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Test ID: MEV1 Methemoglobinemia Evaluation, Blood

Shipping Instructions

Specimen must arrive within 3 days (72 hours) of collection.

Necessary Information

Include recent transfusion information.


Include most recent complete blood cell count results.


Metabolic Hematology Patient Information (T810) is strongly recommended. Testing may proceed without this information, however if the information requested is received, any pertinent reported clinical features and data will drive the focus of the evaluation and be considered in the interpretation.


The laboratory has extensive experience in hemoglobin variant identification and many cases can be confidently classified without molecular testing. However, molecular confirmation is always available, subject to sufficient sample quantity (eg, multiplex ligation-dependent probe amplification testing requires at least 2 mL of sample in addition to protein testing requirements). If no molecular testing or specific molecular tests are desired, utilize the appropriate check boxes on the form. If the form or other communication is not received, the reviewing hematopathologist will select appropriate tests to sufficiently explain the protein findings, which may or may not include molecular testing.

Specimen Required

The following specimens are required for testing:

Whole blood ACD-B specimen

2 Whole blood EDTA specimens


Container/Tube: Lavender top (EDTA) and yellow top (ACD solution B)

Specimen Volume:

EDTA: Two 4-mL tubes

ACD: One 6-mL tube

Collection Instructions: Send whole blood specimen in original tube. Do not aliquot.


1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Metabolic Hematology Patient Information (T810) in Special Instructions

3. If not ordering electronically, complete, print, and send a Benign Hematology Test Request (T755) with the specimen

Useful For

Diagnosis of methemoglobinemia and sulfhemoglobinemia and possible hereditary (congenital) causes


Differentiation of methemoglobinemia and sulfhemoglobinemia from other causes of cyanosis (eg, congenital heart disease)

Profile Information

Test ID Reporting Name Available Separately Always Performed
MEVI Methemoglobinemia Interpretation No Yes
HGBCE Hb Variant, A2 and F Quantitation,B Yes Yes
HPLC HPLC Hb Variant, B No Yes
METH Methemoglobin, B Yes, (Order MET) Yes
SULF Sulfhemoglobin, B Yes, (Order MET) Yes
METR1 Cytochrome b5 Reductase, B Yes Yes

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
SDEX Sickle Solubility, B Yes No
IEF Isoelectric Focusing, B No No
MASS Hb Variant by Mass Spec, B No No
UNHB Hb Stability, B No No
HPFH Hb F Distribution, B No No
ATHAL Alpha-Globin Gene Analysis Yes No
WASQR Alpha Globin Gene Sequencing, B Yes, (Order WASEQ) No
WBSQR Beta Globin Gene Sequencing, B Yes, (Order WBSEQ) No
WBDDR Beta Globin Cluster Locus Del/Dup,B Yes, (Order WBDD) No
WGSQR Gamma Globin Full Gene Sequencing Yes, (Order WGSEQ) No
MEV0 Methemoglobin Summary Interp No No

Testing Algorithm

This is a consultative evaluation in which the case will be evaluated at Mayo Clinic Laboratories, the appropriate tests performed at an additional charge, and the results interpreted. This is an evaluation for methemoglobin and sulfhemoglobin levels and possible hereditary causes. Methemoglobin, sulfhemoglobin levels, cytochrome-b5 reductase (methemoglobin reductase) activity, and protein analysis screening for hemoglobin variants (capillary electrophoresis, cation exchange high performance liquid chromatography and capillary electrophoresis) will always be performed. If additional hemoglobin variant confirmatory testing is required, appropriate reflex testing will be performed. This will vary from additional protein analysis methods to molecular testing, as needed.


One or more of the following molecular tests may be reflexed:

-ATHAL / Alpha-Globin Gene Analysis, Varies

-WASQR / Alpha-Globin Gene Sequencing, Blood

-WBSQR / Beta-Globin Gene Sequencing, Blood

-WBDDR / Beta-Globin Cluster Locus Deletion/Duplication, Blood

-WGSQR / Gamma-Globin Full Gene Sequencing, Varies


After all test results are finalized, an additional consultative interpretation that summarizes all testing and incorporates subsequent genetic results will be provided.


See Benign Hematology Evaluation Comparison in Special Instructions.

Method Name

MEVI, MEV0: Medical Interpretation

HGBCE: Capillary Electrophoresis

HPLC: Cation Exchange/High-Performance Liquid Chromatography (HPLC)

METH, SULF: Spectrophotometry

METR1: Kinetic Spectrophotometry

IEF: Isoelectric Focusing

HPFH: Flow Cytometry

UNHB: Isopropanol and Heat Stability

MASS: Mass Spectrometry (MS)

Reporting Name

Methemoglobinemia Evaluation

Specimen Type

Whole Blood ACD-B
Whole Blood EDTA

Specimen Minimum Volume

EDTA blood: 3 mL
ACD blood: 2.7 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Whole Blood ACD-B Refrigerated 72 hours
Whole Blood EDTA Refrigerated 72 hours

Clinical Information


Methemoglobin forms when the hemoglobin (Hb) molecule iron is in the ferric (Fe3[+]) form instead of the functional ferrous (Fe2[+]) form. Methemoglobinemia can be hereditary or acquired and is present by definition when methemoglobin levels are greater than the normal range. Acquired methemoglobinemia results after toxic exposure to nitrates and nitrites/nitrates (fertilizer, nitric oxide), topical anesthetics (“caines"), dapsone, naphthalene (moth balls/toilet deodorant cakes), and industrial use of aromatic compounds (aniline dyes).


