What does it mean when lab results are outside of the normal reference range?

Understanding Abnormal Laboratory Results

When lab results fall outside the reference range, this does NOT automatically indicate disease—by statistical definition, approximately 5% of healthy individuals will have "abnormal" results, and clinical significance depends entirely on which specific test is abnormal and the patient's clinical context. 1

What "Outside the Reference Range" Actually Means

Reference ranges are statistical constructs, not absolute indicators of health versus disease. The standard methodology involves testing at least 120 healthy individuals and defining the "normal range" as the central 95% of values. 2, 3

This approach has critical implications:

• 5% of healthy people will be labeled "abnormal" by definition 2, 3
• The more tests ordered, the higher the probability that at least one will fall outside the reference range in a completely healthy person 3
• Reference ranges describe population statistics, not individual health status 4, 5

Clinical Significance Depends on Context, Not Just the Number

The magnitude of abnormality does NOT reliably predict clinical importance. 1

Critical examples illustrating this principle:

• A patient with acute hepatitis A may have ALT >1000 U/L but will likely recover completely without intervention 1
• A patient with hepatitis C may have ALT within the "normal" range yet progress to end-stage liver disease without diagnosis and treatment 1
• Common causes of chronic liver disease (NAFLD, alcohol-related disease, hepatitis C) frequently present with only mild or moderate abnormalities 1
• Patients with significant liver fibrosis may have completely normal liver enzymes and synthetic function 1

Key Factors That Influence Laboratory Values

Multiple physiological and technical factors affect whether results fall inside or outside reference ranges:

Individual Biological Variation

• Age-related changes can significantly alter values without representing disease 6
• Sex, ethnicity, body surface area, and physiological state all influence normal values 1
• Intraindividual biological variation over time is common and often exceeds laboratory measurement error 6

Technical and Methodological Issues

• Different laboratories use different testing methods and equipment, producing non-transferable reference ranges 3
• Current upper limits for some tests (like ALT) may be too high due to inclusion of patients with occult disease in "healthy" reference populations 1
• For liver enzymes specifically, treatment guidelines for hepatitis B recommend ALT >30 U/L as significant in males and >19 U/L in females—well below many laboratory "normal" upper limits 1

The Critical Error: Assuming Repeat Testing Clarifies Significance

Simply repeating abnormal tests to see if they normalize is NOT recommended unless there is high clinical suspicion of a transient cause. 1

Evidence against routine repeat testing:

• When abnormal liver enzymes were retested, 84% remained abnormal at 1 month 1
• At 2 years, 75% remained abnormal 1
• For chronic diseases like NAFLD and hepatitis C, normalized values do NOT exclude or indicate resolution of disease 1
• Repeat testing incurs costs (patient recall, specimen transport, laboratory analysis) without necessarily providing diagnostic clarity 1

The Appropriate Response to Abnormal Results

The first abnormality should trigger investigation of etiology, not reflexive repeat testing. 1

Immediate action required for:

• Unexplained jaundice 1
• Suspicion of hepatic or biliary malignancy 1
• ALT >8× upper limit of normal or >5× baseline 7
• ALT >3× upper limit with total bilirubin >2× upper limit (Hy's Law) 7

For other abnormalities, the essential steps are:

• Detailed history focusing on specific symptoms relevant to the abnormal test 7
• Targeted physical examination for findings associated with the specific abnormality 7
• Pattern recognition: classify as hepatocellular, cholestatic, or mixed based on which tests are elevated 7
• Additional testing guided by the pattern and clinical context, not reflexive repetition of the same panel 1, 7

Common Pitfalls to Avoid

• Never assume normal values exclude disease—many serious conditions present with values within reference ranges 1
• Never assume marked abnormalities always indicate serious disease—clinical context determines significance 1
• Never directly compare values between different laboratories or testing methods—reference ranges are method-specific and population-specific 1, 3
• Never ignore mildly abnormal results in high-risk patients—chronic liver diseases often present with minimal elevations 1