How Common is Methemoglobinemia?

Methemoglobinemia is relatively uncommon, with a prevalence of about 0.067% in cases reviewed in one study.

What are signs and symptoms of Methemoglobinemia?

Signs and symptoms of Methemoglobinemia include: - Difficulty breathing - Bluish color to the skin (cyanosis) - Low levels of oxygen in the blood (hypoxemia) that isn't improved with supplemental oxygen - Cyanosis (bluish skin) - Pale skin - Fatigue - Weakness - Headaches - Depression in the central nervous system - High levels of acid in the body (metabolic acidosis) - Seizures - Irregular heart rhythms - Coma - In severe cases, death The severity of these symptoms can vary greatly and depends on factors such as the amount of methemoglobin in the body, how quickly it has built up, the body's ability to remove it, and overall health status. The level of methemoglobin in the body is described as a percentage, and higher percentages may indicate a more severe illness. Health conditions that affect the body's ability to deliver oxygen, such as anemia, heart failure, or chronic obstructive pulmonary disease, can worsen the symptoms of Methemoglobinemia.

How do you get Methemoglobinemia?

Methemoglobinemia can be acquired through exposure to certain substances that cause oxidation of the hemoglobin, or it can be congenital due to genetic mutations in enzymes or proteins involved in hemoglobin production.

What else can Methemoglobinemia be?

The doctor needs to rule out the following conditions when diagnosing Methemoglobinemia: - Anemia - Asthma - Congestive heart failure - Cyanotic congenital heart disease (a heart defect present at birth) - Peripheral cyanosis (bluish discoloration of the skin, often affecting the hands or feet) - Polycythemia (an excess of red blood cells) - Sulfhemoglobinemia (a rare condition that affects red blood cell functionality) - Acrodermatitis enteropathica (a disorder causing skin rashes) - Amiodarone-induced skin pigmentation (skin discoloration caused by a specific medication) - Argyria (a skin condition caused by excessive exposure to chemical compounds of the element silver)

What kinds of test are needed for Methemoglobinemia?

To properly diagnose Methemoglobinemia, a doctor would order the following tests: 1. Blood gas test with co-oximetry: This test measures the different types of hemoglobin in the bloodstream to determine the concentration of methemoglobin, the problematic form of hemoglobin. 2. Pulse oximetry: Traditional pulse oximeters may not give accurate results in Methemoglobinemia. However, this test can still provide some information about oxygen levels in the blood. 3. Saturation gap measurement: This test compares the oxygen saturation levels measured by pulse oximetry (SpO2) and those measured directly from a blood sample (SaO2). A larger than normal gap can indicate the presence of abnormal forms of hemoglobin, including methemoglobin. It's important to note that these tests should be interpreted in conjunction with the patient's medical history and specific symptoms to confirm a diagnosis of Methemoglobinemia.

How is Methemoglobinemia treated?

The treatment for methemoglobinemia involves removing anything that could have caused it and considering the use of an antidote called methylene blue. High flow oxygen delivered through a non-rebreather mask can also be used to enhance the body's natural ability to break down methemoglobin. If methylene blue is necessary, it is typically used when methemoglobin levels exceed 20-30% or if the person is showing symptoms of the disease. Treatment decisions should be based on symptoms rather than waiting for lab result confirmations. In some cases, other options such as ascorbic acid, exchange transfusion, or hyperbaric oxygen therapy may be considered if methylene blue is not effective or cannot be used.

What are the side effects when treating Methemoglobinemia?

The side effects when treating Methemoglobinemia with methylene blue include: - Change in the color of urine to green or blue (harmless but startling) - Methemoglobinemia or hemolysis (breaking down of red blood cells), especially with high doses or if not properly broken down in the body - Increased risk of serotonin syndrome (restlessness and rapid heartbeat) in people taking certain medications - Newborn babies and pregnant individuals should be cautious due to sensitivity to agents that cause oxidation - In people with G6PD-deficiency, using methylene blue can be controversial but not strictly forbidden.

What type of doctor should I see for Methemoglobinemia?

A hematologist or a primary care physician.

Methemoglobinemia

What is Methemoglobinemia?

Methemoglobinemia is a serious health condition where the ability for the blood to transport oxygen is reduced. This occurs because some or all of the four types of iron in the blood change from a reduced form called ferrous [Fe2+] to an oxidized form called ferric [Fe3+]. Ferric iron, unfortunately, can’t carry and circulate oxygen in the body. Having high levels of methemoglobin, the oxidized form of iron, can cause a functional type of anemia, meaning your body doesn’t have enough oxygen circulating, which can be dangerous.

What Causes Methemoglobinemia?

Methemoglobinemia is a condition that can occur from birth (congenital) or develop later in life (acquired).

There are two genetic ways that someone can get congenital methemoglobinemia. One is due to a problem with the enzyme cytochrome b5 reductase (CYB5R). The other is due to mutations in the genes that create proteins called hemoglobins M. There are many types of hemoglobin M, each named after a different place, like Boston or Hyde Park.

