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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 9  |  Issue : 1  |  Page : 29-32

Dapsone-induced methemoglobinemia: Two cases and a short review


Department of Internal Medicine, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication22-Mar-2018

Correspondence Address:
Dr. Arun Valsan
Armed Forces Medical College, Pune - 411 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_26_17

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  Abstract 

Dapsone is a cheap and widely used drug in many diseases. It can rarely cause dose-independent methemoglobinemia. The key to managing such cases is strong clinical suspicion and prompt discontinuation of the drug. Effective antidote is methylene blue which can rapidly reverse effects in seriously ill patients. Here, we present two such cases that we came across who were managed differently and successfully at our center.

Keywords: Dapsone, methemoglobinemia, methylene blue, saturation gap


How to cite this article:
Valsan A, Sharma S, Mathew R, Chengappa A. Dapsone-induced methemoglobinemia: Two cases and a short review. J Appl Hematol 2018;9:29-32

How to cite this URL:
Valsan A, Sharma S, Mathew R, Chengappa A. Dapsone-induced methemoglobinemia: Two cases and a short review. J Appl Hematol [serial online] 2018 [cited 2021 Sep 25];9:29-32. Available from: https://www.jahjournal.org/text.asp?2018/9/1/29/228329


  Introduction Top


Steroid-refractory patients, especially in developing countries, are frequently prescribed dapsone. Dapsone may cause severe oxidant stress on the cell causing methemoglobinemia and rarely other abnormal hemoglobin. Patients may present with a wide variety of symptoms ranging from innocuous bluish discoloration to severe oxygenation defects which may be life-threatening. High index of clinical suspicion, detailed medication history, and good clinical acumen may aid in early diagnosis and prompt reversal with discontinuation. Severe cases may require close observation, methylene blue (MB) administration, and intensive supportive care.


  Case Reports Top


Case 1

A 24-year-old female, a known case of immune thrombocytopenia, was transferred from a peripheral hospital with fever and dyspnea on exertion of 1-day duration. She was on regular outpatient follow-up and had received an infusion of intravenous immunoglobulin 3 days before present admission and had been started on oral dapsone in view of steroid-refractory disease for the past 10 days. Physical examination revealed resting tachycardia, tachypnea, fever, and pulse oximetry revealed saturation of 79% in ambient air; there was pallor, marked peripheral and central cyanosis. She however had no raised jugular venous pressure. Chest examination revealed clear lung fields and normal heart sounds. The clinical photographs of the first case are illustrated in [Figure 1], [Figure 2], [Figure 3]. The patient was admitted to the Intensive Care Unit (ICU) and placed on high-flow oxygen and was empirically started on broad-spectrum antibiotics in view of fever and raised total leukocyte counts. She continued to be tachypneic and cyanosed despite adequate trial of oxygenation. Her arterial blood gas revealed “saturation gap,” and in view of her clinical status, she was given intravenous MB (2 mg/kg infusion) and ascorbic acid. She remained stable without further deterioration few hours postinfusion and dramatically improved over the next 2 days.
Figure 1: Arterial sample containing chocolate-brown-colored sample

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Figure 2: Saturation gap

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Figure 3: Case 1 depicting central cyanosis

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Case 2

A 22-year-old female, another follow-up case of immune thrombocytopenia, presented for routine checkup to the Hematology Outpatient Department. During consultation, she casually pointed out that her fingernails had acquired a bluish tinge over the last couple of days. She had been on oral dapsone for the preceding 23 days. Physical examination was largely unremarkable except for a saturation of 82% in ambient air and mixed cyanosis. In the second case, it was decided to adopt an approach of “masterful inactivity and close observation” as clinical status was stable. She was admitted to the general medical ward, dapsone was discontinued, and oral azathioprine was introduced. The patient made an uneventful recovery.

Investigations

The relevant investigations are summarized in [Table 1].
Table 1: Laboratory parameters of patients

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The provision for methemoglobin estimation was not available at our center at the time.


  Discussion Top


Methemoglobin is an oxidized variant of hemoglobin that alters oxygen binding capacity, thereby limiting tissue delivery. It manifests when the concentration increases from physiological levels (almost 2%). Methemoglobin is formed when ferrous ions (Fe 2+) within the heme moeity are oxidized to ferric ions (Fe 3+), which are incapable of binding oxygen molecules. Moreover, their presence strengthens the O2-binding affinity of the remaining ferrous hemes within the hemoglobin tetramer, impairing their ability to unload oxygen to tissues.[1],[2] As normal reduction pathways become overwhelmed, methemoglobins accumulate and cause a leftward shift of the oxygen dissociation curve causing a state of functional anemia.[3],[4]

It may be congenital and be of various types, most commonly due to cytochrome b5 reductase deficiency.[5] However, a disproportionately large number of clinically encountered cases are due to acquired causes such as drugs and chemical exposure. Common causes of acquired methemoglobinemia include agents that inflict significant oxidant stress on cells. These include drugs such as lidocaine, benzocaine, amyl nitrite, sulfonamides, and chloroquine as well as many environmental agents (industrial nitrates and pesticides).

