The color of our blood can tell on us. What it relays can sometimes be devastating.
At a time when we knew nothing of the secrets hidden in the structure of DNA, nobody could have foreseen what it meant when Martin Fugate, an orphan, who like many left France for a better life in America met Elizabeth Smith and married her to start a family on the Kentucky frontier.
Nowadays a simple qualitative test performed in hospitals can help diagnose whether body tissues are supplied with enough oxygen. Depending on the underlying cause there may be no treatment. If freshly collected venous blood does not turn red but remains brown when compared to an apparently healthy control, methemoglobinemia is indicated. When such suspicion falls, arterial oxygen saturation can be quantified by pulse oximetry and blood gas analysis.
If this saturation is severely decreasing, it begins to show on us. Often the most prominent symptom of methemoglobinemia is cyanosis, a blue-purplish skin discoloration, mostly on lips and extremities. Affected body parts lack oxygenation, which results when circulating blood is carrying too much methemoglobin (MetHb). In this conformation the heme iron occurs as a ferric (Fe3+) instead of a ferrous (Fe2+) ion. The changed oxidation state prevents oxygen from binding and thus being distributed throughout the organism. Left untreated the blood’s reduced oxygen-binding capacity can lead to death.
Ironically, a minimal fraction of total hemoglobin always exists as methemoglobin. Its concentration is kept low by cytochrome-b5 reductase activity. The essential function of this enzyme is captured in one of its synonyms, methemoglobin reductase. In chemical terms this translates to a reduction of methemoglobin back to hemoglobin, thereby keeping tolerable methemoglobin levels within red blood cells. This mechanism keeps a check on naturally-occurring deoxygenated blood.
Medical literature lists non-genetic causes that tip the physiological balance in erythrocytes. Manifesting as acute or chronic condition this typically follows exposure to oxidizing drugs, oxidants in food and the environment such as nitrites, lidocaine, quinine or dapsone. The metabolic imbalance is acquired, and treatment can reverse the toxic accumulation of the dysfunctional hemoglobin form, as it does not participate in the regular oxygen transport cycle. In these cases, identifying and removing the oxidizing agent generally turns out to be effective in self-regulating MetHb levels. However, if the latter ones were elevated higher than 30% of total hemoglobin, more therapeutic intervention might be required.
Though rare, methemoglobinemia can be hereditary due to gene defects either affecting the natural clearance of methemoglobin or altering the hemoglobin structure, which impedes the conversion to a ferrous state. For these cases limited or no treatment options are available. Their management depends on the presenting clinical phenotype. When increasing blood oxygenation by suppling oxygen does not suffice; when the chemical conversion of methemoglobin fails by administering methylene blue, for example, one ultima ratio remains in intervention plans. For such a worst-case scenario only exchange blood transfusion could save a patient’s life.
By far the most famous case of inherited methemoglobinemia had been reported from the Appalachian Mountains of Kentucky. There the Fugate family settled in the early 19th century at the Troublesome Creeks. Its remoteness limited intermarrying with neighboring clans, which caused many descendants to carry on a recessive gene defect leading to methemoglobinemia. This condition became visible in their blue tinted skin. Luckily, once their settlement area got developed and connected to the rest of the Kentucky, gradually less “Blue Fugates” were seen.