Assessing Alkaline Phosphatase Reference Intervals Using Gamma-Glutamyl Transferase as a Surrogate for Normal Liver Function

Abstract

Abstract Limited studies assess reference intervals (RIs) for hepatic enzymes, particularly for alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT). In the US, ALP and GGT RIs were established on Roche assays using a European cohort of ≤ 450 patients that may not reflect population variance. Further, age- and sex-specific variation in ALP and GGT may warrant tiered RIs, but evidence to justify this approach is limited. We aimed to evaluate the manufacturer’s RIs by comparing them to indirectly estimated RIs (IRIs). 217,333 AST, ALT, ALP, and GGT results (Roche c702) performed between 1/1/2019-12/31/2022 on outpatients ≥21 years were extracted from the laboratory information system. The first ALP for each patient was identified, and the earliest AST, ALT, and GGT drawn within 7 days was included. This approach was repeated for GGT. Concordance and correlation were calculated using Weighted Cohen’s Kappa and Spearman’s rank correlation coefficient respectively. {refineR} was applied to patients with “normal” liver function (defined as normal AST, ALT for all IRIs, plus normal GGT for ALP IRIs, and ALP for GGT IRIs). IRIs were estimated for all males, all females, females ≤50, and females >50 years and compared to the method specific manufacturer RI (ALP: 40-129 Units/L for males and 35-104 Units/L for females; GGT: 8-61 Units/L for males and 5-36 Units/L for females). Of the 71,783 outpatients, 54.9% were female, 74% self-identified as white and 19% as black. The median age was 58 (IQR: 43-68 years), the median ALP concentration was 77 (62-97 Units/L), and the median GGT concentration was 28 (17-57 Units/L). A moderate agreement (Kappa = 0.48, 95% confidence interval: 0.46-0.51) and positive correlation (r = 0.51; p<0.0001) between ALP and GGT was observed. For ALP and GGT, no significant differences were observed between the lower limit of the IRIs and the current RI. The upper limit of estimated IRIs was 132 [95% confidence interval: 117-147 Units/L] for patients with normal AST/ALT/GGT (n = 1596). For males, the sex-specific upper limit was 120 [101-140 Units/L] and for females, was 123 [110-136 Units/L]. Age stratified upper limits for females were 120 [101-140 Units/L], and 109 [97-121 Units/L] for ≤50 and >50 years, respectively. The upper limit for all patients with normal AST/ALT/ALP (n = 2,446) was 62 [55-70 Units/L]. For males, all females, females ≤50 and >50 years was 58 [46-69 Units/L], 40 [39-51 Units/L], 31 [23-39 Units/L], and 56 [41-71 Units/L]. Manufacturer RIs agreed well with the IRIs for most subsets, but differed for ALP IRIs of all females with normal hepatobilliary function and in GGT for all females and females >50 years. Further investigation of the impact of preselecting patient populations on IRIs and a direct RI study on select patient subsets is worth investigation.