How do blood gas parameters change?
The accumulation of methemoglobin causes hemic hypoxia.
- Oxygen-carrying capacity of blood (OCC) — ↓ (decreased). This is a hallmark feature of methemoglobinemia.
- $O_2$ content — decreased in both arterial ($CaO_2$) and venous ($C_v O_2$) blood. The arteriovenous oxygen difference ($C_{a-v} O_2$) also drops.
- $O_2$ partial pressure — in arterial blood ($P_a O_2$) and inspired air ($P_I O_2$) remains normal (N), but decreases in venous blood ($P_v O_2$).
- Oxygen saturation — with standard pulse oximetry, arterial oxygen saturation ($S_a O_2$) may appear normal, while venous saturation ($S_v O_2$) is reduced.
- Acid-base balance — metabolic acidosis develops (pH ↓). Hyperventilation occurs as a compensatory mechanism, causing arterial $CO_2$ partial pressure ($P_a CO_2$) to be normal or decreased.
What causes the formation of methemoglobin?
Chemical agents—methemoglobin inducers—provoke the conversion of hemoglobin into its inactive form.
- Nitrates and nitrites — ingested via contaminated well or spring water, vegetables, and cured meats or canned foods where sodium nitrite is used as a food additive. Nitrates are reduced to nitrites by gut microflora, which then oxidize heme iron.
- Medications — inorganic nitrites (vasodilators), local anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfonamides, including dapsone.
- Toxic impurities — illicit or adulterated substances may contain agents causing acute poisonings with methemoglobinemia.
How do erythrocytes reduce methemoglobin?
The formation of methemoglobin is reversible. Upon removal of the triggering factor, heme iron is converted back to its active form ($Fe^{2+}$). Erythrocytes rely on specific enzyme systems for this:
- Methemoglobin reductase (NADH-cytochrome b5 reductase) — reduces methemoglobin back to functional hemoglobin. The reaction requires $NADH$ as a coenzyme, which is generated during anaerobic glycolysis via glyceraldehyde-3-phosphate dehydrogenase.
- Antioxidant defense includes superoxide dismutase, catalase, and the glutathione system. The function of the glutathione system depends on $NADPH$, synthesized by glucose-6-phosphate dehydrogenase ($G6PD$) via the pentose phosphate pathway. $G6PD$ deficiency is frequently associated with drug-induced methemoglobinemia when taking dapsone.
Clinical and Diagnostic Significance
- Toxic cyanosis — bluish discoloration of the lips and skin accompanied by dyspnea. The presence of methemoglobin is considered a diagnosis of exclusion in central cyanosis when other causes are ruled out.
- Well-water methemoglobinemia — an endemic condition of biogeochemical origin. The greatest threat is to infants fed formula reconstituted with nitrate-rich water. Severe hypoxia can lead to death.
- MRI diagnostics — methemoglobin exhibits paramagnetic properties. This property is utilized in magnetic resonance imaging (MRI) to visualize hemorrhagic components, such as in chronic pancreatitis, where it produces a high-intensity signal.