Pathogenesis Low-affinity hemoglobin variants, such as Hb Kansas (β^102Asn→Thr), arise from mutations that impair hemoglobin-oxygen binding or reduce cooperativity. In cases of Hb Kansas, the threonine position, β¹⁰², cannot form a hydrogen bond with aspartic acid at position α⁹⁴. Because this aspartate residue stabilizes the R (oxy) state, Hb Kansas binds oxygen less well and exhibits a right-shifted P₅₀ value (see Fig.1).

Fig1. HEMOGLOBIN–OXYGEN DISSOCIATION CURVES ARE ILLUSTRATED FOR NORMAL HEMOGLOBIN (HBA) AND FOR MODEL ABNORMAL HEMOGLOBINS WITH HIGH AND LOW OXYGEN AFFINITIES. On the abscissa, the partial pressure of oxy gen (Po2 ) is indicated in millimeters of mercury. On the left ordinate, the saturation of hemoglobin with oxygen is indicated as a percentage; on the right ordinate, the oxygen content of the hemoglobin is expressed as volume percent. The three inverted arrows show the Po2 at which the hemoglobin is 50% saturated (P50 ) for the three hemoglobins. This value is lowest for the high-affinity hemoglobin. As the Po2 drops from 100 (arterial) to 40 (tissues) mmHg, hemoglobin desaturates, giving up a portion of its bound oxygen; the numbers on the brackets indicate the amount of oxygen unloaded by the three hemoglobin types expressed as volume percent. Note that the high-affinity hemoglobin delivers less than one-half the oxygen that HbA gives to the tis sues, resulting in tissue anoxia, increased erythropoietin secretion, and erythrocytosis. Conversely, the low-affinity hemoglobin is even more efficient than HbA in supplying tissues with oxygen, resulting in diminished erythropoietin production and anemia. (From Wynngaarden JB, Smith Jr LH, Bennett JC, eds. Cecil Textbook of Medicine. Philadelphia: WB Saunders; 1992.)

Most low-affinity variants possess enough oxygen affinity to become fully saturated in the normal lung. At the low capillary Po2 in other tissues, these hemoglobins deliver higher than normal amounts of oxygen. They become more desaturated than normal hemoglobins. Two abnormalities result from this high level of oxygen delivery. First, because tissue oxygen delivery is so “overly” efficient, normal oxygen requirements can be met by lower-than-normal hematocrit levels. This situation produces a state of “pseudoanemia,” in which the low hematocrit level is deceiving because both oxygen delivery and the patients are completely normal. Second, the amount of desaturated hemoglobin circulating in capillaries and veins can be greater than 5 g/dL. Cyanosis may thus be associated with these variants. This usually ominous finding is entirely misleading in these individuals because it reflects no morbidity.

Diagnosis

Patients with unexplained anemia or cyanosis who appear to be entirely well in all other respects should be evaluated, especially if there is a positive family history. Testing for the abnormal variant follows the same reasoning as that just described for high-affinity variants. The oxygen dissociation curve will be shifted to the right, and the numeric value of the P₅₀ will be higher than normal.

Management

Patients with low-affinity hemoglobins are usually asymptomatic. No treatment is required. It is important to document that a low-affinity hemoglobin is the cause of an apparent anemia or cyanosis to preempt inappropriate work-ups and provide reassurance to the patient. Cyanosis in some patients can pose a cosmetic problem, but correction with transfusions is rarely justified.

Methemoglobinemias

Methemoglobin results from oxidation of the iron moieties in hemoglobin from the ferrous (Fe2+) to the ferric (Fe3+) state. Normal oxygenation of hemoglobin causes a partial transfer of an electron from the iron to the bound oxygen. Iron in this state thus resembles ferric iron and the oxygen resembles superoxide (O₂⁻). Deoxygenation returns the electron to the iron, with release of oxygen. Methemoglobin forms if the electron is not returned. Methemoglobin constitutes 3% or less of the total hemoglobin in normal humans. Under nor mal circumstances, these levels in humans are maintained at 1% or less by the methemoglobin reductase enzyme system (the reduced form of nicotinamide adenine dinucleotide [NADH]–dehydratase, [NADH]-diaphorase, erythrocyte cytochrome b5).

Pathogenesis and Clinical Manifestations

Methemoglobinemias of clinical interest arise by one of three dis tinct mechanisms: (1) globin chain mutations that result in increased formation of methemoglobin, (2) deficiencies of methemoglobin reductase, and (3) “toxic” methemoglobinemia, in which normal red blood cells are exposed to substances that oxidize hemoglobin iron to such a degree that normal reducing mechanisms are subverted or overwhelmed ( Table1).

