Ellis J. Neufeld, MD, PhD
Executive Vice President
Clinical Director
St. Jude Children’s Research Hospital
CLINICAL DILEMMA
I have a 20-year-old male patient with strong family history of recessive hereditary methemoglobinemia. He has had cyanosis since birth but has experienced no medical complications or issues playing sports. None of his family members ever had globin sequence testing. He did well with bilateral inguinal hernia surgery and is now being seen pre-op for a tonsillectomy. His complete blood count hemoglobin (Hb) was 177 g/L, and alpha globin sequencing showed Hb M-Iwate mutation.
My questions are as follows: Do we still need to avoid medications that can cause acquired methemoglobinemia? Assuming the pulse oximeter is inaccurate for perioperative monitoring, would an arterial blood gas (ABG) test be needed in the event of respiratory problems? Is it correct to assume there is never a role for methylene blue? Is there anything else I need to tell this patient?
EXPERT OPINION
Healthy cyanosis is a rare but striking finding that demands attention. The alert hematologist, exemplified by the questioner in this case, can make a firm diagnosis, provide patient education, and help prevent potential unnecessary tests, procedures, or therapies. An excellent expert consensus statement on methemoglobinemia was recently published.1
The medical history reveals much about this patient’s physiology. First, although he is cyanotic, he is well and able to play sports. His Hb level is elevated but not dangerously high. Likewise, we have a family history of several individuals who are cyanotic but well. Genetic analysis revealed a known Hb M mutation: Hb M-Iwate, a dominant change of histidine to tyrosine at codon 87 of the HBA1 or HBA2 gene. This accounts for the observations in the patient and his family.
However, the mere fact that this young, otherwise healthy adult is being seen for a tonsillectomy raises red flags. Why does he need the procedure? Unless it is for recurrent infections, I suggest taking a step back. Does someone suspect sleep apnea? As noted, to accurately determine arterial partial pressure of oxygen (PaO2) and Hb saturation would require an arterial blood gas and co-oximetry, not pulse oximetry. The PaO2 is likely entirely normal here in the absence of cardiopulmonary disease.
The initial question did not specify a percentage of methemoglobin (metHb). The literature suggests that with levels ranging from 10% to 20% (or even somewhat higher), one can be entirely asymptomatic, and considering that the total Hb is around 170 g/L, one could imagine, “If 20% of that is metHb, there is still normal circulating Hb A of about 140 g/L to carry oxygen.”
Generally, it is preferable to avoid strong oxidant medications if one can. We should also be able to trust the personal and family history of anesthesia exposure, in the sense that affected relatives, if they had anesthesia without difficulty, will have had the same drug-gene interaction that this patient would have. I would check the patient’s glucose-6-phosphate dehydrogenase (G6PD) status to be sure he is not deficient, just in case a future caregiver considers methylene blue for him at some point in his life. If he is negative for G6PD, I would put methylene blue on his medication allergy list and even on an alert bracelet in case he is comatose from a car accident and also blue.
It is correct that pulse oximetry will be inaccurate. For perioperative care, ABG may be required to assess oxygenation. Although some might say it isn’t for hematologists to talk people out of (necessary) tonsillectomies, I feel it is our role to help people question the need when risk is high, or when the need itself might not be so high.
Generally, the antioxidants work for toxic methemoglobinemia but not Hb M type. Methylene blue is indicated for acute (toxic) methemoglobinemia when the fraction of metHb is high. You could try high-dose vitamin C as a safe, inexpensive antioxidant for a week or two and see if he gets less blue, but there would be no reason to continue that if it didn’t help. The point about Hb M-Iwate (and the other Hb Ms) is that the problem is not a mismatch of oxidant stress to antioxidant capacity nor a failed Hb reduction system.
Overall, the patient and his family members can be reassured that the problem is cosmetic in this case, and they should be advised to avoid clinicians who would want to look for heart or lung disease.
I will also note that the patient was subsequently tested for metHb, which was not detected, and for the related Fe3+ blue, oxidized compound, sulfhemoglobin, which was present. While initially surprising, this finding has been observed in Hb M. A systematic assessment found that alpha globin mutations that cause methemoglobinemia are prone to sulfhemoglobin formation.2
Acknowledgement: The author is indebted to Josef Prchal, MD, at the University of Utah in Salt Lake City, both for his scholarly “UptoDate” chapter on methemoglobinemia3 and for a discussion about this case.
References
- Iolascon A, Bianchi P, Andolfo I, et al. Recommendations for diagnosis and treatment of methemoglobinemia. Am J Hematol. 2021;96(12):1666-1678.
- Rangan A, Savedra ME, Dergam-Larson C, et al. Interpreting sulfhemoglobin and methemoglobin in patients with cyanosis: An overview of patients with M-hemoglobin variants. Int J Lab Hematol. 2021;43(4):837-844.
- Prchal JT. Methemoglobinemia. UpToDate. Updated January 8, 2024. Accessed May 19, 2024. https://www.uptodate.com/contents/methemoglobinemia.
NEXT MONTH'S CLINICAL DILEMMA
I have a 39-year-old female patient who was diagnosed with cytogenetically normal acute myeloid leukemia (AML) harboring mutations in NPM1, FLT3 (ITD), and DMT3A. She underwent induction with 7+3 (daunorubicin and cytarabine) and midostaurin but had primary induction failure. She then went on to receive salvage chemotherapy with CLIA (cladribine, idarubicin, and cytarabine) and gilteritinib, which resulted in a first morphologic remission (CR1).
Prior to a myeloablative matched sibling donor hematopoietic cell transplantation (HCT), her marrow was negative by both morphology and flow cytometry testing for measurable residual disease (MRD). Molecular testing of the bone marrow was negative for NPM1 (lower limit of quantification [LLOQ] = 10%), but positive for FLT3-ITD (LLOQ = 0.1%).
Post-HCT, she has not had morphologic evidence of disease but has had persistently positive low-level NPM1 detected (0.03% to 0.07%). Testing for FLT3-ITD has been negative. Chimerism testing at both day +29 and +90 was 100% donor for CD33+ and greater than 90% for CD3+.
Due to detectable MRD post-HCT, she began tapering her tacrolimus on day +60 and was started on gilteritinib since her disease was FLT3-ITD positive prior to HCT. She completed the tacrolimus taper by day +100. She also developed mild cutaneous graft-versus-host disease (grade 1, stage 1).
Since the MRD has been persistent despite tapering immunosuppression, what other options should be considered to clear the MRD and prevent frank relapse? Should a regimen of azacitidine +/- venetoclax +/- gilteritinib or donor cellular (lymphocyte) infusion be considered? Since her disease is low copy number NPM1 positivity, is it better to continue to watch and wait with gilteritinib maintenance?
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