HEMOLYTIC ANAEMIA
Introduction:
Hemolytic anemia is a condition in which red blood cells (RBCs) are destroyed prematurely, leading to a shorter lifespan of RBCs than the normal 120 days. The destruction of RBCs, known as hemolysis, can occur within blood vessels (intravascular) or in the spleen and liver (extravascular). Hemolytic anemia can be inherited or acquired and presents with varying degrees of severity, depending on the underlying cause.
Pathophysiology:
Intrinsic Causes (Inherited):
Membrane Defects: Disorders like hereditary spherocytosis and elliptocytosis result in fragile RBC membranes, making them more prone to rupture.
Hemoglobinopathies: Abnormal hemoglobin, such as in sickle cell disease and thalassemia, leads to RBC deformation and destruction.
Enzyme Deficiencies: Glucose-6-phosphate dehydrogenase (G6PD) deficiency results in decreased protection against oxidative damage, leading to RBC hemolysis.
Extrinsic Causes (Acquired):
Immune-Mediated: Autoimmune hemolytic anemia (AIHA) occurs when the immune system produces antibodies that target RBCs for destruction.
Infections: Certain infections like malaria and sepsis can cause RBC destruction.
Mechanical Damage: Conditions such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and heart valve prostheses can cause mechanical injury to RBCs, leading to hemolysis.
Toxins: Exposure to certain drugs, chemicals, or venoms can damage RBCs, resulting in hemolysis.
Site of Hemolysis:
Intravascular Hemolysis: RBCs are destroyed within blood vessels, releasing free hemoglobin into the bloodstream.
Extravascular Hemolysis: RBCs are destroyed by macrophages in the spleen or liver.
Specific Symptoms:
Fatigue and weakness due to anemia.
Pallor: Pale skin and mucous membranes.
Jaundice: Yellowing of the skin and eyes due to increased bilirubin from RBC breakdown.
Dark urine: From hemoglobinuria (free hemoglobin in the urine) in intravascular hemolysis.
Splenomegaly: Enlarged spleen, commonly seen in extravascular hemolysis.
Gallstones: Chronic hemolysis increases bilirubin production, which can lead to pigment gallstones.
Treatment:
1. Pharmacological:
Corticosteroids: In autoimmune hemolytic anemia (AIHA), corticosteroids like prednisone are commonly used to reduce antibody-mediated RBC destruction.
2. Non-Pharmacological:
Blood Transfusions: For severe anemia, transfusions of packed RBCs may be necessary to replenish the body’s RBC count.
Splenectomy: In cases of hereditary spherocytosis or chronic autoimmune hemolytic anemia, removing the spleen can reduce RBC destruction.
Lab Diagnosis:
Complete Blood Count (CBC):
Hemoglobin: Low.
Reticulocyte Count: Elevated, as the bone marrow compensates by producing more RBCs.
Mean Corpuscular Volume (MCV): May be normal or elevated.
Peripheral Blood Smear:
RBC Shape: The presence of spherocytes, schistocytes (fragmented cells), and bite cells (in G6PD deficiency) are characteristic findings.
Lactate Dehydrogenase (LDH):
Elevated due to RBC destruction.
Bilirubin:
Indirect (Unconjugated) Bilirubin is elevated, reflecting increased breakdown of hemoglobin.
Haptoglobin:
Decreased in intravascular hemolysis, as haptoglobin binds free hemoglobin.
Coombs Test (Direct Antiglobulin Test):
Positive in autoimmune hemolytic anemia, indicating the presence of antibodies bound to RBCs.
Urinalysis:
Hemoglobinuria and hemosiderinuria may be present in cases of intravascular hemolysis.
Bone Marrow Examination (if needed):
Shows erythroid hyperplasia as the bone marrow increases RBC production.
Complications:
Severe Anemia: Chronic hemolysis can lead to life-threatening anemia if not adequately managed.
Iron Overload: Repeated blood transfusions can lead to iron accumulation, which requires chelation therapy.
Gallstones: Increased bilirubin from chronic hemolysis can lead to gallstone formation.
