Skip to Main Content


The dyshemoglobinemias are a constellation of disorders in which the hemoglobin molecule is functionally altered and prevented from carrying oxygen. The most clinically relevant dyshemoglobinemias are carboxyhemoglobin, methemoglobin, and sulfhemoglobin.1 Carboxyhemoglobin is created following carbon monoxide exposure and, because of its unique importance and prevalence, is usually considered an environmental emergency (see Chapter 217, Carbon Monoxide). The prevalence for methemoglobinemia and sulfhemoglobinemia is unknown, and presentation to the ED for symptoms related to one of these dyshemoglobinemias is uncommon.




Under normal circumstances, the iron moiety within deoxyhemoglobin exists in the ferrous (bivalent or Fe2+) form. Iron in this oxidation state avidly interacts with compounds seeking electrons, such as oxygen, and in the process is oxidized to the ferric (trivalent or Fe3+) state. On exposure to an oxidizing agent, iron donates an electron and transforms oxidation states from ferrous to ferric. Hemoglobin in the ferric form is unable to bind oxygen and is termed methemoglobin.2–4 Under normal circumstances, <1% to 2% of circulating hemoglobin exists as methemoglobin and accumulation of higher concentrations defines the condition of methemoglobinemia.


Accumulation of methemoglobin is enzymatically limited by the rapid reduction of the ferric iron back to the ferrous form. The enzyme cytochrome b5 reductase is primarily responsible for this reduction, in which reduced nicotinamide adenine dinucleotide (NADH) donates its electrons to cytochrome b5 that subsequently reduces methemoglobin to hemoglobin.5 In this process, oxidized nicotinamide adenine dinucleotide is regenerated (Figure 201-1). This pathway is responsible for reducing nearly 95% of methemoglobin produced under typical circumstances. Methemoglobinemia occurs only when this enzymatic reduction is overwhelmed by an exogenous oxidant stress, such as a drug or chemical agent (Table 201-1).

Figure 201-1.
Graphic Jump Location

Pathophysiology of methemoglobin formation and mechanism of action of methylene blue. G6PD = glucose-6-phosphate dehydrogenase; Hb(Fe2+) = hemoglobin; Hb(Fe3+) = methemoglobin; MetHb = methemoglobin; NAD+ = oxidized nicotinamide adenine dinucleotide; NADH = reduced form of nicotinamide adenine dinucleotide; NADP+ = nicotinamide adenine dinucleotide phosphate; NADPH = reduced form of nicotinamide adenine dinucleotide phosphate; PO4 = phosphate.

Table Graphic Jump Location
Table 201-1 Drugs Commonly Implicated in Patients with Methemoglobinemia

A second enzymatic pathway uses the reduced form of nicotinamide adenine dinucleotide ...

Want remote access to your institution's subscription?

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.


About MyAccess

If your institution subscribes to this resource, and you don't have a MyAccess profile, please contact your library's reference desk for information on how to gain access to this resource from off-campus.

Subscription Options

AccessMedicine Full Site: One-Year Subscription

Connect to the full suite of AccessMedicine content and resources including more than 250 examination and procedural videos, patient safety modules, an extensive drug database, Q&A, Case Files, and more.

$995 USD
Buy Now

Pay Per View: Timed Access to all of AccessMedicine

24 Hour Subscription $34.95

Buy Now

48 Hour Subscription $54.95

Buy Now

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.