Congenital methemoglobinemias are rare. They are due either to:

-A deficiency of cytochrome b5 reductase (methemoglobin reductase) in erythrocytes, an autosomal recessive disorder resulting from genetic variants in either CYB5R3 or CYB5A.(1,2) Type IV is thought to be extraordinarily rare. Type III is no longer a category.


-One of several intrinsic structural disorders of Hb, called M-Hbs; all of which are inherited in an autosomal dominant manner.(3,4) Classically, M-Hbs result from histidine-to tyrosine substitutions at the proximal or distal histidine important in coordinating the oxygen molecule. These include alpha-, beta- and gamma-chain variants. Rarely, other substitutions outside the proximal and distal histidine location can cause Hb variants that increase methemoglobin or sulfhemoglobin levels. Most M-Hb variants are readily identified by high performance liquid chromatography (HPLC) or mass spectrometry methods with characteristic electrophoresis patterns; however, some require more specialized techniques. Most are associated with increased methemoglobin with or without an increase in sulfhemoglobin. Alpha chain M-Hb variants can be associated with increased sulfhemoglobin without an increase in methemoglobin.



Sulfhemoglobin cannot combine with oxygen. When acquired, sulfhemoglobinemia can be associated with cyanosis and often accompanies methemoglobinemia. Sulfhemoglobinemia has been associated with exposure to sumatriptan, sulfonamides, metoclopramide, paint or varnish vapors, dimethyl sulfoxide, acetanilide, phenacetin, trinitroluene, zinc ethylene bisdithiocarbamate (a fungicide), and flutamide. It is important to note that some Hb variants are known to interfere with this test (especially M-Hbs) and sulfhemoglobin absorbance can be increased due to the Hb variant. Hb evaluation that includes the HPLC method is recommended to exclude this possibility.


In contrast to methemoglobinemia, sulfhemoglobinemia persists until the erythrocytes containing it are destroyed. Therefore, blood level of sulfhemoglobin declines gradually over a period of weeks.

Reference Values

Definitive results and an interpretive report will be provided.


This is a consultative evaluation in which the history and previous laboratory values are reviewed by a hematologist who is an expert on these disorders. Appropriate tests are performed, and an interpretive report is issued.

Clinical Reference

1. OMIM: 250800 Methemoglobinemia due to deficiency of methemoglobin reductase. Updated May 20, 2019. Accessed October 19, 2020. Available at

2. OMIM: 250790 Methemoglobinemia and ambiguous genitalia. Updated May 18, 2018. Accessed October 19, 2020. Available at

3. OMIM: 141800 Hemoglobin alpha locus 1; HBA1. Updated November 1, 2019. Accessed October 19, 2020. Available at

4. OMIM: 141900 Hemoglobin beta locus; HBB. Updated November 14, 2019. Accessed October 19, 2020. Available at

5. Haymond S, Cariappa R, Eby CS, Scott MG: Laboratory assessment of oxygenation in methemoglobinemia. Clin Chem. 2005;51(2):434-444

6. Noor M, Beutler E: Acquired sulfhemoglobinemia. An underreported diagnosis? West J Med. 1998;169(6):386-389

7. Thom CS, Dickson CF, Gell DA, Weiss MJ: Hemoglobin variants: biochemical properties and clinical correlates. Cold Spring Harb Perspect Med. 2013;3(3):a011858

8. Percy MJ, McFerran NV, Lappin TR: Disorders of oxidized haemoglobin. Blood Rev. 2005;19(2):61-68

9. Agarwal AM, Prchal JT. Methemoglobinemia and Other Dyshemoglobinemias. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri M, eds. Williams Hematology. 9th ed. McGraw-Hill; 2016: 789-800

Test Classification

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information

83020-26-Hemoglobinopathy Interpretation

83020-Hb Variant, A2 and F Quantitation

83021-HPLC Hb Variant

82657-Methemoglobin reductase

83050-Methemoglobin, quantitative

83060-Sulfhemoglobin, quantitative

82664 (if appropriate)

83068 (if appropriate)

83789 (if appropriate)

88184 (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
MEV1 Methemoglobinemia Evaluation In Process


Result ID Test Result Name Result LOINC Value
8268 Methemoglobin, B 2614-6
8272 Sulfhemoglobin, B 4685-4
41927 Hb A 20572-4
65615 HPLC Hb Variant, B No LOINC Needed
METRB Cytochrome b5 Reductase, B 32703-1
608086 Methemoglobinemia Interpretation 59465-5
608108 Reviewed By 18771-6
41928 Hb F 4576-5
41929 Hb A2 4551-8
41930 Variant 1 24469-9
41931 Variant 2 24469-9
41932 Variant 3 24469-9
41933 HGBCE Interpretation 78748-1

Day(s) Performed

Monday through Saturday

Report Available

3 to 25 days
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