Upper Limit of Normal (ULN) in Medical Testing
The upper limit of normal (ULN) is defined as the 99th percentile value from a normal reference population without the disease or condition being measured, with the assay coefficient of variation ideally being 10% or less. 1
Core Definition and Statistical Basis
ULN represents the threshold above which a test result is considered abnormal, typically set at the 95th or 99th percentile of values obtained from a healthy reference population 1
For cardiac troponins specifically, the ULN is defined as the 99th percentile from a normal reference population without myocardial necrosis, with the coefficient of variation of the assay required to be 10% or less 1
The cutoff value for elevated biomarkers may be set slightly above the upper limit of the performance characteristics of the assay for a normal healthy population 1
Clinical Application and Interpretation
ULN serves as the reference point for categorizing disease severity, with elevations described as multiples of the ULN (e.g., 2× ULN, 3× ULN, 5× ULN) 1, 2
In myocardial infarction, biomarkers like CK-MB rise to a peak of 2 to 5 times the ULN, while cardiac troponins show small elevations above the ULN in small infarctions but can rise to 20 to 50 times the ULN in large infarctions 1
For liver enzymes, abnormal values are defined as any value above the ULN, with approximately 15-17% of COVID-19 patients showing elevations above this threshold 1
Important Considerations for ULN Determination
The ULN varies significantly by demographic factors including sex, age, and geographic location, requiring localized reference ranges rather than universal cutoffs 1, 3, 4, 5
For ALT specifically, optimal thresholds are suggested to be 30 U/L for men and 19 U/L for women, substantially lower than traditionally accepted values of 40-52 U/L 2, 3, 4, 6
Laboratory variation is significant, and results should be interpreted in the context of the specific laboratory's reference range and methodology 2
Practical Use in Clinical Decision-Making
Clinically relevant cutoffs should align with established reference values (e.g., ULN, 2×ULN, 3×ULN) rather than statistically derived values that may overfit specific patient cohorts 1
In pulmonary function testing, both the lower limit of normal (LLN) and upper limit of normal (ULN) are displayed on reports to show where results fall within the normal range 1
The ULN provides a standardized reference point for monitoring disease progression, treatment response, and identifying patients requiring further evaluation or intervention 2, 7
Common Pitfalls
Historical ULN values established in the 1980s likely included individuals with undiagnosed hepatitis C and nonalcoholic fatty liver disease, resulting in artificially elevated reference ranges that miss patients with early liver disease 8
Different assays may have different analytical sensitivities, making it essential for physicians to know the specific characteristics of tests used in their institutions 1
The multiplicity of existing assays for some biomarkers (like cardiac troponin I) creates heterogeneity in ULN values across laboratories 1