Dapsone-induced Methemoglobinemia in a Patient of Leprosy.

Sir,

Methemoglobinemia is a rare possible diagnosis when patients present with cyanosis and other features of hypoxia that are unrelated to cardiopulmonary causes. Methemoglobinemia is usually symptomatic, when methemoglobin (metHb) levels are more than 15% of the total hemoglobin (Hb) value.[1]

A 22-year-old man presented to our hospital with complaints of exertional dyspnea, headache, and cyanosis of 3 days duration. He was on dapsone-based (100 mg OD) multi-drug therapy for Hansen's disease (borderline tuberculoid) since 6 months. He had no history of orthopnea, chest pain, palpitations, cough, syncope, weight loss, edema, hemoptysis, or exposure to chemicals. His past history was negative for heart disease, pulmonary disease, or similar complaints. The patient had central [Figure 1] and peripheral cyanosis, normal vital signs, and SO2 value of 85% by pulse oximetry. Radial artery and venous blood [Figure 2] was dark colored. Arterial blood gas (ABG) analysis revealed the following values: PH - 7.44, PCO2 - 39.8 mmHg, PO2 - 147.5 mmHg, oxygen saturation (SO2) - 99%, Hb - 15 gm/dL, H+ - 36 nmol/L, Na+ - 141 mmol/L, Ca2+ - 7.4 mmol/L, Cl− - 95 mmol/L, and HCO3 - 26.5 mmol/L. All other relevant hematological, biochemical, and radiological parameters were within normal limits. Patient was administered 100% O2 inhalation for initial 2 days, but there was no improvement in cyanosis and SO2 by pulse oximetry remained 85%. Repeat ABG revealed almost same values. He was given oral vitamin C (500 mg/day) and observed thereafter. There was a gradual increase in SO2 level with value of 90% a week later and 99% after 2 weeks. Patient was asymptomatic, no cyanosis was evident [Figure 3], and there was change in color of venous blood by this time [Figure 4]. Dapsone was discontinued since the date of hospitalization.

Figure 1

Central cyanosis at presentation

Figure 2

Chocolate-brown colored venous blood at presentation

Figure 3

Complete resolution of cyanosis after 2 weeks

Figure 4

Normalization of venous blood color after 2 weeks

Methemoglobin is formed by oxidation of the heme iron of hemoglobin to the ferric state. Methemoglobin has very high oxygen affinity and virtually no oxygen is delivered to the tissues. Methemoglobinemia may be congenital or acquired. Congenital methemoglobinemia arises from mutations that stabilize iron in the ferric state (e.g., HbM Iwata (α87His→Tyr)) or from mutations that impair the enzymes that reduce methemoglobin to hemoglobin (e.g., methemoglobin reductase, NADP diaphorase), and manifest early in life.[2]

Many pharmacological agents and toxins have propensity to cause methemoglobinemia [Table 1]. The time of onset of symptoms and duration depend on the agent and its concentration. For many agents, the onset is within hours, but is delayed for others such as dapsone and nitroethane. Cyanotic discoloration of skin due to dark-colored methemoglobin is typically observed at levels greater than 15% and is often one of the earliest clinical manifestations. As methemoglobin levels rise, severity of signs and symptoms increases [Table 2].[3]

Table 1

Agents causing methemoglobinemia

Table 2

Methemoglobin concentrations and symptoms

Dapsone is metabolized in the liver by N-acetylation and N-hydroxylation. Dapsone hydroxylamine is a strong oxidant and responsible for inducing methemoglobinemia. Dapsone induced methemoglobinemia is not related to G6PD activity and significant variation in magnitude of clinical manifestation is observed.[4]

In patients presenting with cyanosis and symptoms of hypoxia, blood oxygen level is determined by the pulse oximetry derived SO2 and the ABG derived PO2 and SO2. Pulse oximetry measures the relative absorbance of two wavelengths of light (660 and 940 nm), that correspond to the absorption of oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb), respectively. Although metHb absorbance at 660 nm is similar to that of HHb, metHb absorbance at 940 nm is markedly greater than that of either HHb or O2Hb. This leads to falsely low value of SO2. The ABG derived PO2 reflects dissolved plasma oxygen content. The PO2 may remain within the normal range in patients of methemoglobinemia. The SO2 measured by ABG analysis is calculated from the blood pH, the PO2, and the standard Hb oxygen dissociation curve. Hence, the SO2 measured by ABG analysis may be falsely elevated. Clue to the diagnosis of methemoglobinemia is the presence of a saturation gap, the difference between the SO2 measured by ABG analysis and pulse oximetry. Typically, this saturation gap is greater than 5% in cases of methemoglobinemia.[56]

CO-oximetry is the appropriate method for detecting and measuring metHb level. The CO-oximeter measures light absorbance of different wavelengths that correspond to the absorption characteristics of HHb, O2Hb, carboxyhemoglobin, and metHb; providing a more accurate measurement of SO2.[7]

Intravenous injection of methylene blue at an initial dose of 1-2 mg/kg (0.1-0.2 mL/kg of a 1% solution) is effective for emergency therapy. Milder cases and follow up of severe cases can be treated orally with methylene blue (60 mg three to four times each day) or ascorbic acid (300-600 mg/day).[8] Ascorbic acid decreases oxidative stress, protecting RBC from hemolysis and also reduces methemoglobin formation.[9]

As dosage of Dapsone in leprosy treatment usually does not produce significant methemoglobinemia, clinician must be aware of this adverse effect for safely using Dapsone in practice.