Heart Failure: Prolonged, severe anemia can strain the cardiovascular system.
Splenic Rupture: In cases of splenomegaly, the spleen may become overburdened and rupture, leading to life-threatening bleeding.
Summary:
Hemolytic anemia is characterized by the premature destruction of red blood cells, which can be caused by intrinsic factors (membrane defects, enzyme deficiencies) or extrinsic factors (immune-mediated, mechanical damage). Symptoms include fatigue, jaundice, dark urine, and splenomegaly, with the specific findings dependent on the underlying cause. Diagnosis is based on blood tests, peripheral smear, and Coombs test, while treatment may involve corticosteroids, blood transfusions, or splenectomy. Complications include severe anemia, iron overload, and gallstones.
Introduction:
Spherocytosis is a type of hemolytic anemia characterized by the presence of spherical (spherocytic) red blood cells (RBCs) that are more prone to rupture, leading to chronic hemolysis. The most common form is hereditary spherocytosis (HS), which is an inherited condition caused by defects in the proteins of the red blood cell membrane, leading to membrane instability and spherocyte formation.
Pathophysiology:
Membrane Protein Defects:
In hereditary spherocytosis, mutations occur in genes encoding structural proteins like spectrin, ankyrin, band 3, or protein 4.2. These proteins maintain the biconcave shape and flexibility of RBCs.
Deficiency or dysfunction in these proteins causes the RBC membrane to become unstable, reducing its surface area-to-volume ratio, resulting in a more spherical shape.
Reduced Deformability:
Spherocytes lack the normal biconcave shape, which is crucial for RBCs to deform and pass through narrow capillaries and the splenic sinusoids.
This leads to the premature destruction of RBCs in the spleen (extravascular hemolysis), where macrophages identify and destroy the abnormal spherocytes.
Chronic Hemolysis:
As RBCs are continually destroyed in the spleen, the bone marrow attempts to compensate by increasing RBC production. However, the rate of hemolysis often exceeds production, resulting in chronic anemia.
Specific Symptoms:
Fatigue and weakness due to anemia.
Jaundice: Yellowing of the skin and eyes due to increased bilirubin from hemolysis.
Splenomegaly: Enlargement of the spleen due to the excessive destruction of spherocytes.
Gallstones: Chronic hemolysis increases bilirubin production, leading to the formation of pigment gallstones.
Pallor: Pale skin and mucous membranes.
Episodes of Aplastic Crisis: Often triggered by parvovirus B19 infection, which temporarily halts red blood cell production in the bone marrow, leading to severe anemia.
Treatment:
1. Pharmacological:
Folic Acid Supplementation: Daily folic acid (1 mg) is recommended to support increased red blood cell production, as hemolysis causes a higher demand for folic acid.
2. Non-Pharmacological:
Splenectomy: Removal of the spleen is the definitive treatment in moderate to severe cases. It reduces the destruction of spherocytes and improves anemia. However, it increases the risk of infections, so patients require vaccinations and prophylactic antibiotics post-splenectomy.
Lab Diagnosis:
Complete Blood Count (CBC):
Hemoglobin: Low to normal, depending on the severity.
Reticulocyte Count: Elevated due to increased RBC production in response to hemolysis.
Mean Corpuscular Volume (MCV): Normal or slightly low, but Mean Corpuscular Hemoglobin Concentration (MCHC) is often elevated.
Peripheral Blood Smear:
RBC Shape: Presence of spherocytes, which are round, lack the central pallor, and are smaller than normal RBCs.
Osmotic Fragility Test:
Spherocytes have increased fragility when exposed to hypotonic saline, which can be used to diagnose hereditary spherocytosis.
Direct Antiglobulin Test (Coombs Test):
Negative in hereditary spherocytosis, helping to differentiate it from autoimmune hemolytic anemia.
Flow Cytometry (EMA Binding Test):
This test detects decreased binding of eosin-5-maleimide (EMA) to RBC membrane proteins and is used for more accurate diagnosis of hereditary spherocytosis.
