Test Catalog

Test ID: METR1    
Cytochrome b5 Reductase Enzyme Activity, Blood

Useful For Suggests clinical disorders or settings where the test may be helpful

Evaluation of patients with cyanosis


Confirming cases of suspected cytochrome b5 reductase (methemoglobin reductase) deficiency


Functional studies in families with cytochrome b5 reductase deficiency

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Cytochrome b5 reductase (CYB5R), also called methemoglobin reductase, is the enzyme within the erythrocyte that maintains hemoglobin in the reduced (non-methemoglobin) state. A deficiency of CYB5R in erythrocytes is an autosomal recessive disorder resulting from variants in the CYB5R3 or the CYB5A genes.


Persons who are heterozygous for CYB5R genetic variants have no clinical or laboratory abnormalities, are not cyanotic, and have normal methemoglobin concentrations in their blood. However, they hold an increased risk for more severely symptomatic acute episodes of methemoglobinemia with exposure to inducing agents.


Persons who are homozygous for CYB5R genetic variants have normal arterial oxygen saturation but have varying quantities of methemoglobin in their blood, generally 15% to 20%, and are quite cyanotic. Paradoxically, homozygotes typically have normal blood counts; the condition only rarely causes polycythemia. The presence of methemoglobin shifts the hemoglobin-O2 dissociation curve to the right, so although the transport of oxygen is diminished, the delivery of oxygen to tissues is normal. Because of the chronicity, the homozygous condition is usually compensated and, therefore, quite benign, but it may cause concern to parents of affected children, be a cosmetic embarrassment to the children, and alarm the attending physician. The cyanosis may be treated with methylene blue.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

> or =12 months of age: 7.8-13.1 U/g Hb

Reference values have not been established for patients who are <12 months of age.

Interpretation Provides information to assist in interpretation of the test results

Cytochrome b5 reductase (methemoglobin reductase) activity in neonates (0-6 weeks) is normally 60% of the normal adult value. Adult values are attained by 2 to 3 months of age.


Heterozygotes have results slightly lower than the reference range. Homozygotes demonstrate little to no cytochrome b5 reductase activity and increased levels of methemoglobin.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Individuals who are glucose-6-phosphate dehydrogenase (G6PD) deficient are not candidates for methylene blue therapy. Administration of methylene blue to such persons will cause hemolysis or methemoglobin formation.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Agarwal AM, Prchal JT: Methemoglobinemia and other dyshemoglobinemias. In: Kaushansky K, Lichtman MA, Prchal JT, et al, eds. Williams Hematology. 9th ed. McGraw-Hill; 2016:789-800

2. Percy MJ, Barnes C, Crighton G, et al: Methemoglobin reductase deficiency: Novel mutation is associated with a disease phenotype of intermediate severity. J Pediatr Haematol Oncol. 2012;34:457-460