|Year : 2011 | Volume
| Issue : 4 | Page : 543-545
Blue cures blue but be cautious
Pranav Sikka1, VK Bindra2, Seema Kapoor3, Vivek Jain4, KK Saxena1
1 Department of Pharmacology, LLRM Medical College, Muradnagar (Ghaziabad), India
2 Department of Medicine, IDST, Muradnagar (Ghaziabad), India
3 Departments of Oral Pathology and Microbiology, ITS- CDSR, Muradnagar (Ghaziabad), India
4 Consultant dermatologist, Lokpriya Hospital, Meerut, Uttar Pradesh, India
|Date of Submission||09-Feb-2011|
|Date of Decision||11-Apr-2011|
|Date of Acceptance||14-May-2011|
|Date of Web Publication||23-Nov-2011|
Department of Pharmacology, LLRM Medical College, Muradnagar (Ghaziabad)
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Methemoglobinemia is a disorder characterized by the presence of >1% methemoglobin (metHb) in the blood. Spontaneous formation of methemoglobin is normally counteracted by protective enzyme systems, for example, nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase. Methemoglobinemia is treated with supplemental oxygen and methylene blue (1-2 mg/kg) administered slow intravenously, which acts by providing an artificial electron acceptor for NADPH methemoglobin reductase. But known or suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency is a relative contraindication to the use of methylene blue because G6PD is the key enzyme in the formation of NADPH through pentose phosphate pathway and G6PD-deficient individuals generate insufficient NADPH to efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the NADPH-dependent methemoglobin reductase system. So, we should be careful using methylene blue in methemoglobinemia patient before G6PD levels.
Keywords: G6PD deficiency, methemoglobinemia, methylene blue
|How to cite this article:|
Sikka P, Bindra V K, Kapoor S, Jain V, Saxena K K. Blue cures blue but be cautious. J Pharm Bioall Sci 2011;3:543-5
Glucose-6-phosphate dehydrogenase (G6PD) is a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency, an X-linked recessive hereditary disorder, is the most common human enzyme defect.  Although the exact prevalence of G6PD deficiency in India is not known, various studies have reported its prevalence ranging from 2% to 27.9% in different communities.  In India the most common mutation is the G6PD Mediterranean (563 C→T) seen in the Vatalia Prajapatis of North India and the Parsis.  The other two mutations commonly found in India are the G6PD Kerala-Kalyan mutation (949 G→A) reported from Maharashtra, Kerala, Andhra Pradesh, Tamil Nadu, and Punjab; and the G6PD Orissa (131 C→G) found in the tribals of central, eastern, and southern India. G6PD Chatham (1003 G→A) with undetected red cell enzyme activity and G6PD Insuli [a variant of G6PD](989 G→A) with normal G6PD activity are very rare in the Indian population. Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of oxidative stresses. A young male patient presented with clinical features of G6PD deficiency and was having Methemoglobinemia as well. Methemoglobinemia is usually treated with methylene blue but known or suspected G6PD deficiency is a relative contraindication to the use of methylene blue.  Therefore, Methylene blue is not the ideal mode of treatment in G6PD-deficient patients, since it can worsen the condition of the patient by increasing hemolysis. Thus, it is necessary to assess any G6PD deficiency before methylene blue administration.
| Case Report|| |
A 14-year-old boy presented to the emergency of a renowned hospital in Meerut (U.P., India) with the chief complaints of fever, jaundice[Figure 1]a, dark urine [Figure 2]a, and pain in the upper abdomen for the previous 2 days. Four days earlier, he was detected positive for malaria and was prescribed chloroquine (600 mg) and primaquine (15 mg) for the same.
|Figure 1: (a) Icterus before treatment; (b) normal skin color after treatment|
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|Figure 2: (a) Cola colored urine before treatment; (b) normal amber colored urine after treatment|
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There was no history of headache, vomiting, cough, dyspnea, chest pain, edema, palpitations, oliguria, or bleeding. He had no past history of cyanosis, jaundice, anemia, dyspnoea, deep vein thrombosis, pain in abdomen, neurologic deficit, or any renal disease. No significant family history was found.
General examination revealed no abnormal findings except pulse rate of 104/min, pallor and icterus with mild cyanosis. SpO 2 of 75% was observed (without O 2 therapy).
