What does it mean to have abnormal lab results and what are the next steps for evaluation and management?

Interpreting Abnormal Lab Results: A Systematic Approach

Do not simply repeat abnormal laboratory tests hoping they will normalize—immediately investigate the underlying cause unless you have high clinical certainty the abnormality is transient. 1

Why Routine Repeat Testing is Ineffective

The evidence strongly argues against the common practice of "wait and repeat":

• 84% of abnormal liver tests remain abnormal at 1 month, and 75% remain abnormal at 2 years, making routine repeat testing an inefficient strategy that only delays diagnosis of treatable conditions 1
• The most frequent cause of an abnormal test result is physiologic variation or laboratory variation, but this does not mean the result should be ignored 2, 3
• Repeating tests is only justified when you have high clinical certainty the abnormality will resolve in response to an identified acute insult (e.g., recent viral illness, muscle injury, or short-term medication exposure) 1

Confirming True Abnormalities

Before pursuing extensive workup, verify the abnormality is real:

• In the absence of unequivocal clinical findings, diagnosis of any condition requires two abnormal test results from the same sample or in two separate test samples 4
• If using two separate test samples, the second test should be performed without delay 4
• All tests have preanalytic and analytic variability—samples for plasma glucose must be spun and separated immediately after they are drawn to avoid spurious results 4
• Marked discrepancies between different test results should prompt consideration of assay interference or preanalytical errors 4, 5

Initial Diagnostic Approach Based on Test Type

For Abnormal Glucose/Diabetes Testing

• If A1C is 7.0% and repeat is 6.8%, diabetes is confirmed 4
• If two different tests (A1C and fasting plasma glucose) are both above diagnostic threshold, diagnosis is confirmed 4
• With discordant results from two different tests, repeat the test that is above the diagnostic cut point 4
• For patients with test results near diagnostic margins, repeat testing in 3-6 months is reasonable 4
• A1C is unreliable in conditions with increased red blood cell turnover (sickle cell disease, pregnancy second/third trimesters, G6PD deficiency, hemodialysis, recent blood loss/transfusion, erythropoietin therapy)—use only plasma glucose criteria in these patients 4

For Abnormal Liver Tests

Perform a comprehensive etiologic workup immediately rather than repeating tests 1:

• Core laboratory panel: complete blood count, comprehensive metabolic panel, hepatitis B surface antigen, hepatitis C antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, serum immunoglobulins, simultaneous serum ferritin and transferrin saturation 4, 1
• Abdominal ultrasound is mandatory first-line imaging (98% positive predictive value for cirrhosis, 71-97% specificity for excluding biliary obstruction) 4, 6, 1
• If ALT >1000 U/L, add hepatitis A, E, and cytomegalovirus serologies 1
• The extent of liver blood test abnormality is not necessarily a guide to clinical significance—mild elevations can represent serious progressive disease 4, 1

For Bilirubinuria (Bilirubin in Urine)

The presence of bilirubin in urine indicates conjugated hyperbilirubinemia requiring prompt diagnostic evaluation 6:

• Verify conjugated bilirubin represents >35% of total bilirubin 6
• Ultrasound abdomen is first-line imaging with 98% positive predictive value and 65-95% sensitivity for liver parenchymal disease 6
• Consider viral hepatitis serologies, autoimmune markers, and drug toxicity evaluation 6
• Do not simply repeat urinalysis or wait to see if bilirubinuria resolves—most abnormalities represent true pathology requiring diagnosis 6

Critical Pitfalls to Avoid

• Don't assume mild elevations are insignificant—conditions like NAFLD, hepatitis C, and alcohol-related liver disease often present with only mild abnormalities but can progress to cirrhosis 1
• Don't stop investigating if tests normalize—normal liver tests do not exclude chronic liver disease 1
• Absence of symptoms does not mean benign disease—many patients with significant liver fibrosis remain asymptomatic until advanced disease develops 6
• Pre-analytical errors (improper sample collection, handling, or transport) are the most common source of laboratory mistakes (46-68.2% of total errors) 7
• False-positive laboratory results are 8 times more frequent than true positives in patients undergoing routine testing 4

When to Refer Urgently

Immediate specialist referral is indicated for 6, 1:

• Clinical jaundice
• Suspicion of hepatobiliary malignancy
• Markedly elevated transaminases (>1000 U/L)
• Evidence of hepatic decompensation
• Positive hepatitis B or C serology
• Abnormal liver tests with negative extended workup and no NAFLD risk factors
• Evidence of advanced liver disease or cirrhosis

Special Populations

In children, the differential diagnosis is broader and alpha-1-antitrypsin level, caeruloplasmin (age >3 years), and anti-liver kidney microsomal antibody should be included in the workup 4, 1

In neonates and infants, conjugated bilirubin >25 μmol/L requires urgent pediatric assessment for possible liver disease 6