Elevated C4A at 1868 ng/mL: No Immediate Concern
A C4A level of 1868 ng/mL (1.868 μg/mL) is markedly elevated and falls well outside the range associated with complement deficiency states, therefore it does not indicate hereditary angioedema, lupus, or other complement-consuming diseases that require urgent intervention.
Understanding the Clinical Context
The complement component C4A you're asking about appears to be confused with the 7α-hydroxy-4-cholesten-3-one (C4) marker used in bile acid diarrhea diagnosis, which is measured in ng/mL. However, I'll address both possibilities:
If This is Serum C4 (Complement Component)
Low C4 levels, not high ones, indicate pathology. At least 95% of patients with C1 inhibitor deficiency demonstrate reduced C4 levels, and low C4 serves as an excellent screening tool for hereditary angioedema and complement-consuming autoimmune diseases 1.
Your level of 1868 ng/mL is substantially elevated compared to typical reference ranges, which generally fall between 100-400 mg/L (10,000-40,000 ng/mL for total C4). If your result is truly 1868 ng/mL for complement C4, this would actually be low, not high.
Low C4 requires immediate evaluation for C1 inhibitor deficiency, hereditary angioedema, or complement-consuming processes like systemic lupus erythematosus 2.
If This is the C4 Bile Acid Marker
Elevated C4 (7α-hydroxy-4-cholesten-3-one) suggests bile acid diarrhea. Cut-off values for diagnosing bile acid diarrhea range from 30-52.5 ng/mL, with one prospective study using 52.5 ng/mL or greater as diagnostic 3.
Your level of 1868 ng/mL is dramatically elevated (35-60 times the diagnostic threshold), strongly suggesting bile acid malabsorption if you have chronic diarrhea 3.
However, the diagnostic accuracy of serum C4 for bile acid diarrhea is limited, with sensitivity of only 40% and specificity of 85% when validated against fecal bile acid measurements 3.
Recommended Action Algorithm
Step 1: Clarify the Test Ordered
- Confirm with your laboratory whether this is:
- Complement component C4 (typically measured in mg/dL or mg/L)
- 7α-hydroxy-4-cholesten-3-one (C4) for bile acid synthesis (measured in ng/mL)
Step 2: If Complement C4 and Result is Low (< 10 mg/dL)
- Immediately measure C1 inhibitor antigen and functional levels to distinguish between hereditary angioedema types I and II versus acquired C1 inhibitor deficiency 1.
- Check C1q levels to differentiate hereditary from acquired forms (low C1q suggests acquired deficiency) 1.
- Discontinue ACE inhibitors or ARBs immediately if taking these medications, as they are contraindicated in C1 inhibitor deficiency 1.
- Recognize that traditional therapies (epinephrine, antihistamines, corticosteroids) are ineffective for C1 inhibitor deficiency-related angioedema 1.
Step 3: If This is Bile Acid C4 Marker and Elevated
- Evaluate for chronic diarrhea symptoms (>4 weeks duration, watery stools, urgency) 3.
- Consider risk factors: prior cholecystectomy, terminal ileum resection, Crohn's disease, microscopic colitis, or irritable bowel syndrome with diarrhea 3.
- Do not rely on C4 alone for diagnosis due to very low certainty of evidence and lack of well-defined cut-off values 3.
- If bile acid diarrhea is suspected, consider empiric trial of bile acid sequestrants (cholestyramine, colesevelam) or pursue SeHCAT testing where available 3.
Critical Pitfalls to Avoid
- Do not assume the test name alone clarifies which marker was measured—units and reference ranges are essential for interpretation 3, 1.
- Do not rely on C4 levels during treatment, as C4 can normalize in patients already receiving therapy for hereditary angioedema, requiring repeat testing during an attack 1.
- Ensure timely laboratory processing, as C4 samples must be sent to the laboratory promptly to avoid artificially low results due to degradation 1.
- Do not assume normal C4 excludes hereditary angioedema, as HAE with normal C1 inhibitor levels exists as a separate entity 1.
Additional Considerations
- Genetic variation in C4A copy number can result in constitutively higher baseline levels in some individuals, though this is primarily relevant in research contexts examining schizophrenia risk rather than clinical disease 2, 4.
- Complete deficiencies of C4A are strong genetic risk factors for systemic lupus erythematosus, but elevated levels do not indicate SLE 5, 6.
Bottom line: Clarify which test was performed. If complement C4 and the value is truly low, pursue C1 inhibitor testing urgently. If bile acid C4 marker and elevated with chronic diarrhea, consider bile acid malabsorption. An isolated elevated value without symptoms requires no immediate action.