Methemoglobinemia

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Methemoglobinemia
Other names Hemoglobin M disease, [1]
ChocolateBrownBlood (cropped).jpg
Chocolate-brown blood due to methemoglobinemia
Specialty Toxicology, haematology
Symptoms Headache, dizziness, shortness of breath, nausea, poor muscle coordination, blue-colored skin [2]
Causes Benzocaine, nitrites, dapsone, genetics [3]
Diagnostic method Blood gas [3]
Differential diagnosis Argyria, sulfhemoglobinemia, heart failure [3]
Treatment Oxygen therapy, methylene blue [3]
Prognosis Generally good with treatment [3]
FrequencyRelatively uncommon [3]

Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. [2] Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). [2] Complications may include seizures and heart arrhythmias. [3] [4]

Contents

Methemoglobinemia can be due to certain medications, chemicals, or food or it can be inherited. [2] Substances involved may include benzocaine, nitrites, or dapsone. [3] The underlying mechanism involves some of the iron in hemoglobin being converted from the ferrous [Fe2+] to the ferric [Fe3+] form. [3] The diagnosis is often suspected based on symptoms and a low blood oxygen that does not improve with oxygen therapy. [3] Diagnosis is confirmed by a blood gas. [3]

Treatment is generally with oxygen therapy and methylene blue. [3] Other treatments may include vitamin C, exchange transfusion, and hyperbaric oxygen therapy. [3] Outcomes are generally good with treatment. [3] Methemoglobinemia is relatively uncommon, with most cases being acquired rather than genetic. [3]

Signs and symptoms

Chocolate-brown blood due to methemoglobinemia ChocolateBrownBlood (cropped)2.jpg
Chocolate-brown blood due to methemoglobinemia

Signs and symptoms of methemoglobinemia (methemoglobin level above 10%) include shortness of breath, cyanosis, mental status changes (~50%), headache, fatigue, exercise intolerance, dizziness, and loss of consciousness. [5]

People with severe methemoglobinemia (methemoglobin level above 50%) may exhibit seizures, coma, and death (level above 70%). [6] Healthy people may not have many symptoms with methemoglobin levels below 15%. However, people with co-morbidities such as anemia, cardiovascular disease, lung disease, sepsis, or who have abnormal hemoglobin species (e.g. carboxyhemoglobin, sulfhemoglobinemia or sickle hemoglobin) may experience moderate to severe symptoms at much lower levels (as low as 5–8%).[ citation needed ]

Cause

Acquired

Methemoglobinemia may be acquired. [7] Classical drug causes of methemoglobinaemia include various antibiotics (trimethoprim, sulfonamides, and dapsone [8] ), local anesthetics (especially articaine, benzocaine, prilocaine, [9] and lidocaine [10] ), and aniline dyes, metoclopramide, rasburicase, umbellulone, chlorates, bromates, and nitrites. [11] Nitrates are suspected to cause methemoglobinemia. [12]

In otherwise healthy individuals, the protective enzyme systems normally present in red blood cells rapidly reduce the methemoglobin back to hemoglobin and hence maintain methemoglobin levels at less than one percent of the total hemoglobin concentration. Exposure to exogenous oxidizing drugs and their metabolites (such as benzocaine, dapsone, and nitrates) may lead to an increase of up to a thousandfold of the methemoglobin formation rate, overwhelming the protective enzyme systems and acutely increasing methemoglobin levels.[ citation needed ]

Infants under 6 months of age have lower levels of a key methemoglobin reduction enzyme (NADH-cytochrome b5 reductase) in their red blood cells. This results in a major risk of methemoglobinemia caused by nitrates ingested in drinking water, [13] dehydration (usually caused by gastroenteritis with diarrhea), sepsis, or topical anesthetics containing benzocaine or prilocaine resulting in blue baby syndrome. Nitrates used in agricultural fertilizers may leak into the ground and may contaminate well water. The current EPA standard of 10 ppm nitrate-nitrogen for drinking water is specifically set to protect infants. [13] Benzocaine applied to the gums or throat (as commonly used in baby teething gels, or sore throat lozenges) can cause methemoglobinemia. [14] [15]

Genetic

The congenital form of methemoglobinemia has an autosomal recessive pattern of inheritance. Autorecessive.svg
The congenital form of methemoglobinemia has an autosomal recessive pattern of inheritance.