Congenital methemoglobinemia itself also has two types. Type I happens when the CYB5R problem only appears in red blood cells. In type II, all cells have the CYB5R problem.

Hemoglobin M disease is when there are mutations near the heme iron part of the alpha or beta chains of hemoglobin. Heme iron is a substance that helps carry oxygen in the blood. These mutations can lead to the iron in hemoglobin getting too easily oxidized to a state known as ferric [Fe3+].

Acquired methemoglobinemia, which is more common, is caused by exposure to certain substances. These substances can cause oxidation of the hemoglobin, creating a type of hemoglobin called methemoglobin. The body is unable to change methemoglobin back to its normal state. This can happen from direct oxidizing agents like the local anesthetic agents benzocaine and prilocaine, indirect oxidation from compounds like nitrates, or metabolic activation from substances like aniline or dapsone. Some examples include exposure to benzocaine during endoscopy and infants who drink well water that contains nitrates.

Risk Factors and Frequency for Methemoglobinemia

Methemoglobinemia due to cytochrome b5 reductase deficiency is a very rare birth defect, and the exact number of people affected is unknown. It appears to be more common in certain ethnic groups such as Siberian Yakuts, Athabaskans, Eskimos, and Navajo. However, acquired methemoglobinemia, which develops later in life, is more common than the congenital (born with) form. It typically happens because of exposure to certain chemicals or from using certain types of anesthetics.

One study that reviewed nearly 30,000 heart ultrasounds found that methemoglobinemia occurred in about 0.067% of cases.
A separate review of cases found that an anesthetic called benzocaine was involved in two-thirds of local anesthetic-related methemoglobinemia cases.
Because of the high number of cases linked to benzocaine, the U.S. Food and Drug Administration (FDA) has issued several public warnings about the use of oral products containing benzocaine.

Signs and Symptoms of Methemoglobinemia

Methemoglobinemia is a medical condition that should be considered if you experience difficulty breathing, a bluish color to your skin (cyanosis), or low levels of oxygen in your blood (hypoxemia) that isn’t improved with supplemental oxygen. The symptoms can vary greatly – from barely noticeable to severe – and include cyanosis, pale skin, fatigue, weakness, headaches, depression in the central nervous system, high levels of acid in the body (metabolic acidosis), seizures, irregular heart rhythms, coma, and in severe cases, death.

The severity of these symptoms depends on many factors, including how much methemoglobin is in your body, how quickly it has built up, your body’s ability to remove it, and your overall health status. How long and how much you’ve been exposed to an oxidizing agent (something that can cause this condition) also play a part. The level of methemoglobin in your body is described as a percentage.

To better understand, think of the methemoglobin as a fraction of your total hemoglobin (a protein in your blood that carries oxygen). So, a higher percentage of methemoglobin might be a better sign of how severe the illness is compared to the overall concentration. Say, for instance, two people both have a methemoglobin concentration of 1.5 g/dL. In a healthy person with a total hemoglobin level of 15 mg/dL, this equates to 10%. In contrast, a person with anemia, who has a total hemoglobin level of 8 g/dL, this same concentration represents 18.75% – a much larger proportion of their total hemoglobin.

Furthermore, health conditions that affect your body’s ability to deliver oxygen – like anemia, heart failure, or chronic obstructive pulmonary disease – can worsen the symptoms of methemoglobinemia.

Even the healthiest person can observe cyanosis with as low as 10% of methemoglobin. The blood might appear “chocolate brown” at 15%. With levels reaching around 20%, it is common to experience anxiety, light-headedness, and headaches. Methemoglobin levels between 30-50% can result in rapid breathing, confusion, and loss of consciousness. At approximately 50%, there are risks of seizures, irregular heart rhythms, metabolic acidosis, and coma. Methemoglobinemia can be fatal if the level exceeds 70%.

The following is a summary of symptoms based on Methemoglobin level:

10% – Cyanosis (bluish skin)
15% – “Chocolate brown” blood
20% – Anxiety, light-headedness, headaches
30-50% – Rapid breathing, confusion, loss of consciousness
Around 50% – Risks of seizures, irregular heart rhythms, metabolic acidosis, and coma
Above 70% – Often fatal

Testing for Methemoglobinemia

Methemoglobinemia is a condition suspected based on a patient’s medical history and specific symptoms. A clear-cut sign includes difficulty in increasing the oxygen levels in the blood in spite of supplemental oxygen and the possible presence of blood that is chocolate in color.

To confirm if a patient has this condition, a doctor will order a blood gas test with co-oximetry. This analysis measures the different types of hemoglobin (protein in red blood cells) in the bloodstream to determine the concentration of methemoglobin, the problematic form of hemoglobin. However, it’s key to understand that just measuring the amount of oxygen in the blood (SpO2) doesn’t give an accurate picture of the severity of methemoglobinemia.

A significant hint toward methemoglobinemia is having “refractory hypoxemia”. This means that the patient’s blood contains less oxygen (SpO2) than typical as measured by a small device called a pulse oximeter, which reads the blood’s oxygen level based on light absorption. On the other hand, when the oxygen level is calculated directly from a blood sample (SaO2), it might appear normal.

