One distinguishes:

(1) dominant forms or hemoglobinopathies M: structural anomaly of globin: isolated well tolerated cyanosis from birth; the presence of 25-30 % methemoglobinemia does not require any treatment.

Classification according to the involved chain:

• 5 variants for the γ chain, (only fetal Hb is affected): they present as neonatal cyanosis, the symptomatology of which improves progressively as HbF is replaced by Hb A (see specific terms):

-        HbFM Osaka, where histidine is replaced by tyrosine in position 63

-        HbFM Fort Ripley, where histidine is replaced by tyrosine in position 92

-        HbFM Circleville, where histidine is replaced by leucine in position 63

-        HbFM Cincinnati, where phenylalanine is replaced by serine in position 41

-        HbFM Viseu, where leucine is replaced by methionine in position 28, which modifies
                       the configuration of the Hb in position 63

• 3 variants for the β chain, which are only detectables around 3 to 6 months of age, when the β chain replaces the γ chain.

-        HbM Saskatoon

-        HbM Hydepark or M-Akita

-        HbM Milwaukee: decreased affinity of Hb for O2

• 3 variants for the α chain, which present as neonatal cyanosis

-        HbM Boston

-        HbM Iwate (see hemoglobin Miwate)

-        HbM Yantai

(2) recessive forms caused by deficiency in cytochrome B5 reductase or diaphorase, two forms of which exist: a soluble intraerythrocytic one and an ubiquitous membranar one:

-    type I:          mutation of the CYBR3R5 gene (22q13.31-qter)  [MIM 250 800]: absence of enzyme activity limited to the erythrocytes; isolated cyanosis, from 6-9 months of age; asymptomatic even with levels of MethHb up to 40 %. 

-   type II:  mutation of the CYBR3R3 gene (22q13.31-qter)  [MIM 250 800]:enzyme deficiency affecting various tissues, including the central nervous system; most severe form: cyanosis and early, severe encephalopathy; treatment: methylene blue IV, ascorbic acid, riboflavin

-   type III:  deficiency limited to hematopoietic cells: recently withdrawn from the classification 

-   type IV:  mutation of the CYB5A gene (18q22.3) [MIM 250 790]: decreased enzyme activity in all tissues, similar to type I; sexual ambiguity is sometimes associated

Anesthetic implications: 

Beware, the iron heme of the methemoglobin does not carry oxygen (risk of tissue hypoxia) and the affinity of its ferrous heme for O2 increases (thus moving the HbO2 dissociation curve to the left): anemia is therefore poorly tolerated in case of severe methemoglobinemia.  Measure of SpO2 and of the level of MetHb using the Radical 7â cooximeter (Masimo)

Avoid methemoglobinizing agents: prilocaine, mepivacaine, bupivacaine, lidocaine at high doses, metoclopramide, trimethoprim. Paracetamol (acetaminophen), ropivacaine and dexmetedomidine can be used safely. Do not administer methylene blue in case of hemoglobin M or associated deficiency in glucose-6-phosphate dehydrogenase because it is inefficient (the efficacy depends on NADPH produced by G6PD) and can induce hemolysis

References:

-        Beauvais P.
Les méthémoglobinémies héréditaires.
Arch Pédiatr 2000 ; 7 : 513-8

-        Kuji A, Satoh Y, Kikuchi K, Satoh K, Joh S.
The anaesthetic management of a patient with haemoglobin Miwate.
Anesth Analg 2001; 93: 1192-3

-        Baraka AS, Ayoub CM, Yasbeck-Karam V et al.
Prophylactic methylene blue in a patient with congenital methemoglobinemia.
Can J Anesth 2005; 52: 258-61.

-        Stucke AG, Riess ML, Connolly LA.
Hemoglobin M (Milwaukee) affects arterial oxygen saturation and makes pulse oximetry unreliable.
Anesthesiology 2006; 104: 887-8.

-        Sharma D, Pandia MP, Bithal PK.
Methylene blue in congenital methemoglobinemia: prophylactic or on demand?
Can J Anesth 2005; 52: 884-5.

-        Johnson D.
Perioperative methemoglobinemia.
Can J Anesth 2005; 52 : 665-8

-        Alonso-Ojembarrena A, Lubian-Lopez SP.
Hemoglobin M disease as a cause of cyanosis in a newborn.
J Pediatr Hematol Oncol 2016; 38:173-5.

-        Mathew PJ, Gupta A, Natarajan V, Ganesan R, Sharma R.
Failure of pulse oximetry and cooximetry as monitors in a patient with hemoglobin Miwate. a case report.
A&A Practice 2018 ; 10 : 293-5.

-        Yin W, Jung F, Adams D, Konig G, Romeo RC, Lim G.
Case report of remifentanil labor analgesia for a pregnant patient with congenital methemoglobinemia type 1.
A&A Practice 2021; 15 e01373

-        Bhaskar P, Rehman S, Lone RA, John J, Sahabudheen AFA.
Intraoperative management of a child undergoing cardiac surgery with congenital methemoglobinemia detected in the operating room.
A&A Practice 2021; 135: e01395

-        Ri H, Park Y, Jeon Y.
Anesthetic experience: congenital methemoglobinemia due to hemoglobin M.
J Dent Anesth Pain Med 2021;21 :471-4

-        Choi S-W, Putnam E.
Anesthetic management of a pediatric patient with congenital methemoglobinemia.
Case Reports in Anesthesiology 2023; doi.org/10.1155/2023/3474638

-        Limper U, Covrig D, Lange J, Annecke T.
Perioperative management of oxygenation in hereditary methaemoglobinaemia.
Br J Anaesth 2024 ; 132 : 793-5

Updated: April 2024