Due to a deficiency of the enzyme diaphorase I (cytochrome b5 reductase), methemoglobin levels rise and the blood of met-Hb patients has reduced oxygen-carrying capacity. Instead of being red in color, the arterial blood of met-Hb patients is brown. This results in the skin of white patients gaining a bluish hue. Hereditary met-Hb is caused by a recessive gene. If only one parent has this gene, offspring will have normal-hued skin, but if both parents carry the gene, there is a chance the offspring will have blue-hued skin.[ citation needed ]

Another cause of congenital methemoglobinemia is seen in patients with abnormal hemoglobin variants such as hemoglobin M (HbM), or hemoglobin H (HbH), which are not amenable to reduction despite intact enzyme systems.[ citation needed ]

Methemoglobinemia can also arise in patients with pyruvate kinase deficiency due to impaired production of NADH  – the essential cofactor for diaphorase I. Similarly, patients with glucose-6-phosphate dehydrogenase deficiency may have impaired production of another co-factor, NADPH. [16]

Pathophysiology

The affinity for oxygen of ferric iron is impaired. The binding of oxygen to methemoglobin results in an increased affinity for oxygen in the remaining heme sites that are in ferrous state within the same tetrameric hemoglobin unit. [17] This leads to an overall reduced ability of the red blood cell to release oxygen to tissues, with the associated oxygen–hemoglobin dissociation curve therefore shifted to the left. When methemoglobin concentration is elevated in red blood cells, tissue hypoxia may occur. [18]

Normally, methemoglobin levels are <1%, as measured by the CO-oximetry test. Elevated levels of methemoglobin in the blood are caused when the mechanisms that defend against oxidative stress within the red blood cell are overwhelmed and the oxygen carrying ferrous ion (Fe2+) of the heme group of the hemoglobin molecule is oxidized to the ferric state (Fe3+). This converts hemoglobin to methemoglobin, resulting in a reduced ability to release oxygen to tissues and thereby hypoxia. This can give the blood a bluish or chocolate-brown color. Spontaneously formed methemoglobin is normally reduced (regenerating normal hemoglobin) by protective enzyme systems, e.g., NADH methemoglobin reductase (cytochrome-b5 reductase) (major pathway), NADPH methemoglobin reductase (minor pathway) and to a lesser extent the ascorbic acid and glutathione enzyme systems. Disruptions with these enzyme systems lead to methemoglobinemia. Hypoxia occurs due to the decreased oxygen-binding capacity of methemoglobin, as well as the increased oxygen-binding affinity of other subunits in the same hemoglobin molecule, which prevents them from releasing oxygen at normal tissue oxygen levels.[ citation needed ]

Diagnosis

Color chart for the detection of the amount of methemoglobin in the blood MethemoglobinDiag.jpg
Color chart for the detection of the amount of methemoglobin in the blood

The diagnosis of methemoglobinemia is made with the typical symptoms, a suggestive history, low oxygen saturation on pulse oximetry measurements (SpO2) and these symptoms (cyanosis and hypoxia) failing to improve on oxygen treatment. The definitive test would be obtaining either CO-oximeter or a methemoglobin level on an arterial blood gas test. [3] Arterial blood with an elevated methemoglobin level has a characteristic chocolate-brown color as compared to normal bright red oxygen-containing arterial blood; the color can be compared with reference charts. [6]

The SaO2 calculation in the arterial blood gas analysis is falsely normal, as it is calculated under the premise of hemoglobin either being oxyhemoglobin or deoxyhemoglobin. However, co-oximetry can distinguish the methemoglobin concentration and percentage of hemoglobin. [3] At the same time, the SpO2 concentration as measured by pulse ox is false high, because methemoglobin absorbs the pulse ox light at the 2 wavelengths it uses to calculate the ratio of oxyhemoglobin and deoxyhemoglobin. For example with a methemoglobin level of 30–35%, this ratio of light absorbance is 1.0, which translates into a false high SpO2 of 85%. [3]