Lactate Dehydrogenase (LDH):
Elevated due to red blood cell breakdown.
Bilirubin:
Increased indirect (unconjugated) bilirubin due to hemolysis.
Complications:
Hemolytic Crises: Episodes of increased hemolysis, often triggered by infections, leading to worsening anemia and jaundice.
Aplastic Crisis: Temporary cessation of RBC production, often triggered by parvovirus B19 infection, leading to severe anemia and requiring urgent medical attention.
Gallstones: Due to chronic hemolysis and increased bilirubin production, patients are at high risk of developing pigment gallstones.
Infections: Post-splenectomy patients are at increased risk for severe bacterial infections, particularly from encapsulated organisms like Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
Summary:
Spherocytosis, particularly hereditary spherocytosis, is a genetic disorder that leads to the formation of spherical red blood cells, which are prone to premature destruction in the spleen. It presents with symptoms of anemia, jaundice, and splenomegaly, and may be complicated by gallstones and aplastic crises. Diagnosis is based on blood tests, osmotic fragility testing, and a peripheral blood smear showing spherocytes. Treatment includes folic acid supplementation and, in severe cases, splenectomy to reduce hemolysis.
Elliptocytosis
Introduction:
Elliptocytosis, also known as hereditary elliptocytosis (HE), is a genetic disorder characterized by the presence of abnormally shaped elliptical or oval red blood cells (RBCs) in the blood. It is typically inherited in an autosomal dominant manner, with variable clinical expression. Most cases of hereditary elliptocytosis are mild, but some can lead to significant hemolysis and anemia.
Pathophysiology:
Defects in RBC Membrane Proteins:
Hereditary elliptocytosis is caused by mutations in genes encoding RBC cytoskeletal proteins, most commonly spectrin, protein 4.1, or glycophorin C.
These proteins are responsible for maintaining the normal biconcave, disc shape of RBCs. Mutations in these proteins lead to membrane instability, causing the RBCs to become elliptical or oval in shape.
Increased RBC Fragility:
The defective cytoskeletal structure leads to decreased RBC flexibility and increased fragility, making the cells more prone to fragmentation when passing through the microcirculation, especially in the spleen.
The degree of hemolysis depends on the severity of the structural defects. In mild cases, there may be no noticeable symptoms, while severe cases result in significant hemolysis and anemia.
Splenic Destruction:
Like spherocytes in hereditary spherocytosis, elliptocytes can be recognized and destroyed prematurely by macrophages in the spleen, leading to extravascular hemolysis.
Specific Symptoms:
Mild Cases:
Many individuals are asymptomatic and may not experience any symptoms.
If symptoms occur, they may include mild fatigue and pallor due to mild anemia.
Moderate to Severe Cases:
Jaundice: Yellowing of the skin and eyes due to increased breakdown of hemoglobin, resulting in elevated bilirubin.
Splenomegaly: Enlarged spleen due to the increased destruction of elliptocytes.
Gallstones: Chronic hemolysis can lead to an accumulation of bilirubin, increasing the risk of pigment gallstones.
Fatigue: More pronounced in cases with significant hemolysis and anemia.
Treatment:
1. Pharmacological:
Folic Acid Supplementation: In patients with hemolysis, folic acid supplementation (1 mg/day) is recommended to support the increased RBC production by the bone marrow.
2. Non-Pharmacological:
Splenectomy: In moderate to severe cases with significant hemolysis, splenectomy may be considered. Removal of the spleen reduces the destruction of elliptocytes and improves anemia. However, patients require immunization and may need prophylactic antibiotics due to the increased risk of infection post-splenectomy.
Lab Diagnosis:
Complete Blood Count (CBC):
Hemoglobin: Can range from normal in mild cases to low in severe cases.
Reticulocyte Count: Elevated due to increased RBC production in response to hemolysis.
Peripheral Blood Smear:
RBC Shape: The hallmark of hereditary elliptocytosis is the presence of elliptocytes, which are oval or elliptical RBCs. More than 25% of RBCs are elliptical in patients with the condition.