Dapsone (4,4'-diaminodiphenyl sulfone) is a sulfone group of antibiotic (via its antagonistic effects on folate synthesis as a para-aminobenzoic acid analog) and a potent anti-inflammatory agent (via direct inhibition of neutrophil).[6] Dapsone formed the backbone of multidrug regimens in Hansen's disease, dermatitis herpetiformis, maduromycosis, ulcerative colitis and Pneumocystis jirovecii pneumonia, toxoplasmosis, and also as a second-line agent in immune thrombocytopenia.[7]

Dapsone is particularly potent because of its pro-oxidant metabolite hydroxylamine which has a very long half-life (catalyzed by a variety of hepatic enzymes or via myeloperoxidase present in white blood cells).[8],[9] When administered in standard doses of 100 mg/day, it can induce significant methemoglobinemia in biochemically normal patients. In the first case, it would have been accelerated with coexistent anemia, fever, and coadministration of immunoglobulin. Thromboxane and prostaglandin synthesis in response to infection increases oxidative stress on erythrocytes. In a healthy and biochemically normal individual, cyanosis develops when levels reach 15%–20% and symptoms ensue with levels of 25%–50%. While headache, dyspnea, lightheadedness, weakness, and confusion are reported in mild methemoglobinemia, individuals with more severe disease are at risk of cardiac arrhythmias, seizures, and coma. Diagnosis in patients with acquired methemoglobinemia requires high index of clinical suspicion and a thorough drug history. First, direct observation may reveal an arterial sample that is chocolate-brown in appearance. Second, the presence of cyanosis in an individual with a normal PaO2 level may suggest the diagnosis.

Treatment

Treatment depends on the clinical severity. In asymptomatic patients (with a methemoglobin level of <20%), simple measures such as discontinuing the offending agent may be all that is required. In symptomatic patients (or where the methemoglobin level exceeds 20%), administration of supplemental oxygen and MB may be indicated. This dichotomous approach has been aptly brought out in the cases illustrated in this report, with the first patient who was symptomatic requiring ICU care and use of MB for reversal of methemoglobinemia and in the second case with discontinuation of dapsone alone.[7],[10]

MB promotes the enzymatic reduction of methemoglobin by nicotinamide adenine dinucleotide phosphate-methemoglobin reductase, thereby re-establishing the ferrous state. The response to MB may be dramatic but the efficacy has not been evaluated in well-controlled studies. MB may pose significant problems if overdosed (hemolysis especially if glucose 6-phosphate dehydrogenase [G6PD] deficient and chest pain) and may also interfere in methemoglobin assessment by oximetry, requiring specific methods such as Evelyn-Malloy's. In patients with G6PD deficiency, ascorbic acid may be particularly useful. Other therapeutic options with lesser efficiency are riboflavin (20–30 mg/day) in congenital variants and cimetidine (acting via selective inhibition of N hydroxylation and thereby increasing tolerance) especially in subacute cases of dapsone-induced methemoglobinemia.[11] In life-threatening cases, hyperbaric oxygenation and exchange transfusion have been used in literature.[10]


  Conclusion and Take Home Messages Top


  1. Altered hemoglobin should not be missing from the diagnostic possibilities in a cyanotic patient in the setting of clear lung fields and normal cardiovascular examination
  2. Saturation gap defined as a low SpO2 with normal PaO2 and SaO2 should alert the treating physicians to the presence of abnormal hemoglobin compounds such as methemoglobin, especially in a resource-limited setting where facilities for quantitate or qualitative estimation are nonexistent
  3. Stopping the offending drug may suffice if detected early and in patients who are clinically stable
  4. MB is an effective and cheap antidote and should be used in cases where there is hemodynamic instability.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology 1989;70:112-7.  Back to cited text no. 1
    
2.
Edwards CJ, Fuller J. Oxidative stress in erythrocytes. Comp Haematol Int 1996;6:24-31.  Back to cited text no. 2
    
3.
Darling R, Roughton F. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol 1942;137:56-8.  Back to cited text no. 3
    
4.
Donnelly GB, Randlett D. Images in clinical medicine. Methemoglobinemia. N Engl J Med 2000;343:337.  Back to cited text no. 4
    
5.
Hegesh E, Hegesh J, Kaftory A. Congenital methemoglobinemia with a deficiency of cytochrome b5. N Engl J Med 1986;314:757-61.  Back to cited text no. 5
    
6.
Booth SA, Moody CE, Dahl MV, Herron MJ, Nelson RD. Dapsone suppresses integrin-mediated neutrophil adherence function. J Invest Dermatol 1992;98:135-40.  Back to cited text no. 6
    
7.
Zosel A, Rychter K, Leikin JB. Dapsone-induced methemoglobinemia: Case report and literature review. Am J Ther 2007;14:585-7.  Back to cited text no. 7
    
8.
Ashurst JV, Wasson MN, Hauger W, Fritz WT. Pathophysiologic mechanisms, diagnosis, and management of dapsone-induced methemoglobinemia. J Am Osteopath Assoc 2010;110:16-20.  Back to cited text no. 8
    
9.
Bradberry SM. Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev 2003;22:13-27.  Back to cited text no. 9
    
10.
Coleman MD. Dapsone: Modes of action, toxicity and possible strategies for increasing patient tolerance. Br J Dermatol 1993;129:507-13.   Back to cited text no. 10
    
11.
Kaplan JC, Chirouze M. Therapy of recessive congenital methaemoglobinaemia by oral riboflavine. Lancet 1978;2:1043-4.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1]


This article has been cited by
1 A case of dapsone-induced methaemoglobinaemia
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Clinical Medicine. 2020; 20(5): 519
[Pubmed] | [DOI]



 

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