Methemoglobinemia

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Introduction0:00–0:12

Methemoglobinemia is a disorder characterized by elevated levels of methemoglobin in the blood, which leads to tissue hypoxia.
Normally, our red blood cells are loaded with millions of copies of a protein called hemoglobin. Each hemoglobin protein is made of four globin subunits, each with an iron containing heme group.

Physiology0:12–2:24

Oxygen can bind to the iron molecule, so each hemoglobin molecule can bind four molecules of oxygen. The iron molecules, called ferrum in latin, are usually in the ferrous state, which means that the iron atom has lost two electrons to form Fe2+.
When iron is in the ferrous state, it can bind oxygen easily when it reaches the lungs, and release oxygen easily when it reaches the other tissues in the body that need oxygen.
Now, methemoglobin is an oxidized form of hemoglobin, and is normally spontaneously formed in our blood in small amounts.
In methemoglobin, one of the iron molecules is in the ferric state, which means that the iron atom has lost three electrons, instead of two, to form Fe3+.
The heme with the Fe3+ is like the lazy co-worker with a decreased ability to bind oxygen. The other three heme groups still have iron in the Fe2+ state, and they try to compensate for the slacker by binding to oxygen more tightly.
However, this ends up being more harmful than helpful, as it prevents them from releasing oxygen to the tissues. Too much methemoglobin can eventually lead to tissue hypoxia, so in order to protect ourselves, we have a few enzyme systems that convert methemoglobin to normal hemoglobin.
The most important one is cytochrome b5 reductase, also known as methemoglobin reductase, because it uses a NADH as a reducing agent to donate electrons to an iron in the Fe3+ state and reduces it to the Fe2+ state.
So it’s like the boss that comes by to make the lazy heme productive again. This enzyme is found in red blood cells and other cells like neutrophils, and helps to keep the level of methemoglobin in our blood very low, approximately 1% of total hemoglobin.
OK, but if the function of these enzyme systems is disrupted, methemoglobin levels get higher than normal, and we call this condition methemoglobinemia.

Pathology2:24–3:19

Methemoglobinemia can be congenital or acquired. In congenital methemoglobinemia, there’a a problem with the synthesis of cytochrome b5 reductase.
Two main types of congenital methemoglobinemia exist and both are inherited in an autosomal recessive pattern. In type I, which is the most common type, cytochrome b5 reductase is absent only in red blood cells, and methemoglobin levels typically range from 10-35%.
Type II methemoglobinemia is much more severe because cytochrome b5 reductase is absent in every cell in the body, and methemoglobin levels are much higher than 35%.

Acquired methemoglobinemia3:19–4:08

Now, acquired methemoglobinemia is much more common than the congenital form. They are caused by exposure to certain substances, for example: Local anesthetics like benzocaine; dapsone, which is used for the treatment of leprosy; and nitrates or nitrites.
These substances act as oxidants, and therefore increase the production of the oxidized form of hemoglobin, or methemoglobin.
This excessive production of methemoglobin can overwhelm cytochrome b5 reductase and the other enzyme systems that normally reduce methemoglobin.
So in congenital methemoglobinemia there’s a lack of boss enzymes, while in acquired methemoglobinemia certain substances, like medications, create more slacker heme groups.

Congenital methemoglobinemia4:08–6:27

The risk for methemoglobinemia increases if there is a family history of methemoglobinemia. Also, acquired methemoglobinemia is more common among infants because fetal hemoglobin is oxidized more easily and they have lower levels of cytochrome b5 reductase.
Alright, now patients with type I congenital methemoglobinemia have cyanosis, which means that their skin takes on a bluish discoloration due to the hypoxia, but are otherwise asymptomatic.
However, type II congenital methemoglobinemia presents with developmental delay and severe neurological symptoms, which are usually fatal in the first year of life.
Acquired methemoglobinemia presents acutely, and symptoms depend on the level of methemoglobin produced. If methemoglobin levels reach 15%, the first symptom we have is cyanosis in the skin and oral mucosa.
As levels rise above 15%, organs with high oxygen demands, like the central nervous system and the cardiovascular system, start to manifest symptoms of hypoxia.
Typical symptoms from the central nervous system include headache; mental status alterations, like confusion or syncope; seizures; and even coma.
Cardiovascular symptoms include dyspnea, heart palpitations, chest pain, cardiac arrhythmias, and myocardial infarction.
Levels that are higher than 70% are usually fatal. Unfortunately, methemoglobinemia can be fatal.
But surprisingly, methemoglobinemia can be induced to treat other fatal conditions. For example, when someone has cyanide poisoning, the cyanide molecules bind and inhibit cytochrome c oxidase, a protein that is necessary for ATP synthesis.
Without ATP, the cells are unable to do their metabolic activities and that leads to cell death. Now as an antidote, we give nitrites that induce the production of methemoglobin, which has a higher affinity for cyanide, so methemoglobin binds to these toxic molecules before they can bind to the cytochrome c oxidase enzymes.
Alright, for diagnosis, people with methemoglobinemia will often have cyanosis. A fresh blood sample will show a characteristic unhealthy, bluish, chocolate-brown color; instead of the normal healthy red.

Diagnosis6:27–7:11

They have normal partial pressure of oxygen, which means there’s a normal amount of oxygen in the blood. Pulse oximetry, which shows the percentage of hemoglobin bound to oxygen, can be decreased, but this test is not very reliable.
The most accurate test to confirm the diagnosis is a multiple wavelength co-oximeter, which is a blood gas analyzer that measures methemoglobin as a percentage of the total hemoglobin concentration in the blood sample.

Treatment7:11–7:44

Now, management of patients with congenital methemoglobinemia is focused on avoiding agents that can further induce the production of methemoglobin.
Acquired methemoglobinemia is considered a medical emergency, and the mainstay of treatment is supplemental oxygen, along with intravenous methylene blue.
Methylene blue is a dye that reduces the iron in methemoglobin back to its ferrous state, so it converts methemoglobin to normal hemoglobin.
Alright, as a quick recap. Methemoglobinemia is a condition characterized by increased levels of methemoglobin, and leads to tissue hypoxia.

Review7:44–8:31

Methemoglobin is an oxidized form of hemoglobin, which means that one of the iron molecules is in the ferric state, instead of the ferrous state.
Methemoglobinemia can be congenital, where there’s decreased levels of cytochrome b5 reductase; or acquired, after exposure to an oxidant substance.
Symptom includes cyanosis, neurological, and cardiovascular symptoms. Treatment for the acquired form includes methylene blue and supplemental oxygen, while management of the congenital form focuses on avoiding oxidants.