Differential diagnosis

Other conditions that can cause bluish skin include argyria, sulfhemoglobinemia, heart failure, [3] amiodarone-induced bluish skin pigmentation and acrodermatitis enteropathica. [3]

Treatment

Cyanosis from methemoglobinemia Eplasty16ic18 fig1.jpg
Cyanosis from methemoglobinemia
Resolved after methylene blue Eplasty16ic18 fig3.jpg
Resolved after methylene blue

Methemoglobinemia can be treated with supplemental oxygen and methylene blue. [19] Methylene blue is given as a 1% solution (10 mg/ml) 1 to 2 mg/kg administered intravenously slowly over five minutes. Although the response is usually rapid, the dose may be repeated in one hour if the level of methemoglobin is still high one hour after the initial infusion. Methylene blue inhibits monoamine oxidase, and serotonin toxicity can occur if taken with an SSRI (selective serotonin reuptake inhibitor) medicine. [20]

Methylene blue restores the iron in hemoglobin to its normal (reduced) oxygen-carrying state. [4] This is achieved by providing an artificial electron acceptor (such as methylene blue or flavin) for NADPH methemoglobin reductase (RBCs usually don't have one; the presence of methylene blue allows the enzyme to function at 5× normal levels). [21] The NADPH is generated via the hexose monophosphate shunt.

Genetically induced chronic low-level methemoglobinemia may be treated with oral methylene blue daily. Also, vitamin C can occasionally reduce cyanosis associated with chronic methemoglobinemia, and may be helpful in settings in which methylene blue is unavailable or contraindicated (e.g., in an individual with G6PD deficiency). [22] Diaphorase (cytochrome b5 reductase) normally contributes only a small percentage of the red blood cell's reducing capacity, but can be pharmacologically activated by exogenous cofactors (such as methylene blue) to five times its normal level of activity.[ citation needed ]

Epidemiology

Methemoglobinemia mostly affects infants under 6 months of age (particularly those under 4 months) due to low hepatic production of methemoglobin reductase. [23] [24] The most at-risk populations are those with water sources high in nitrates, such as wells and other water that is not monitored or treated by a water treatment facility. The nitrates can be hazardous to the infants. [25] [26] The link between blue baby syndrome in infants and high nitrate levels is well established for waters exceeding the normal limit of 10 mg/L. [27] [28] However, there is also evidence that breastfeeding is protective in exposed populations. [29]

Society and culture

Blue Fugates

The Fugates, a family that lived in the hills of Kentucky in the US, had the hereditary form. They are known as the "Blue Fugates". [30] Martin Fugate and Elizabeth Smith, who had married and settled near Hazard, Kentucky, around 1800, were both carriers of the recessive methemoglobinemia (met-H) gene, as was a nearby clan with whom the Fugates descendants intermarried. As a result, many descendants of the Fugates were born with met-H. [31] [32] [33] [34]

Blue Men of Lurgan

The "blue men of Lurgan" were a pair of Lurgan men suffering from what was described as "familial idiopathic methemoglobinemia" who were treated by James Deeny in 1942. Deeny, who would later become the Chief Medical Officer of the Republic of Ireland, prescribed a course of ascorbic acid and sodium bicarbonate. In case one, by the eighth day of treatments, there was a marked change in appearance, and by the twelfth day of treatment, the patient's complexion was normal. In case two, the patient's complexion reached normality over a month-long duration of treatment. [35]

See also

Related Research Articles

<span class="mw-page-title-main">Amyl nitrite</span> Chemical compound

Amyl nitrite is a chemical compound with the formula C5H11ONO. A variety of isomers are known, but they all feature an amyl group attached to the nitrite functional group. The alkyl group is unreactive and the chemical and biological properties are mainly due to the nitrite group. Like other alkyl nitrites, amyl nitrite is bioactive in mammals, being a vasodilator, which is the basis of its use as a prescription medicine. As an inhalant, it also has a psychoactive effect, which has led to its recreational use, with its smell being described as that of old socks or dirty feet. It was first documented in 1844 and came into medical use in 1867.