Osmotic Fragility Test:
May show increased fragility in more severe cases, but this test is more commonly used for hereditary spherocytosis.
Flow Cytometry:
A specialized test to assess the structure of RBC membrane proteins, particularly in diagnosing hereditary RBC membrane disorders.
Lactate Dehydrogenase (LDH):
Elevated in cases of significant hemolysis.
Bilirubin:
Increased levels of indirect (unconjugated) bilirubin, reflecting the breakdown of hemoglobin from destroyed RBCs.
Coombs Test:
Negative in hereditary elliptocytosis, distinguishing it from autoimmune hemolytic anemia.
Complications:
Hemolytic Anemia: In severe cases, chronic hemolysis can lead to significant anemia that requires blood transfusions.
Gallstones: Chronic hemolysis increases the risk of pigment gallstone formation.
Aplastic Crisis: Like hereditary spherocytosis, parvovirus B19 infection can temporarily halt RBC production, leading to a life-threatening aplastic crisis.
Splenic Rupture: Rare but possible in cases of significant splenomegaly, splenic rupture can occur.
Summary:
Hereditary elliptocytosis is a genetic condition characterized by elliptical RBCs resulting from defects in cytoskeletal proteins like spectrin. It usually has a mild presentation, but severe cases can result in significant hemolysis, anemia, jaundice, and splenomegaly. Diagnosis is based on blood tests and a peripheral smear showing elliptocytes. Treatment focuses on folic acid supplementation, and splenectomy may be necessary in severe cases. Complications include hemolytic anemia, gallstones, and aplastic crises.
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Introduction:
G6PD deficiency is the most common enzymatic disorder of red blood cells (RBCs), affecting over 400 million people worldwide. It is an X-linked recessive genetic condition that leads to reduced levels of the enzyme glucose-6-phosphate dehydrogenase. This enzyme is critical for the proper functioning of the pentose phosphate pathway, which helps protect RBCs from oxidative damage. Deficiency of G6PD predisposes RBCs to hemolysis, particularly under oxidative stress.
Pathophysiology:
Role of G6PD:
G6PD is involved in the production of nicotinamide adenine dinucleotide phosphate (NADPH), which is crucial for maintaining the level of glutathione in its reduced form. Reduced glutathione protects RBCs from oxidative damage caused by free radicals and reactive oxygen species.
Deficiency of G6PD:
Without sufficient G6PD, RBCs are unable to regenerate reduced glutathione, leaving them vulnerable to oxidative damage. This results in the breakdown of hemoglobin and destruction of the RBC membrane, leading to hemolysis.
Triggers of Hemolysis:
Hemolysis in G6PD deficiency is usually triggered by oxidative stress. Common triggers include:
Infections: Bacterial and viral infections increase oxidative stress on RBCs.
Medications: Certain drugs, including antimalarials (e.g., primaquine), sulfonamides, and antibiotics (e.g., dapsone), can precipitate hemolysis.
Fava beans: Consumption of fava beans (favism) can lead to a rapid hemolytic episode in susceptible individuals.
Chemicals: Exposure to chemicals like naphthalene (found in mothballs) can trigger hemolysis.
Hemolysis:
In G6PD deficiency, hemolysis is intravascular and extravascular. The damaged RBCs are either destroyed in the circulation or sequestered and destroyed in the spleen.
Specific Symptoms:
Acute Hemolytic Episodes (following exposure to triggers):
Fatigue and weakness due to sudden anemia.
Jaundice: Yellowing of the skin and eyes due to elevated bilirubin levels from RBC breakdown.
Dark Urine: Due to the presence of hemoglobin and its breakdown products in the urine (hemoglobinuria).
Shortness of Breath: Resulting from anemia.
Rapid Heartbeat (Tachycardia): As the body tries to compensate for reduced oxygen-carrying capacity.
Pallor: Pale appearance due to anemia.
Chronic Non-Spherocytic Hemolytic Anemia (CNSHA): In rare cases, patients have chronic hemolysis with no apparent triggers.
