4476-8 Complement Cl esterase inhibitor.functional [Mass/volume] in Serum or Plasma may be incorrect

General
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Functional assays for C1 inhibitor (chromogenic or EIA) are expressed as the percentage of the mean level in normal specimens rather than as a mass concentration. The mass concentration of C1 inhibitor in a subject with low C1 inhibitor function may be low or normal depending on whether the patient has normal amounts of a dysfunctional protein.

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Hello Bruce, it is great to hear from you! I would like to circulate this comment through the Lab LOINC committee list serve. Do you have a particular reagent manufacturer in mind for this measurement?
Be in touch soon; the committee is on summer hiatus until August.
Pam

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Hi Pam. Nice hearing from you as well. The 2 most widely used functional C1 inhibitor assays are the Quidel MicroVue™ C1-Inhibitor Plus EIA and the Technoclone TECHNOCHROM® C1-INH chromogenic assay. Both report results as a %age of a normal population. I am not aware of any functional C1 inhibitor assay that is reporting results as a mass concentration. We are about to switch from the chromogenic assay to the EIA and need to remap to LOINC which is when I noticed this apparant issue. Please let mne know how I can participate.

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Hi Pam. Just wondering if you have received any feedback on this topic?

Bruce

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Hi Bruce! Apologies for the delay. Canada did an initial response and was going to ping their implementers. This is on the top of my follow up to do’s. More soon, Pam

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Anil Patel had found a mix of reporting this assay:

In Canada, we have a mixture. One commercial lab sends the C1 Esterase inhibitor, functional to Quest Diagnostics in the US and Report back a percentage.

  • Reference Range
    ≥68% Normal
    41-67 % Equivocal
    ≤40 % Abnormal
    Less than 40% of the reference functional activity indicates a likely diagnosis of hereditary angioedema or acquired C1 Inhibitor deficiency.

https://tests.lifelabs.com/s/article/C1-ESTERASE-INHIBITOR-FUNCTIONAL-Ontario?searchedValue=C1%20inhibitor (Serum )

One other major commercial lab reports back mg/L (Gamma Dynaca re)

https://www.dynacare.ca/specialpages/secondarynav/find-a-test/nat/c1%C2%A0esterase%C2%A0inhibitor.aspx?sr=NAT&st= (Se rum)

London Health Sciences (Chromogenic Assay)

Report 0.75 – 1. 59 U/mL

https://www.lhsc.on.ca/lab-test-info-guide/c1-esterase-inhibitor-function (Pla sma)

Shared Health (Manitoba). Send to Mayo Clinic (Enzyme Immunoas say (EIA))

Report ≥6 mo: 0.21 – 0.38 g/L

https://apps.sbgh.mb.ca/labmanual/test/view?seedId=2 97 (Serum)

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Hi Pam. Thank you for your response. My interpretation is below:

  1. Lifelab is reporting results as a %.
  2. The link for dynacare shows results for the antigen and not the functional assay which is correctly reported as a mass concentration.
  3. The link for Shared Health is also for the antigen level (Optilite turbidimetry) and correctly reporting as mass concentration. If they are sending the functional test to Mayo, Mayo is reporting as percentage.
  4. The only lab reporting functional activity as an arbitrary concentration is London Health Sciences.
    Most labs standardize results against a pooled normal human plasma reference and report as a % as specified in the directions for use of the common assay kits for EIA (Quidel) and chromogenic assays (Technoclone and Behringer). In the US most labs are using the Quidel assay as it is the only functional test that is FDA approved. This facilitates comparison of results between labs. Some specialized laboratories performing functional assays will convert the absolute readings into arbitrary concentrations using a standard curve. I think it is important that LOINC includes a concept with the property of NFr or RTO and example UCUM units of % as it is likely to be more commonly encountered than arbitrary concentration.
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Hi Bruce,

Thank you for raising this. I agree that the current LOINC property for “4476-8 Complement C1 esterase inhibitor.functional [Mass/volume] in Serum or Plasma” appears problematic, or at least requires review.

The concern is that functional C1 inhibitor assays measure activity/function, whereas mass concentration reflects the amount of C1 inhibitor protein present. These are clinically different measurements. As you noted, a patient may have a normal antigenic level of C1 inhibitor but reduced functional activity, which is important in the assessment of hereditary or acquired angioedema.

The examples we found in Canada show inconsistent reporting patterns. Some laboratories report functional C1 esterase inhibitor as a percentage of normal activity, while others appear to report values in U/mL, g/L, or mg/L. However, some of those mass concentration examples may reflect antigenic/quantitative C1 inhibitor testing rather than true functional activity, or may represent local reporting conventions that need further clarification.

Given this, I think the next step maybe be to separate the question into two parts:

  1. Does LOINC 4476-8 correctly represent a functional C1 inhibitor assay, given that the property is currently Mass concentration?
  2. Are laboratories using this LOINC code for both functional and antigenic/quantitative assays, creating a mapping and interoperability risk?

It may be helpful for LOINC to review the manufacturer package inserts and common reference lab catalogues. The Quidel MicroVue C1-Inhibitor Plus EIA is described as measuring functional C1 inhibitor in serum or plasma, and Quest distinguishes between C1 Inhibitor Protein, which measures concentration, and C1 Inhibitor Functional, which measures relative functionality by EIA. This supports your concern that the functional test should not be treated simply as a mass concentration result.

From a terminology perspective, this may require either a correction to the property for 4476-8, creation or review of an activity/relative-activity term, or guidance that laboratories should not map antigenic C1 inhibitor concentration and functional C1 inhibitor activity to the same LOINC concept.

I think this could also be a great presentation for the Health Terminology Committee (HTC) to bring awareness of the issue.

Anil

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Hi Anil. It seems that there was a radial immunodiffusion test for C1 inhibitor function that would report results as a mass concentration or a % of a normal population (See Späth PJ, Wüthrich B, Bütler R.Complement. 1984;1(3):147-59. doi: 10.1159/000467830.PMID: 6443347). It was manufactured by Diamedix as the first commercially available clinical test for C1 inhibitor function. Quidel was acquired by another company and the test is no longer being manufactured. We used to perform this assay many years ago prior to the availability of the modern chromogenic and EIA assays and I almost forgot about it.

I have summarized the LOINC concepts related to C1 inhibitor testing on ser/plas:

Picture1
Picture1470×439 7.36 KB

These leaves us with

10634-4 Complement C1 esterase inhibitor.functional/Complement C1 esterase inhibitor.total in Serum or Plasma which LOINC indicates is incorrectly being used instead of 48494-9. If so, I am not sure of what this means and if it can’t be disambiguated it should be deprecated

4476-8 Complement C1 esterase inhibitor.functional [Mass/volume] in Serum or Plasma might refer to the functional RID which appears to no longer being manufactured. Would need to check if any labs are still performing as a home brew test prior to deprecating

15161-3 Complement C1 esterase inhibitor.functional [Presence] in Serum or Plasma. I am not sure what this means unless this also represents the functional RID in which the presence of a precipitin ring is recorded rather than quantitation by measuring the ring diameter against a standard curve. I don’t remember how we performed the test.

82876-4

Complement C1 esterase inhibitor [Units/volume] in Serum or Plasma by Chromogenic method. This has a property of ACnc with units of IU/mL. Although correct for some labs, I think most would use a property of RelCCnc with units of %

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