<span class="mw-page-title-main">Hypoxia (medicine)</span> Medical condition of lack of oxygen in the tissues

Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body. Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise.

<span class="mw-page-title-main">Nitrate</span> Polyatomic ion (NO₃, charge –1) found in explosives and fertilisers

Nitrate is a polyatomic ion with the chemical formula NO−
3. Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insoluble nitrate is bismuth oxynitrate.

<span class="mw-page-title-main">Hemoglobinopathy</span> Any of various genetic disorders of blood

Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.

<span class="mw-page-title-main">Methylene blue</span> Blue dye also used as a medication

Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye and as a medication. As a medication, it is mainly used to treat methemoglobinemia by chemically reducing the ferric iron in hemoglobin to ferrous iron. Specifically, it is used to treat methemoglobin levels that are greater than 30% or in which there are symptoms despite oxygen therapy. It has previously been used for treating cyanide poisoning and urinary tract infections, but this use is no longer recommended.

The nitrite ion has the chemical formula NO−
2. Nitrite is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also refers to organic compounds having the –ONO group, which are esters of nitrous acid.

<span class="mw-page-title-main">Cyanosis</span> Decreased oxygen in the blood

Cyanosis is the change of body tissue color to a bluish-purple hue, as a result of decrease in the amount of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Cyanosis is apparent usually in the body tissues covered with thin skin, including the mucous membranes, lips, nail beds, and ear lobes. Some medications may cause discoloration such as medications containing amiodarone or silver. Furthermore, mongolian spots, large birthmarks, and the consumption of food products with blue or purple dyes can also result in the bluish skin tissue discoloration and may be mistaken for cyanosis. Appropriate physical examination and history taking is a crucial part to diagnose cyanosis. Management of cyanosis involves treating the main cause, as cyanosis isn’t a disease, it is a symptom.

<span class="mw-page-title-main">Sodium nitrite</span> Chemical compound

Sodium nitrite is an inorganic compound with the chemical formula NaNO2. It is a white to slightly yellowish crystalline powder that is very soluble in water and is hygroscopic. From an industrial perspective, it is the most important nitrite salt. It is a precursor to a variety of organic compounds, such as pharmaceuticals, dyes, and pesticides, but it is probably best known as a food additive used in processed meats and (in some countries) in fish products.

<span class="mw-page-title-main">Blue baby syndrome</span> Two situations that lead to cyanosis in infants

Blue baby syndrome can refer to conditions that cause cyanosis, or blueness of the skin, in babies as a result of low oxygen levels in the blood. This term has traditionally been applied to cyanosis as a result of:.

  1. Cyanotic heart disease, which is a category of congenital heart defect that results in low levels of oxygen in the blood. This can be caused by either reduced blood flow to the lungs or mixing of oxygenated and deoxygenated blood.
  2. Methemoglobinemia, which is a disease defined by high levels of methemoglobin in the blood. Increased levels of methemoglobin prevent oxygen from being released into the tissues and result in hypoxemia.
<span class="mw-page-title-main">Methemoglobin</span> Type of hemoglobin

Methemoglobin (British: methaemoglobin, shortened MetHb) (pronounced "met-hemoglobin") is a hemoglobin in the form of metalloprotein, in which the iron in the heme group is in the Fe3+ (ferric) state, not the Fe2+ (ferrous) of normal hemoglobin. Sometimes, it is also referred to as ferrihemoglobin. Methemoglobin cannot bind oxygen, which means it cannot carry oxygen to tissues. It is bluish chocolate-brown in color. In human blood a trace amount of methemoglobin is normally produced spontaneously, but when present in excess the blood becomes abnormally dark bluish brown. The NADH-dependent enzyme methemoglobin reductase (a type of diaphorase) is responsible for converting methemoglobin back to hemoglobin.