Treatment:
1. Pharmacological:
Avoidance of Triggers: The most important treatment is avoiding known triggers such as certain medications, foods (fava beans), and chemicals that induce oxidative stress.
2. Non-Pharmacological:
Blood Transfusions: In cases of severe hemolysis with significant anemia, blood transfusions may be necessary to replenish RBCs.
Supportive Care: During acute episodes, patients may need hydration and oxygen therapy to support kidney function and tissue oxygenation.
Lab Diagnosis:
Complete Blood Count (CBC):
Hemoglobin: Reduced during hemolytic episodes.
Reticulocyte Count: Elevated as the bone marrow compensates for the hemolysis by increasing RBC production.
Peripheral Blood Smear:
RBC Shape: During hemolytic episodes, the smear may show bite cells (RBCs with portions "bitten" off) and Heinz bodies (denatured hemoglobin precipitates within RBCs), which are characteristic findings.
G6PD Assay:
Measures the activity of G6PD in RBCs. Low levels confirm the diagnosis of G6PD deficiency. This test is typically performed after the acute hemolytic episode has resolved, as testing during hemolysis may give a false normal result (due to the higher enzyme activity in young RBCs).
Bilirubin:
Increased indirect (unconjugated) bilirubin due to hemolysis.
Lactate Dehydrogenase (LDH):
Elevated due to the breakdown of RBCs.
Haptoglobin:
Decreased because free hemoglobin released during hemolysis binds to haptoglobin, depleting its levels.
Coombs Test:
Negative, helping to differentiate G6PD deficiency from autoimmune hemolytic anemia.
Complications:
Acute Kidney Injury (AKI): Massive hemolysis can overwhelm the kidneys' ability to process the breakdown products of hemoglobin, leading to acute kidney injury.
Severe Anemia: In cases of recurrent or severe hemolytic episodes, patients can develop severe anemia, requiring hospital admission and blood transfusions.
Neonatal Jaundice: Newborns with G6PD deficiency may develop severe jaundice soon after birth, leading to kernicterus (bilirubin-induced brain damage) if not treated.
Summary:
G6PD deficiency is an X-linked recessive disorder that leads to a deficiency of the G6PD enzyme, which protects RBCs from oxidative damage. When exposed to oxidative stress (due to infections, medications, or certain foods), RBCs undergo hemolysis, leading to anemia, jaundice, and dark urine. Diagnosis involves measuring G6PD enzyme activity, and treatment focuses on avoiding triggers and providing supportive care during hemolytic episodes. Complications include acute kidney injury and severe anemia.
Pyruvate Kinase Deficiency
Introduction:
Pyruvate kinase (PK) deficiency is a rare inherited disorder of red blood cells (RBCs) that leads to a type of chronic hemolytic anemia. It is caused by a deficiency of the enzyme pyruvate kinase, which plays a crucial role in glycolysis, the metabolic pathway by which RBCs generate energy. Pyruvate kinase deficiency is inherited in an autosomal recessive manner and is one of the most common enzymatic causes of nonspherocytic hemolytic anemia.
Pathophysiology:
Role of Pyruvate Kinase:
Pyruvate kinase is an enzyme in the glycolytic pathway that converts phosphoenolpyruvate (PEP) to pyruvate, producing adenosine triphosphate (ATP). Since mature RBCs lack mitochondria, they rely solely on glycolysis for their energy production.
Energy Deficiency in RBCs:
A deficiency in pyruvate kinase results in reduced ATP production, leading to an energy crisis in RBCs. Without enough ATP, RBC membrane function is impaired, causing loss of membrane integrity and deformability.
Hemolysis:
The energy-deficient RBCs are less flexible and more fragile, making them prone to destruction. This leads to chronic hemolysis that is primarily extravascular, occurring in the spleen and liver, where macrophages phagocytose the defective cells.
Splenic Destruction:
As the spleen removes damaged RBCs from the circulation, splenomegaly (enlargement of the spleen) can develop.
Specific Symptoms:
Chronic Hemolytic Anemia:
Symptoms of chronic anemia include fatigue, weakness, pallor, and shortness of breath.
