An elevated gamma gap (>4 g/dL), the difference between serum total protein and albumin, can trigger testing for chronic infections or monoclonal gammopathy, despite a lack of evidence supporting this clinical threshold.Using the National Health and Nutrition Examination Survey (NHANES) 1999-2014, gamma gap was derived in three subpopulations based on availability of testing for human immunodeficiency virus (HIV; N = 25,680), hepatitis C (HCV; N = 45,134), and monoclonal gammopathy of unknown significance (MGUS; N = 6,118). Disease status was confirmed by HIV antibody and Western blot, HCV RNA test, or electrophoresis with immunofixation. Sensitivity, specificity, and likelihood ratios were calculated for different gamma gap thresholds. Area under the curve (AUC) was used to assess performance and cubic splines were used to characterize the relationship between the gamma gap and each disease.Mean gamma gaps of participants with HIV, HCV, or MGUS ranged from 3.4-3.8 g/dL. The AUC was 0.80 (95%CI: 0.75,0.85) for HIV, 0.74 (0.72,0.76) for HCV, and 0.64 (0.60,0.69) for MGUS. An elevated gamma gap of over 4 g/dL corresponded to sensitivities of 39.3%, 19.0%, and 15.4% and specificities of 98.4%, 97.8%, and 95.4% for HIV, HCV, and MGUS, respectively. A higher prevalence of all three diseases was observed at both low and high gamma gaps.An elevated gamma gap of 4 g/dL is insensitive for HIV, HCV, or MGUS, but has a high specificity for HIV and HCV, suggesting that the absence of an elevated gamma gap does not rule out HIV, HCV, or MGUS. Conversely, an elevated gap may justify further testing for HIV and HCV, but does not justify electrophoresis in the absence of additional clinical information.