<span class="mw-page-title-main">Glutathione reductase</span> Enzyme

Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell. Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH:

The Fugates, commonly known as the "Blue Fugates" or the "Blue People of Kentucky", are an ancestral family living in the hills of Kentucky starting in the 19th century, where they are known for having a genetic trait that led to the blood disorder methemoglobinemia, causing the skin to appear blue.

Heinz bodies are inclusions within red blood cells composed of denatured hemoglobin. They are not visible with routine blood staining techniques, but can be seen with supravital staining. The presence of Heinz bodies represents damage to hemoglobin and is classically observed in G6PD deficiency, a genetic disorder that causes hemolytic anemia. In veterinary medicine, Heinz bodies may be seen following the consumption of foods containing thiosulfate and propylene glycol compounds by cats, dogs and certain primates.

The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.

<span class="mw-page-title-main">Nitrate reductase</span> Class of enzymes

Nitrate reductases are molybdoenzymes that reduce nitrate to nitrite. This reaction is critical for the production of protein in most crop plants, as nitrate is the predominant source of nitrogen in fertilized soils.

<span class="mw-page-title-main">Cytochrome b5 reductase</span> Class of enzymes

Cytochrome-b5 reductase is a NADH-dependent enzyme that converts ferricytochrome from a Fe3+ form to a Fe2+ form. It contains FAD and catalyzes the reaction:

Sulfhemoglobinemia is a rare condition in which there is excess sulfhemoglobin (SulfHb) in the blood. The pigment is a greenish derivative of hemoglobin which cannot be converted back to normal, functional hemoglobin. It causes cyanosis even at low blood levels.

<span class="mw-page-title-main">Hemoglobinemia</span> Abnormally increased hemoglobin in blood plasma

Hemoglobinemia is a medical condition in which there is an excess of hemoglobin in the blood plasma. This is an effect of intravascular hemolysis, in which hemoglobin separates from red blood cells, a form of anemia.

The phytoglobin-nitric oxide cycle is a metabolic pathway induced in plants under hypoxic conditions which involves nitric oxide (NO) and phytoglobin (Pgb). It provides an alternative type of respiration to mitochondrial electron transport under the conditions of limited oxygen supply. Phytoglobin in hypoxic plants acts as part of a soluble terminal nitric oxide dioxygenase system, yielding nitrate ion from the reaction of oxygenated phytoglobin with NO. Class 1 phytoglobins are induced in plants under hypoxia, bind oxygen very tightly at nanomolar concentrations, and can effectively scavenge NO at oxygen levels far below the saturation of cytochrome c oxidase. In the course of the reaction, phytoglobin is oxidized to metphytoglobin which has to be reduced for continuous operation of the cycle. Nitrate is reduced to nitrite by nitrate reductase, while NO is mainly formed due to anaerobic reduction of nitrite which may take place in mitochondria by complex III and complex IV in the absence of oxygen, in the side reaction of nitrate reductase, or by electron transport proteins on the plasma membrane. The overall reaction sequence of the cycle consumes NADH and can contribute to the maintenance of ATP level in highly hypoxic conditions.

<span class="mw-page-title-main">Hemoglobin M disease</span> Medical condition

Hemoglobin M disease is a rare form of hemoglobinopathy, characterized by the presence of hemoglobin M (HbM) and elevated methemoglobin (metHb) level in blood. HbM is an altered form of hemoglobin (Hb) due to point mutation occurring in globin-encoding genes, mostly involving tyrosine substitution for proximal (F8) or distal (E7) histidine residues. HbM variants are inherited as autosomal dominant disorders and have altered oxygen affinity. The pathophysiology of hemoglobin M disease involves heme iron autoxidation promoted by heme pocket structural alteration.

References

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  32. ↑ "Appalachia's Blue People". Tri City Herald. 7 November 1974. p. 32.
  33. ↑ Fugates of Kentucky: Skin Bluer than Lake Louise
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  35. ↑ Deeny J (1995). The End of an Epidemic. Dublin: A.& A.Farmar. ISBN   978-1-899047-06-2.
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