Jaundice:
Due to increased bilirubin levels from the breakdown of hemoglobin in destroyed RBCs, patients may present with jaundice (yellowing of the skin and eyes).
Gallstones:
Chronic hemolysis leads to excess bilirubin production, which can cause the formation of pigment gallstones.
Splenomegaly:
The spleen is often enlarged due to its increased role in destroying defective RBCs.
Neonatal Jaundice:
Infants with pyruvate kinase deficiency may develop severe jaundice shortly after birth, requiring treatment to prevent complications such as kernicterus.
Treatment:
1. Pharmacological:
Folic Acid Supplementation: Folic acid (1 mg/day) is often given to support increased RBC production in the bone marrow to compensate for ongoing hemolysis.
2. Non-Pharmacological:
Splenectomy: In cases of severe hemolysis, a splenectomy (removal of the spleen) may be considered to reduce the destruction of RBCs. Splenectomy usually improves anemia, but the patient becomes more susceptible to infections.
Blood Transfusions: Patients with severe anemia, especially during periods of stress or illness, may require blood transfusions.
Lab Diagnosis:
Complete Blood Count (CBC):
Hemoglobin: Usually low due to chronic hemolysis.
Reticulocyte Count: Elevated due to the bone marrow’s response to hemolysis by increasing RBC production.
Peripheral Blood Smear:
RBC Shape: The smear may show RBCs with spiculated projections (known as echinocytes or burr cells) due to membrane damage.
Pyruvate Kinase Assay:
The definitive diagnosis is made by measuring the activity of pyruvate kinase in RBCs, which will be decreased in patients with PK deficiency.
Bilirubin:
Elevated indirect (unconjugated) bilirubin due to increased RBC destruction.
Lactate Dehydrogenase (LDH):
Elevated as a marker of hemolysis.
Haptoglobin:
Low, as free hemoglobin released during hemolysis binds to haptoglobin, depleting its levels.
Coombs Test:
Negative, helping to rule out autoimmune causes of hemolysis.
Complications:
Severe Anemia: Chronic hemolytic anemia can lead to severe fatigue, pallor, and reduced oxygen-carrying capacity.
Gallstones: The chronic hemolysis increases the risk of developing pigment gallstones due to the excessive breakdown of hemoglobin.
Aplastic Crisis: Similar to other hemolytic anemias, infection with parvovirus B19 can temporarily halt RBC production, causing a life-threatening aplastic crisis.
Iron Overload: In patients who require multiple blood transfusions, iron overload can develop, potentially damaging organs such as the liver, heart, and endocrine glands.
Summary:
Pyruvate kinase deficiency is an autosomal recessive disorder causing chronic hemolytic anemia due to decreased energy production in RBCs. The lack of ATP leads to RBC membrane instability, causing premature destruction of RBCs, primarily in the spleen. Patients may experience chronic anemia, jaundice, and splenomegaly. Diagnosis is confirmed by measuring pyruvate kinase activity, and treatment includes folic acid supplementation, splenectomy in severe cases, and supportive care during hemolytic episodes. Complications include gallstones, aplastic crisis, and iron overload from frequent transfusions.
Cytochrome b5 Deficiency
Introduction:
Cytochrome b5 deficiency is a rare inherited disorder that affects the cytochrome b5 reductase enzyme system, leading to abnormalities in hemoglobin function. It typically causes a condition known as hereditary methemoglobinemia, where an abnormally high level of methemoglobin (an oxidized form of hemoglobin) is present in the blood, resulting in impaired oxygen delivery to tissues. There are three recognized types of cytochrome b5 reductase deficiency, ranging from mild to severe, depending on which tissues are affected.
Pathophysiology:
Role of Cytochrome b5:
Cytochrome b5 is a hemoprotein that plays a key role in electron transport, particularly in the reduction of methemoglobin back to hemoglobin. It works in conjunction with cytochrome b5 reductase, an enzyme that transfers electrons from NADH to reduce methemoglobin (Fe³⁺) to hemoglobin (Fe²⁺), restoring its oxygen-carrying ability.