Hematologic examination detected hemoglobin-6.8 gm%, total leukocyte count-17,000 (N 84 L 12 E 03 M 01 B 0 ), reticulocyte count-18%, urea-110 mg/dL, serum creatinine-4.5 μg/dL, bilirubin (total)-9 mg/dL, direct-2.6 mg/dL, indirect-6.4 mg/dL, lactate dehydrogenase (LDH)-3125 U/L, serum glutamic-oxaloacetic transaminase (SGOT)-180 U/L, and serum glutamic-pyruvic transaminase (SGPT)-78 U/L. Serum alkaline phosphatase, albumin, and electrolyte levels were normal. Urine analysis showed dark brown color with turbidity and alkaline pH, microscopy was almost normal but biochemically, albumin was ++++. Arterial blood gas (ABG) analysis showed pH of 7.39, pCO 2 = 29.0 mmHg, pO 2 = 179 mm Hg, and O 2 saturation = 99.6%. Viral serology for hepatitis A, B, and C virus was negative. Electrocardiogram showed only sinus tachycardia. Radiologic examination revealed a normal chest. Ultrasonography (bedside) of the whole abdomen showed hepatosplenomegaly and gall bladder sludge. Most notable finding of general blood picture (GBP) was the presence of BITE cells [Figure 3], which lead to suspicion of G6PD enzyme deficiency.
|Figure 3: Peripheral blood smear (100×) showing bite cells (red and blue arrows) and Heinz bodies (black arrow)|
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Thus, there were enough findings to clinically diagnose G6PD deficiency, such as history of primaquine intake, dark urine, indirect positive jaundice, high LDH, high reticulocyte count, hemoglobinuria and most important, bite cells on GBP.
Apart from this, another finding was that the saturation gap, that is, SpO 2 (by pulse oximeter) was 75% and SaO 2 (by ABG) was 99.6% with pO 2 = 179 mmHg. SpO 2 did not even improve on O 2 therapy. Thus, methemoglobinemia was suspected. Furthermore, blood examination showed a chocolate brown color [Figure 4]. Co-oximetry, which is a diagnostic test for methemoglobinemia, showed methemoglobin level of 3.7% (normal range is 0.4%-1.0%).
|Figure 4: Normal blood color compared with chocolate brown color of blood in methemoglobinemia patient|
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Clinical hints for methemoglobinemia were history of primaquine intake, saturation gap, normal pO 2 , chocolate brown blood, no change in the color of blood on exposure to air (unlike deoxyhemoglobin).
Such patients are required to be treated with Methylene blue 1-2 mg/kg body weight intravenously, however, due to G6PD deficiency, the only mode of treatment left was either blood transfusion or exchange transfusion. 
Finally, exchange transfusion was done with four units of whole blood and the patient responded positively [Figure 1]b and [Figure 2]b.
Now, 3 months have elapsed after the treatment, and the patient is on a regular follow-up and doing well. His hemoglobin in last report was 13.2 gm% and peripheral blood smear showed only mild reticulocytosis.
| Discussion|| |
G6PD deficiency is an X-linked recessive hereditary disease. It is the most common human enzyme defect, being present in more than 400 million people worldwide.  G6PD is a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of causes, most commonly infection or exposure to certain medications or chemicals (oxidants). G6PD is the rate-limiting enzyme of this metabolic pathway that supplies reducing energy to cells by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the supply of reduced glutathione in the cells that is used to mop up free radicals that cause oxidative damage. The G6PD/NADPH pathway is the only source of reduced glutathione in red blood cells. The role of red cells as oxygen carriers puts them at a substantial risk of damage from oxidizing free radicals except for the protective effect of G6PD/NADPH/glutathione. People with G6PD deficiency are therefore at risk for hemolytic anemia in states of oxidative stress.
Methemoglobinemia is a disorder characterized by the presence of >1% methemoglobin (metHb) in the blood.  Methemoglobin, an oxidized form of hemoglobin (contains Fe 3+ in place of Fe 2+ in Hb),  has slightly greater affinity for oxygen due to its chemical structure, thus shifting the oxygen dissociation curve to the left, resulting in decreased release of oxygen in tissues. Spontaneous formation of methemoglobin is normally counteracted by protective enzyme systems, for example, NADH methemoglobin reductase (cytochrome-b5 reductase) (major pathway), NADPH methemoglobin reductase (minor pathway)  and to a lesser extent the ascorbic acid and glutathione enzyme systems. Methemoglobinemia can be treated with supplemental oxygen and methylene blue, which acts by providing an artificial electron acceptor for NADPH methemoglobin reductase.
However, known or suspected G6PD deficiency is a relative contraindication to the use of methylene blue. G6PD-deficient individuals generate insufficient NADPH to efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the NADPH-dependent methemoglobin reductase system. G6PD-deficient individuals are also prone to methylene blue-induced hemolysis. Methylene blue may also add to oxidative hemolysis. Moreover, in the presence of hemolysis, high-dose methylene blue can itself initiate methemoglobin formation. ,
| Conclusion|| |
Methylene blue (BLUE) cures cyanosis (BLUE) of methemoglobinemia but we should be cautious about the presence of accompanying G6PD deficiency or else, it can be potentially hazardous to the condition of patient causing excessive hemolysis and sometimes, even leading to fatality.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]