Table1. Types of Methemoglobinemia Congenital

Abnormal hemoglobins producing methemoglobinemia (M hemoglobins) arise from mutations that stabilize the heme iron in the ferric state. Classically a histidine in the vicinity of the heme pocket is replaced by a tyrosine (e.g., Hb M-Iwate, → β87 (F8) His → Tyr); the hydroxyl group of the tyrosine forms a complex that stabilizes the iron in the ferric state (Fig.2). The oxidized heme iron is relatively resistant to reduction by the methemoglobin reductase system.

Fig2. MODIFICATIONS OF THE HEME AND ITS ENVIRONMENT THAT ACCOUNT FOR TWO COMMON M HEMOGLOBINS. (A) Hemoglobin A has a His residue at the α58(E7) position. (B) In hemoglobin M-Boston, the histidine is replaced by a tyrosine, the phenolic side chain of which is capable of covalently binding to the heme iron, resulting in stabilization in the oxidized form. (C) HbA has a Val residue at position β67(E11). (D) Hb M-Milwaukee has a glutamic acid substitution for the β67 valine. The carboxylic side chain of the Glu forms a bond with iron, shifting the equilibrium toward the ferric state. (Modified from Dickerson RE, Geis I. Hemoglobin: Structure, Function, Evolution, and Pathology. Menlo Park, CA: Benjamin-Cummings; 1983. Copyright Irving Geis.)

Methemoglobin has a brownish to blue color that does not revert to red on exposure to oxygen. Patients with methemoglobinemia thus appear to be cyanotic. In contrast to truly cyanotic people, however, arterial partial pressure of oxygen (Pao2 ) values are usually normal. Pulse oximeters will produce ambiguous results. Patients with these hemoglobins are otherwise asymptomatic because methemoglobin is usually less than 30% to 50%, the levels at which symptoms become apparent.

Hereditary methemoglobinemia resulting from methemoglobin reductase deficiency (cytochrome-b5 reductase deficiency) is very rare. Mutations in the b5 reductase gene cause two distinct phenotypes. In cases of type I methemoglobin reductase deficiency, patients suffer solely from cyanosis; in cases of type II dis ease, patients manifest both cyanosis and severe mental retardation. One isoform of the b5 reductase gene is expressed in diverse tissues for participation in a variety of cellular processes. A second isoform, produced by alternative splicing, is expressed in erythrocytes, producing a soluble protein that reduces methemoglobin. Mutations causing type I methemoglobin reductase deficiency occur throughout the gene and result in an unstable protein. Such mutations are primarily significant in erythrocytes that, without nuclei, cannot replace the degraded protein. Mutations causing type II disease occur in the critical NADH or flavin adenine dinucleotide (FAD)-binding domains, causing inactivation of the protein in all tissues and the more severe clinical phenotype.

Like patients with M hemoglobins, patients with methemoglobin reductase deficiency exhibit slate-gray “pseudocyanosis.” However, even homozygotes rarely accumulate more than 25% methemoglobin, a level compatible with minimal symptoms. Heterozygotes can have normal methemoglobin levels but are especially sensitive to agents causing methemoglobinemia.

A third toxic form of methemoglobinemia is caused by exposure to certain chemical agents and drugs that accelerate the oxidation of hemoglobin to methemoglobin (Table2). Some compounds directly oxidize hemoglobin, whereas other compounds produce reactive oxygen intermediates that oxidize hemoglobin. Nitrite com pounds are especially notorious and common. Some of these com pounds also have a propensity to exacerbate G6PD deficiency and the precipitation of unstable hemoglobins.

Table2. Drugs and Chemicals Having Toxic Effects on Hemoglobin Molecule

Nitrates are a frequent environmental cause of toxic methemoglobinemia. Nitrates do not directly interact with either hemoglobin or the reductase pathway but are converted to nitrites in the gut. Well water is a frequently encountered source of excessive nitrates. In general, substantial intake of these agents is required before significant amounts of methemoglobin are generated. Very young infants have lower levels of methemoglobin reductase in erythrocytes and are therefore more susceptible to these agents than are adults. However, all age groups are at risk, given sufficient exposure. Systemic acidosis, particularly in young infants suffering from diarrhea and dehydration, can also cause clinically significant methemoglobinemia.

Acquired methemoglobinemia is virtually the only situation in which life-threatening amounts of methemoglobin accumulate. In general, the only symptom produced when methemoglobin constitutes less than 30% of total hemoglobin is the cosmetic effect of cyanosis. However, as levels of methemoglobin rise to greater than 30%, patients begin to exhibit symptoms of oxygen deprivation, such as malaise, giddiness, and other alterations of mental status. The symptoms reflect a true lack of oxygen availability at the tissue level. Methemoglobin is a markedly left-shifted hemoglobin that delivers little oxygen to the tissues. When methemoglobin accounts for more than 50% of total hemoglobin, loss of consciousness, coma, and death can rapidly ensue. At this level the blood is chocolate brown.