Traditional pulse oximeters may not give accurate results in methemoglobinemia. This is because they use two specific light wavelengths, and methemoglobin absorbs a lot of light at both these wavelengths. This results in a reading that is usually not accurate. Typically, when methemoglobin levels reach around 30-35%, the oximeter reads an SpO2 of 85%.

There is a complex relationship between methemoglobin concentration and SpO2. Although SpO2 is generally lower than normal, it might give a false suggestion of normal oxygen saturation, and this can vary depending on the specific device used.

While SpO2 measurements might be lower due to interference from methemoglobin, SaO2 measurements may appear falsely normal. This is because they assume oxygen is being carried either by normal hemoglobin or by hemoglobin not carrying oxygen, without accounting for methemoglobin. The difference between these lower than normal SpO2 and falsely normal SaO2 values is referred to as the “saturation gap.” This gap can hint at the presence of a problem with the hemoglobin but can’t be used alone to confirm a diagnosis of methemoglobinemia. A gap larger than 5% is usually seen in conditions where abnormal forms of hemoglobin like carboxyhemoglobin, methemoglobin, and sulfhemoglobin are elevated.

Treatment Options for Methemoglobinemia

If a person has methemoglobinemia, a blood disorder causing decreased ability of the red blood cells to release oxygen to the body, the first step for treatment is removing anything that could have caused it. There’s an antidote called methylene blue that might be considered too. High flow oxygen delivered through a specific type of mask, called a non-rebreather mask, enhances the body’s natural ability to break down methemoglobin, the substance causing the disorder.

Methylene blue can work quickly and effectively. It plays a key role in one of the secondary pathways our bodies use to reduce methemoglobin. In this pathway, an enzyme (a type of protein in our bodies that speeds up chemical reactions) called NADPH-MetHb reductase, changes methylene blue to leukomethylene blue using a source of energy from one of our body’s processes called the G6PD-dependent hexose monophosphate shunt. Leukomethylene blue then helps to change the methemoglobin back to the normal hemoglobin. If treatment with methylene blue is necessary, it is usually used when methemoglobin levels exceed 20-30%, or if the person is showing symptoms of the disease. Decisions should be based on the person’s symptoms rather than waiting for lab result confirmations.

Methylene blue has some side effects you should be aware of. It can change the color of your urine to green or blue, which is harmless, but can be startling if you’re not expecting it. More serious side effects include methemoglobinemia or hemolysis (breaking down of red blood cells), especially with high doses or if it’s not properly broken down in your body. Plus, methylene blue can increase the risk of serotonin syndrome, a group of symptoms like restlessness and rapid heartbeat, in people taking certain medications. Newborn babies, who are very sensitive to agents that cause oxidation (a chemical reaction that can produce free radicals, leading to chain reactions that may damage cells), and people who are pregnant should also be careful with methylene blue.

In people with a genetic disorder called G6PD-deficiency, which reduced levels of an important type of protein, using methylene blue can be controversial. However, it’s not strictly forbidden, and should be used carefully. G6PD deficient patients can often still respond adequately to the treatment, and denial of treatment based on this alone is not advised.

If methylene blue doesn’t work after the second dose, it might be because of underlying conditions like G6PD and NADPH-MetHb reductase deficiency. However, just having methemoglobinemia is no reason to check for these conditions on its own. When methylene blue can’t be used or isn’t effective, other options might include ascorbic acid (also known as Vitamin C), exchange transfusion (a method of removing the patient’s blood and replacing it with fresh donor blood or plasma), or hyperbaric oxygen therapy (inhaling pure oxygen in a pressurized room or tube).

In particular, high doses of ascorbic acid could be used to treat methemoglobinemia, but this isn’t the usual course of treatment because it isn’t generally effective. Furthermore, high doses of ascorbic acid could lead to side effects like increased excretion of a substance called oxalate in urine, potentially causing kidney failure if the person already has kidney problems.

In diagnosing the symptom of cyanosis, which is blue or purplish discoloration of the skin or mucous membranes due to low levels of oxygen in the blood, doctors might consider the following conditions:

Anemia
Asthma
Congestive heart failure
Cyanotic congenital heart disease (a heart defect present at birth)
Peripheral cyanosis (bluish discoloration of the skin, often affecting the hands or feet)
Polycythemia (an excess of red blood cells)
Sulfhemoglobinemia (a rare condition that affects red blood cell functionality)

If someone is experiencing a bluish skin discoloration, it might also be helpful for doctors to consider the following conditions:

Acrodermatitis enteropathica (a disorder causing skin rashes)
Amiodarone-induced skin pigmentation (skin discoloration caused by a specific medication)
Argyria (a skin condition caused by excessive exposure to chemical compounds of the element silver)

What to expect with Methemoglobinemia

Generally, people with methemoglobinemia, a condition that affects the oxygen-carrying capability of red blood cells, react positively to treatment and can be sent home after a short period of monitoring. If a person continues to show symptoms after the initial treatment, or if their other existing health conditions become worse, they may need to be admitted to the hospital for further observation and care.