): S183-5.
Hashash, Jana G et al. “Elevated serum globulin fraction as a biomarker of multiyear disease severity in inflammatory bowel disease.” Annals of gastroenterology vol. 35,6 (2022): 609-617. doi:10.20524/aog.2022.0748
Juraschek, Stephen P et al. “The Gamma Gap and All-Cause Mortality.” PloS one vol. 10,12 e0143494. 2 Dec. 2015, doi:10.1371/journal.pone.0143494
Kalahasthi, Ravibabu, et al. "Assessment of diagnostic accuracy and optimal cut points of blood lead levels on serum proteins among workers exposed to Pb at a lead battery plant." Int J Med Biochem 2.3 (2019): 81-7.
Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.
Pecoraro, Antonio et al. “Validation of Calculated Globulin (CG) as a Screening Test for Antibody Deficiency in an Italian University Hospital.” Current pharmaceutical biotechnology vol. 19,9 (2018): 728-733. doi:10.2174/1389201019666180808163311
Yang, Ming et al. “The gamma gap predicts 4-year all-cause mortality among nonagenarians and centenarians.” Scientific reports vol. 8,1 1046. 18 Jan. 2018, doi:10.1038/s41598-018-19534-4
Ye, Yongyu et al. “Serum globulin and albumin to globulin ratio as potential diagnostic biomarkers for periprosthetic joint infection: a retrospective review.” Journal of orthopaedic surgery and research vol. 15,1 459. 7 Oct. 2020, doi:10.1186/s13018-020-01959-1