Diagnosis

Methemoglobinemia should be suspected in patients with unexplained cyanosis. It is obviously a medical emergency when any patient has cyanosis and altered mental status; a Pao2 more normal than expected on the basis of the O2 saturation should trigger a consideration of methemoglobinemia. The ingestion of nitrites as a suicidal gesture, especially in people knowledgeable with respect to chemistry, medicine, or pharmacology, should be considered. Exposure to nitrate-containing therapeutic compounds (e.g., in the setting of the intensive care unit) should also raise suspicion. Methemoglobinemia can be suspected from the brownish color of blood when it is drawn. Laboratory detection is simple; methemoglobin exhibits characteristic peaks of absorption at 630 and 502 nm, rendering it easily distinguishable from normal hemoglobin. Pulse oximetry, using a ratio of absorption at 660 nm and 940 nm, gives an inaccurate reading of 85% oxygen saturation for blood with 100% methemoglobin. The inherited M hemoglobin mutants are frequently detectable by altered electrophoretic mobility, especially if ferricyanide treatment in vitro is used to convert all the hemoglobin solution to methemoglobin.

In the case of toxic methemoglobinemia, recognition of exposure to an appropriate agent provides the most important historical clue. Acute poisoning can represent a life-threatening emergency; therefore laboratory evaluation for methemoglobin should be requested for any person displaying atypical cyanosis or cyanosis occurring along with more normal than anticipated blood gas values. Methemoglobin due to deficiencies of the reductase system can be further evaluated in reference laboratories by direct analysis of these enzymes.

Management

 Patients with M hemoglobins are usually asymptomatic and require no management. The secondary cyanosis can present a cosmetic problem. The cyanosis is not reversible because ascorbic acid and methylene blue are usually ineffective.

Patients with deficiency of the reductase system usually do not require treatment. Cyanosis in these cases can be improved by treatment with oral methylene blue, 100 to 300 mg/day, or 500 mg/day of oral ascorbic acid. Riboflavin (20 mg/day) has also been reported to be effective and may be the preferred agent, because methylene blue produces discolored (blue) urine and ascorbic acid can cause sodium oxalate stones.

Emergency treatment of high levels of toxic methemoglobinemia begins with 1 to 2 mg/kg of intravenous methylene blue as a 1% solution in saline. It is usually infused rapidly (over 3 to 5 minutes); the dose can be repeated at 1 mg/kg after 30 minutes if necessary. This treatment is usually effective. Methylene blue acts through the reduced form of nicotinamide adenine dinucleotide (NADPH) reductase system, which in turn requires G6PD activity. The method is therefore ineffective in patients who also have G6PD deficiency. These patients or patients who are severely affected may require exchange transfusion or hyperbaric oxygen therapy. Oral ascorbic acid is not useful for emergency situations because it acts too slowly. However, follow-up maintenance management can be accomplished with either ascorbic acid or oral methylene blue.

Mild cases of methemoglobin intoxication do not require treatment. The patient can be monitored for 1 to 3 days, during which time methemoglobin levels gradually return to normal if the offending agent is eliminated. The most important follow-up therapy for patients with toxic methemoglobinemia involves a thorough search for the offending agent and its removal from the environment.

Hemoglobin Variants That Modify the Clinical Phenotypes of Thalassemia and Sickle Cell Anemia

 There are a number of rare structural variants that, when coinherited with a thalassemia or sickle hemoglobin allele, create doubly heterozygous states that modify the thalassemia or sickle cell presentation.

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خبير يكشف 5 حقائق طبية صادمة وغير معروفة

ليس الأسود ولا الحيتان.. "كائن صغير" هو أخطر قاتل للبشر!

بارقة أمل لمرضى "الإيدز".. علاج خلوي ينجح في كبح الفيروس

ظاهرة مقلقة تتوسع.. "المستنشقات" خطر صامت يهدد المراهقين

المزيد

الآخبار التكنلوجية

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المزيد

مواضيع ذات صلة

Kallikreins and Kinins

Biological Actions of NO

Biological Actions of Endothelins

Red Blood Cell Enzymopathies- Metabolic Pathways

Chemistry, Biosynthesis, and Secretion of Nitric Oxide System

Chemistry, Biosynthesis, and Secretion of Endothelins

Chemistry, Biosynthesis, and Secretion of ANP

Hemoglobins with Increased Oxygen Affinity

Specific Enzymes are Associated with Compartments Separated by the Mitochondrial Membranes

ATP Acts as the “Energy Currency” of The Cell

Living Organisms Package Transition Metals Within Organometallic Complexes

Androgen Biosynthesis