What are normal levels of Corticosteroid-Binding Globulin (CBG)?

Normal Levels of Corticosteroid-Binding Globulin (CBG)

Normal serum CBG concentrations range from 30-52 μg/mL (or 2.4-4.4 mg/100 mL), with no significant sex differences but age-dependent variations. 1, 2

Reference Ranges by Measurement Method

• Standard immunoassay: Normal adult CBG levels are 30-52 μg/mL, established through radioimmunoassay using purified CBG standards 2
• Alternative reporting units: The same normal range can be expressed as 2.4-4.4 mg/100 mL (mean ± 2 SD) 1
• Women-specific reference: Normal women have mean CBG concentrations of 38.8 ± 3.8 mg/L (approximately 44 ± 6 mg/L in some studies) 3, 4

Physiologic Variations in CBG Levels

Age-Related Changes

• CBG demonstrates significant biphasic age dependence, with levels varying across the lifespan, though specific pediatric ranges differ from adults 1
• Pre-pubertal and post-pubertal children have distinct reference ranges that are slightly lower than adult values 3

Hormonal Influences

• Pregnancy and estrogen therapy: CBG levels increase substantially during pregnancy and with oral estrogen use, making CBG a more sensitive indicator of estrogenic activity than thyroxine-binding globulin (TBG) 1
• Menstrual cycle variations: Women with normal CBG production show cyclic variations in CBG concentrations that parallel estradiol fluctuations during the menstrual cycle 4
• Postmenopausal state: CBG levels typically decrease after menopause in the absence of hormone replacement therapy 4

Clinical Significance of Abnormal CBG Levels

Elevated CBG

• Inherited abnormalities: Rare familial cases show markedly elevated CBG (55.7-78.8 mg/L) without pregnancy or exogenous estrogen use 4
• Estrogen-induced elevation: Oral estrogens, pregnancy, and chronic active hepatitis increase CBG levels, which can falsely elevate total cortisol measurements while free cortisol remains normal 5

Decreased CBG

• Heterozygous deficiency: Null mutation heterozygotes have approximately 50% reduction in CBG (mean 18.7 ± 1.3 μg/mL) 2
• Homozygous deficiency: Complete CBG deficiency results in undetectable immunoreactive CBG with total cortisol levels <1.8 μg/dL, though free cortisol concentrations remain relatively normal 2
• Acquired conditions: Nephrotic syndrome, severe liver disease, and critical illness can decrease CBG and albumin levels 5

Relationship Between CBG and Cortisol Measurements

Cortisol Binding Characteristics

• Binding capacity: Approximately 80-90% of serum cortisol binds to CBG with high affinity, while only 5% remains unbound and biologically active 6
• Normal binding affinity: The association constant (Ka) for cortisol binding to normal CBG is approximately 0.66-0.82 L/nmol 3
• Free cortisol percentage: Normal percent-free (dialyzable) serum cortisol is 2.9-3.9% 3

Impact on Cortisol Interpretation

• Total vs. free cortisol: When CBG levels are abnormal, total serum cortisol may not accurately reflect free (bioactive) cortisol concentrations, with correlation between free and total cortisol dropping to only 50-60% in critically ill patients with low CBG 5
• Compensatory mechanisms: In CBG deficiency, increased percentage of non-protein-bound cortisol offsets low total cortisol levels to maintain approximately normal free cortisol concentrations 3

Common Clinical Pitfalls

Misdiagnosis Risk

• False ACTH deficiency: Abnormal CBG concentrations or binding affinity can lead to misdiagnosis of isolated ACTH deficiency when only total cortisol is measured 2
• Dexamethasone suppression test interference: Increased CBG from oral estrogens can cause false-positive results on overnight 1-mg dexamethasone suppression testing by elevating total cortisol levels 5
• Critical illness considerations: In critically ill patients with low CBG and hypoalbuminemia, measuring free cortisol or calculating free cortisol from total cortisol and CBG measurements provides more accurate assessment than total cortisol alone 5

Associated Clinical Findings

• CBG deficiency syndrome: Null or low-function CBG mutations associate with chronic fatigue (86% prevalence), relative hypotension (54% with systolic BP below 3rd percentile), and low total cortisol despite normal HPA axis function 2
• Genetic variants: The Lyon variant (Asp367→Asn) reduces CBG cortisol-binding affinity approximately 4-fold (Ka = 0.15 L/nmol vs. normal 0.66 L/nmol) while maintaining normal free cortisol through compensatory mechanisms 3