Test code: 16293

Clinical use

• Assess growth disorders
• Monitor response to therapy

Clinical background

Measuring IGF-1 is useful in assessing and managing growth-related disorders. For example, guidelines recommend IGF-1 measurements to help with diagnosis, monitoring, and/or therapy of acromegaly (growth hormone [GH] excess) and GH deficiency (GHD).^1-3 In addition to growth-related disorders, evidence is emerging that IGF-1 measurement may have utility as a biomarker for symptom severity after traumatic brain injury.⁴ Serum-based testing is typically used to assess IGF-1 levels because concentrations are 100- to 1,000-fold higher than in urine⁵; IGF-1 is degraded during renal clearance.⁶

Immunoassays used to assess IGF-1, while simple to perform, have several shortcomings. IGF-1 binding proteins (IGFBPs), if not completely dissociated from IGF-1, may mask IGF-1 binding sites from antibodies used in immunoassays.⁷ This interference leads to artificially low IGF-1 values⁸ and the potential for misdiagnosis. In addition, inconsistency between laboratories has been reported; contributing factors include lack of standardization of the different immunochemical methods, protocols, reference materials, and reference ranges used to establish normal and abnormal values.⁸

Quest Diagnostics offers an advanced liquid chromatography/mass spectrometry (LC/MS)–based test that circumvents many of these shortcomings. The LC/MS method has demonstrated assay equivalence with radioimmunoassay (RIA) but has the advantage of not involving the handling and disposal of radioactive materials.⁹ RIA has a diagnostic sensitivity of 70%, specificity of 99%, and positive and negative predictive values of 95% for differentiating individuals with GHD from apparently healthy individuals matched for age, sex, and body-mass index (BMI).¹⁰

Clinicians should be aware of assay differences when considering switching between assay platforms; changes in IGF-1 values when measured using different technologies should not be used to guide patient management decisions.^8,12 IGF1-levels determined using the LC/MS assay are highly correlated with some other types of immunoassays (eg, electrochemiluminescence [ECL]). However, when the methods are compared, the LC/MS method yields generally lower IGF-1 values.^8,9,11 Widely disparate results in some specimens can be explained by the presence of IGF-1 variants, indistinguishable from the wild type by immunoassay and, until recently, not routinely measured by LC/MS.^8,11,13 However, the variants are relatively rare (<0.5% in the clinical population¹⁴) and cannot explain the overall trend toward lower values by LC/MS.^8,11 Instead, technical differences have been proposed as major contributors to the discordance between LC/MS- and ECL-based assays.⁸

The Acromegaly Consensus Group has recommended that assays used to monitor IGF-1 levels over time adhere to accepted performance standards.¹² LC/MS methodology achieves these standards by combining molecular specificity, quantitative performance, well-characterized reference materials, and detailed age-/sex-specific reference intervals. Importantly, the recommendation specifies that the same assay should be consistently used for IGF-1 measurements over time.¹²

Interpretive information

For an individual, relative to the sex- and age-adjusted means for a healthy population (in the absence of IGF-1 variants)

• A Z-score (number of standard deviations from the mean) >2.0 is compatible with GH excess (eg, suggestive of acromegaly or consistent with overtreatment with GH).
• A Z-score within ±2.0 indicates normal levels of IGF-1. This result suggests that acromegaly is less likely. However, patients with a small GH-secreting pituitary tumor may have normal IGF-1 levels. Consequently, dynamic testing (eg, GH glucose suppression) may be necessary to identify patients with mild acromegaly or to assess residual tumor burden in patients following surgery to remove a GH-secreting tumor.¹ In addition, individuals with GHD may have normal IGF-1 levels (such as those with an increased BMI).^3,15
• A Z-score <-2.0 indicates a low level of IGF-1 and may suggest GHD. Follow-up GH stimulation tests, usually using glucagon, may be considered, although such confirmation may not be necessary for some individuals (such as those with multiple hormone deficiencies or proven genetic causes of GHD).^2,3,15

In managing GH disorders, age-normalized serum IGF-1 values signify that

• Acromegaly is controlled,¹ whereas elevated values indicate that acromegaly is not controlled. According to the Pituitary Society guidelines, postoperative remission can be assessed by measuring IGF-1 levels after 6 weeks, but levels may remain mildly elevated for 3 to 6 months.²⁰
• GH or IGF-1 deficiency has been successfully dosed (if other clinical GH parameters are also favorably assessed in the absence of adverse effects),^3,15 whereas elevated values could indicate overdosing and low values could indicate underdosing.

The presence of rare IGF-1 variants and their estimated levels are reported; their presence may indicate that

• The wild-type concentration only represents half the circulating IGF-1 for heterozygous individuals.
• The absence of wild type IGF-1 can be explained by the individual’s being homozygous for the variant or heterozygous for 2 different variants.

In either case, these variants have unclear clinical significance.¹⁸