Deficiency of Cytochrome b5 Reductase:
In cytochrome b5 deficiency, there is a malfunction in this reduction process, leading to an accumulation of methemoglobin in the blood. Methemoglobin cannot bind oxygen effectively, impairing oxygen delivery to tissues.
Types of Cytochrome b5 Deficiency:
Type I (Erythrocyte Methemoglobinemia): Limited to red blood cells. Patients generally have a mild, well-compensated form of methemoglobinemia and present with cyanosis.
Type II (Generalized Methemoglobinemia): Affects all cells and tissues, leading to a more severe form of methemoglobinemia. This type is associated with neurological abnormalities and developmental delays.
Type III (Erythrocyte and Leukocyte Methemoglobinemia): Affects red blood cells and white blood cells, but its clinical significance is less well understood.
Specific Symptoms:
Cyanosis: A bluish discoloration of the skin, lips, and mucous membranes due to increased levels of deoxygenated blood. This is typically the first sign and is more prominent when methemoglobin levels exceed 10%.
Fatigue: Due to impaired oxygen delivery to tissues, patients may experience fatigue and weakness.
Shortness of Breath: Patients with significant methemoglobinemia may experience breathlessness, especially during exertion.
Neurological Symptoms (Type II): In severe cases, particularly in Type II, patients may present with developmental delays, seizures, intellectual disability, and movement disorders due to the involvement of brain tissue.
Treatment:
1. Pharmacological:
Methylene Blue: The mainstay of treatment for acute methemoglobinemia is the administration of methylene blue, which serves as an artificial electron carrier. It accelerates the reduction of methemoglobin to hemoglobin through the NADPH-dependent pathway. However, it is ineffective in patients with G6PD deficiency.
2. Non-Pharmacological:
Avoidance of Oxidative Stress: Patients should avoid known triggers that can increase methemoglobin levels, such as certain medications (e.g., sulfonamides, dapsone, local anesthetics like benzocaine), chemicals, and foods that can induce oxidative stress.
Ascorbic Acid: Chronic low-level methemoglobinemia may be managed with daily doses of ascorbic acid (vitamin C), which can reduce methemoglobin levels over time.
Lab Diagnosis:
Arterial Blood Gas (ABG) Analysis:
Despite cyanosis, oxygen saturation by pulse oximetry can appear falsely normal (85%), while the true oxygen-carrying capacity of hemoglobin is impaired.
Methemoglobin Levels:
Blood tests can directly measure methemoglobin levels, which will be elevated in patients with cytochrome b5 deficiency.
Complete Blood Count (CBC):
Typically normal in cases of methemoglobinemia, except for the presence of elevated methemoglobin levels.
Peripheral Blood Smear:
RBCs may appear normal in shape, but in severe cases, methemoglobin may give a chocolate-brown discoloration to the blood.
Enzyme Assay:
Measurement of cytochrome b5 reductase activity in red blood cells confirms the diagnosis.
Co-oximetry:
This specialized test can differentiate between different forms of hemoglobin (oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin) and accurately measures methemoglobin levels.
Complications:
Severe Tissue Hypoxia: Elevated levels of methemoglobin reduce the oxygen-carrying capacity of hemoglobin, leading to tissue hypoxia, which can be life-threatening if left untreated.
Neurological Damage: In Type II deficiency, there can be severe neurological impairment, including intellectual disability, seizures, and movement disorders.
Death: In rare cases, if methemoglobin levels rise excessively (above 50-70%), patients may experience life-threatening hypoxia, shock, or death.
Summary:
Cytochrome b5 deficiency is a genetic disorder leading to impaired reduction of methemoglobin, resulting in cyanosis, fatigue, and in severe cases, neurological deficits. Diagnosis is confirmed through measuring methemoglobin levels and enzyme activity. Treatment involves methylene blue for acute episodes and ascorbic acid for chronic management. Avoidance of oxidative triggers is crucial to prevent hemolytic episodes. Complications include severe hypoxia and potential neurological damage in the more severe forms of the disease.