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A 25-year-old man presented with bluish discoloration of body, lips and nails since birth. He denied any other significant complaints. General examination revealed presence of central cyanosis with steel-grey complexion of the body. He did not have clubbing of nails. Systemic examination was unremarkable. Investigations showed a haemoglobin of 17.2 g/dl and a normal blood chemistry. The arterial blood gas analysis while the patient was breathing room air revealed a PaO2 of 100.9 mmHg and an oxygen saturation of 97.8%.
- What is the probable diagnosis?
- What are the common causes of central cyanosis?
- How would you approach a patient with central cyanosis?
- What is the appropriate management in the present case?
As this patient had central cyanosis since birth and was asymptomatic, the probable diagnosis is congenital methaemoglobinaemia. This diagnosis is supported by a normal arterial blood gas analysis.
A number of cardiac and pulmonary diseases can produce central cyanosis (box FB1). Rarely, central cyanosis is produced by disorders of haemoglobin.
Duration of cyanosis (cyanosis present since birth is usually due to congenital heart disease or methaemoglobinaemia), symptoms related to cardiovascular and pulmonary systems, and exposure to drugs or chemicals that may produce methaemoglobinaemia are important points in the history of a patient who presents with central cyanosis. Central cyanosis should be differentiated from peripheral cyanosis, as the tongue is spared in the latter condition. Clubbing, and any abnormality in cardiac and pulmonary systems should be looked for. Clubbing with cyanosis is present in patients with congenital cyanotic heart diseases, and occasionally in patients with pulmonary diseases such as lung abscess or pulmonary arteriovenous shunts. Chest radiograph, electrocardiograph and echocardiograph may be obtained if there are any suggestions of pulmonary or cardiovascular diseases on history and examination. If there is no evidence of cardiopulmonary disease, a diagnosis of methaemoglobinaemia should be considered.
Pulse oximetry may be helpful in detecting methaemoglobinaemia. Pulse oximeter meas-ures the light absorbance changes by arterial pulsations at only two wavelengths, one in the red (660 nm) and the other in the near infrared (940 nm) range. Methaemoglobin has a high absorbance at both wavelengths, tending to drive the ratio of absorbance toward 1, which corresponds to an oxygen saturation of nearly 85%. Hence, with a high level of methaemoglobin in the blood, pulse oximeter readings will tend to be around 85%. In contrast, the saturation as reported on an arterial blood gas is a calculated value based on the partial pressure of dissolved oxygen and assumes no abnormal haemoglobin is present. Therefore, the reported oxygen saturation from the laboratory is generally higher than that measured with a pulse oximeter.1 2 This difference is called the saturation gap and is typically more than 5% in patients with methaemoglobinaemia. Qualitative confirmation of methaemoglobinaemia is done by blood spectrophotometry. Once confirmed, electrophoresis of haemoglobin and estimation of methaemoglobin reductase are required to diagnose the cause of methaemoglobinaemia.
In the present case, the oxygen saturation measured by pulse oximetry was 90%, and the oxygen saturation gap 7.8%. Spectrophotometry of the haemolysate of the patient's blood revealed a methaemoglobin band at 630 nm. On quantification estimation, methaemoglobin was found to be 30%. Electrophoresis of the haemoglobin revealed no abnormal haemoglobin. Estimation of NADH-cytochrome b5 reductase could not be done due to the lack of laboratory facilities.
The patient was given ascorbic acid tablets (500 mg) twice daily and cyanosis disappeared within a week; it reappeared on cessation of the treatment. However, since the patient was clinically asymptomatic, no further treatment was given and the patient was reassured.
Methaemoglobinaemia is a clinical condition in which more than 1% of haemoglobin is oxidised to methaemoglobin. It manifests as cyanosis when levels of methaemoglobin are more than 10% (1.5 g/dl). Presence of cyanosis from birth without clubbing distinguishes this condition from congenital cyanotic disease.
Methaemoglobin results when the normally reduced ferrous iron in the heme molecule is oxidised to the ferric state. This oxidation results in an inability of the heme molecule to reversibly bind oxygen. Normally, the ferrous iron of haemoglobin is oxidised slowly to methaemoglobin at a rate of about 3% per day. Under physiologic conditions, the red cell can reduce methaemoglobin back to haemoglobin by the action of NADH-cytochrome b5 reductase (methaemoglobin reductase).3 This reaction utilises flavin-containing cytochrome b5 as an electron-carrying intermediate between NADH (derived from glycolysis) and methaemoglobin as shown below: NADH + (Ox) cyto b5 (Fe3+) → NAD + (R) cyto b5 (Fe2+) (R) cyto b5 (Fe2+) + metHb (Fe3+) → (Ox) cyto b5 (Fe3+) + Hb (Fe2+)
Besides the major cytochrome b5 reductase enzyme system, minor pathways to reduce methaemoglobin into haemoglobin are also present in the body. NADPH-methaemoglobin reductase reduces flavin in the presence of NADPH, and reduced flavin further reduces methaemoglobin. This reductase is not essential and is probably responsible for only 5% of methaemoglobin reduction.3 This enzyme, however, is important in patients with hereditary methaemoglobinaemia since it reduces methaemoglobin rapidly in the presence of methylene blue. In addition to these enzymatic pathways, ascorbic acid and glutathione can reduce methaemoglobin directly but quantitatively are not very important, accounting for a very small amount of the methaemoglobin reduction.
