Did you know there is a condition called blue person disease?

By Samuel Lux

Did you know here is a condition called blue person disease, and that there are families with skin “bluer than Lake Louise”?

Methemoglobinemia is a blood disorder in which an abnormal amount of methemoglobin — a form of hemoglobin — is produced. The disorder can be inherited (autosomal recessive) or caused by exposure to certain drugs and chemicals such as anesthetic drugs like benzocaine and xylocaine. There are two types of congenital cytochrome b5 reductase methemoglobinemia: type 1 with deficiency only in red cells where methemoglobinemia is the only consequence, and type 2 affecting the reductase in all cells, which is also accompanied by mental deficiency. 

There is a well known family from Kentucky, the Fugates, that has been called the “blue Fugates of Troublesome Creek”. A French orphan named Martin Fugate, settled in Troublesome Creek in 1820. He was heterozygous for the CYP5R3 gene, which encodes cytochrome b5 methemoglobin reductase that normally catalyzes a reaction that converts a type of hemoglobin with poor oxygen affinity, methemoglobin, back into normal hemoglobin by adding an electron. His wife, Elizabeth Smith, was also a carrier for this very rare disease, and four of their seven children were blue. After extensive inbreeding in the isolated community, a large pedigree of “blue people” of both sexes arose.

Painting of the Fugates in the early 80s by a local artist, Walter Spitzmiller.

Methemoglobin is a very high affinity hemoglobin so you would expect that the tightly bound oxygen would cause the patient to be pink not blue. But the oxidized iron (methemoglobin is Fe3+-Hb instead of Fe2+-Hb) changes the color of the hemoglobin so the oxidized form is brown instead of red (see figure below). So the “blue” cyanosis is slightly different than the cyanosis seen with deoxygenated (low affinity) hemoglobins. Brown blood is pathognomonic of methemoglobinemia. Nothing else produces that color. Also O2 doesn’t improve the color of patients with methemoglobinemia. 

The usual therapy in acquired methemoglobinemia (say from exposure to certain oxidant drugs like benzocaine) is methylene blue but that doesn’t work in patients with G6PD deficiency because the reductase that methylene blue uses to reduce methemoglobin requires NADPH and that is generated and replenished by G6PD. 

Interestingly, there are rare patients who are REALLY blue, or more accurately purple, like the famous Paul Karason, who was called Papa Smurf (died recently). But they don’t have methemoglobinemia, they have argyria from imbibing too much silver. 

Other rare causes of bluish skin are chromhidrosis and pseudochromhidrosis.