Methaemoglobinaemia may be hereditary or acquired (box FB2). Hereditary methaemoglobinaemia is a very rare condition. It has been reported among Navajo and Alaskan Indians, Cubans, Puerto Ricans, North Africans, Arabs, Hindus, Chinese, Japanese, Siberians and African-Americans.4 Around 500 cases of inherited methaemoglobinaemia have been reported in the literature, and most of the reports are descriptions of sibships derived from inbred populations. Hereditary methaemoglobinaemia is due to either the enzyme deficiency or an abnormality of haemoglobin in molecular structure, ie, haemoglobin M and unstable haemoglobins. Very rarely, it can occur due to deficiency of cytochrome b5 itself. Hereditary methaemoglobinaemia due to the deficiency of NADH-cytochrome b5 reductase is an autosomal recessive disorder. Therefore, patients who are heterozygotes for the deficiency of cytochrome b5 reductase do not have any cyanosis as the enzyme activity is approximately 50%. Patients homozygotes for the enzyme deficiency are usually asymptomatic except for central cyanosis. These patients have normal life expectancy unless the methaemoglobin level is above 35–40%. Clinically, three phenotypes have been reported.5 Type I is a red cell type with mild cyanosis due to deficiency of cytochrome b5 reductase in red cells only. Type II is known as a generalised type with deficiency of the enzyme in various tissues resulting in severe cyanosis and mental retardation with other neurologic features. Type III is a haematopoietic phenotype with deficiency of the enzyme in red cells, leukocytes and platelets, without mental retardation. Patients with haemoglobin M are cyanotic but otherwise asymptomatic. Cyanosis may appear at birth or later in life depending upon the subunit of haemoglobin affected by mutation. In haemoglobin M, methaemoglobin is relatively resistant to the reducing system of the red cell. Some patients with unstable haemoglobin variants show an elevated level of methaemoglobin. However, methaemoglobinaemia does not contribute significantly to the clinical picture, since red cell haemolysis is dominant. Methaemoglobinaemia in these patients occurs when they are exposed to any oxidative stress.3
Acquired methaemoglobinaemia is caused by a wide variety of drugs and toxins (box FB2) that result in direct oxidation of the ferrous ion in the heme.6 7 Infants below the age of 4 months are more susceptible to acquired toxin-induced methaemoglobinaemia due to a lower concentration of NADH cytochrome b5 reductase.
Manifestations of methaemoglobinaemia are purely the result of a decreased oxygen-carrying capacity of the blood and depend on the concentration of methaemoglobin in blood (table). Symptoms due to hypoxia appear only if methaemoglobin levels in blood increase above 35%. Patients with methaemoglobinaemia may manifest tachycardia, headache, dizziness, weakness, slate-blue colour, and terminally coma and death.7
The diagnosis of methaemoglobinaemia is based largely on history (including exposure to drugs and toxins), the characteristic central cyanosis unresponsive to oxygen administration, a normal PaO2, and a normal calculated oxygen saturation with a reduced measured oxygen saturation. A simple bedside test may be used to differentiate methaemoglobinaemia from cyanosis due to other causes. Dark-coloured blood from patients with cardiac or pulmonary disorders brightens rapidly after shaking in air. On the other hand, in methaemoglobinaemia, the blood remains dark-coloured even on shaking. Blood from patients with sulphaemoglobinaemia also remains dark on exposure to air, but this condition is very rare.
Patients with methaemoglobinaemia who have cyanosis and systemic manifestations need to be treated. In severe cases, intravenous methylene blue is required. Methylene blue is reduced to leucomethylene blue by NADPH. In turn, leucomethylene blue reduces methaemoglobin to haemoglobin. The recommended dose is 1–2 mg/kg of 1% solution administered over 5 minutes and the same dose may be repeated in one hour if symptoms of hypoxia persist.7 Cumulative doses of methylene blue exceeding 7 mg/kg may cause dyspnoea, chest pain, tremor, cyanosis and haemolysis. As the efficacy of methylene blue depends on adequate amounts of NADPH, care should be taken to exclude glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methylene blue can produce methaemoglobinaemia in patients who are G6PD deficient. Due to its slow action, ascorbic acid is not recommended as the only method of treatment in toxic methaemoglobinemia. Exchange transfusion may be required in severe cases not responding to methylene blue, when G6PD deficiency precludes use of methylene blue, or in case of aniline poisoning. Since patients with congenital NADH-cytochrome b5 reductase deficiency are usually asymptomatic except for cyanosis, no treatment is indicated; however, for cosmetic purposes, ascorbic acid may be administered. It has a direct reducing action on methaemoglobin. Reduction of cyanosis is appreciated clinically about 9 to 10 days after therapy with ascorbic acid.8 No treatment is available for methaemoglobinaemia due to M haemoglobins.
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