48 Erythrocyte Enzyme Disorder Flashcards
Two principal types of hemolysis:
- Enzyme abnormalities that make the red cell susceptible to acute and/or episodic hemolysis after exposure to oxidants or infection or after eating fava beans (favism)
- Enzyme abnormalities that result in chronic hemolytic anemia (hereditary nonspherocytic anemia)
The normal energy source of the red cell
Glucose
Glucose is metabolized by the erythrocyte along 2 major routes:
- The glycolytic pathway
- The hexose monophosphate shunt
Unlike most other cells, the red cell lacks a citric acid cycle and extracts energy from glucose almost solely by anaerobic glycolysis
Transport of glucose into the red cell is facilitated by glucose receptor GLUT1 and regulated by the abundantly expressed membrane protein stomatin
The primary controlling factor for 2,3-BPG levels
pH
RBC inclusion that represents denatured hemoglobin
Heinz bodies
A hereditary sex-linked enzyme deficiency that affected primarily the erythrocytes, older cells being more severely affected than newly formed ones because of age-dependent decline of mutant enzyme activity
The most common red cell enzyme abnormality
G6PD deficiency
- Very prevalent in individuals of African, Mediterranean, and Asian ethnic origins, but could be found in virtually any population
- Discovered in the 1950s of the hemolytic effect of the antimalarial drug primaquine
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)
The “normal” or wild-type enzyme
G6PD B
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)
The principal deficient variant found among people of African ancestry
G6PD A–
G6PD A+: A mutant enzyme with normal activity; polymorphic among persons of African descent; has substitution of Asn to Asp at codon 126, resulting from nucleotide change c.376A>G
Classes of G6PD variants
- Class I (severe deficiency, chronic hemolysis)
- Class II (severe deficiency, intermittent hemolysis)
- Class III (moderate deficiency, intermittent hemolysis)
- Class IV (normal activity)
- Class V (increased activity)
The majority of mutations (85%) are ______________ mutations causing the substitution of a single amino acid, more severe mutations causing a complete loss of activity are absent, indicating that some residual activity is required for survival.
Missense mutations
The major clinical consequence of G6PD deficiency is ___________ in adults and ___________- in infants, and the anemia is usually episodic
Hemolytic anemia
Neonatal icterus
Some unusual variants may cause nonspherocytic congenital hemolytic disease
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)
Typically, drug-induced hemolysis begins _______ days after drug exposure.
1 to 3 days
When severe, it may be associated with abdominal or back pain. The urine may become dark, even black.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)
Drugs That Can Incite Hemolysis
Predictable Hemolysis
Antiparasitics
* Dapsone
* Primaquine
* Methylene blue
Analgesics/Antipyretic
* Phenazopyridine
Antibacterials
* Cotrimoxazole
* Sulfadiazine
* Quinolones (including nalidixic acid, ciprofloxacin, ofloxacin)
* Nitrofurantoin
Other
* Rasburicase
* Toluidine blue
Infections that can precipitate hemolysis
- Hepatitis A and B
- Cytomegalovirus
- Pneumonia
- Typhoid fever
The fulminating form of the disease occurs particularly frequently among G6PD-deficient patients who are infected with Rocky Mountain spotted fever.
- Jaundice is not a prominent part of the clinical picture, except where hemolysis occurs in association with infectious hepatitis.
- Reticulocytosis is usually absent, and recovery from the anemia is generally delayeduntil after the active infection has abated.
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)
One of the most severe hematologic consequences of G6PD deficiency, and for many affected subjects
Hemolysis occurs within hours to days after ingestion of the fava beans
Favism
Not all G6PD-deficient subjects develop hemolysis when they ingest fava beans. The enzyme deficiency is a necessary but not sufficient factor.
________ allows for reliable confirmation of G6PD deficiency in female carriers.
DNA analysis
Assays or screening tests for G6PD deficiency are most reliable in healthy affected (hemizygous) males and may be normal in females with G6PD deficiency.
TRUE OR FALSE
The majority of studies conclude that G6PD deficiency in hemizygous males, and probably also homozygous females, confers significant protection against malarial infection
TRUE
The majority of studies conclude that G6PD deficiency in hemizygous males, and probably also homozygous females, confers significant protection against malarial infection
Chronic hemolysis in the absence of a stress; occur with severely deficient variants of G6PD deficiency (however, these are very rare; referred to as class 1 G6PD deficiency)
More likely caused by other red cell enzyme deficiencies than G6PD.
Chronic jaundice, splenomegaly, and gallstones are common, and some patients develop ankle ulcers.
HEREDITARY NONSPHEROCYTIC HEMOLYTIC ANEMIA (HNSHA)
The most common disorder of red blood cell glycolysis
The most common cause of HNSHA
Pyruvate kinase (PK) deficiency
An oral, small-molecule allosteric activator of pyruvate kinase
Mitapivat
Second most common cause of HNSHA
Glucose phosphate isomerase deficiency
Anemia is usually relatively mild, but fetal hydrops has been observed several times with this enzyme deficiency.
The most devastating of the red cell enzyme defects
Most patients die of neuromuscular complications before the age of 6 years
Characterized by hemolytic anemia, often accompanied by neonatal hyperbilirubinemia requiring exchange transfusion
Triosephosphate isomerase deficiency
Characterized by prominent basophilic stippling and is, therefore, the only cause of HNSHA in which a provisional diagnosis is possible from morphologic analysis
The most common enzyme abnormality affecting nucleotide metabolism (more than 100 patients reported)
Pyrimidine 5′-nucleotidase deficiency
Acquired deficiency of pyrimidine 5′-nucleotidase may result from lead poisoning (lead preferentially occupies the enzyme’s active site).
Characterized predominantly by mild to severe myopathy, in particular exercise intolerance, cramps, and myoglobinuria
The associated hemolysis is usually mild but may be absent
PFK deficiency
TRUE OR FALSE
Enzyme tests may require retesting more than 2 months after the patient is fully recovered from hemolytic episode because some enzymes levels, eg, PK and G6PD, are higher in reticulocytes and young red cells.
TRUE
Enzyme tests may require retesting more than 2 months after the patient is fully recovered from hemolytic episode because some enzymes levels, eg, PK and G6PD, are higher in reticulocytes and young red cells.
This is especially common during a hemolytic episode in G6PD A– patients because residual young red cells have normal levels of G6PD.
TRUE OR FALSE
Folic acid therapy is often given but is without proven hematologic benefit unless a deficiency is found in the red cells.
TRUE
Folic acid therapy is often given but is without proven hematologic benefit unless a deficiency is found in the red cells.
Glucocorticoids are of no known value in enzymopathies
TRUE OR FALSE
Iron therapy is contraindicated unless unrelated causes of iron deficiency are present and its diagnosis established.
TRUE
Iron therapy is contraindicated unless unrelated causes of iron deficiency are present and its diagnosis established.
It occurs particularly in infants who are G6PD deficient or inheriting red cell membrane disorders who have also inherited a mutation of the UDP-glucuronosyltransferase-1 gene promoter (Gilbert syndrome).
Results probably principally from inadequate bilirubin processing, but shortened red cell span plays a contributory role
Frequently unaccompanied by changes in hematologic indices reflective of a hemolytic process, and the reason for this discrepancy is unclear
ICTERUS NEONATORUM
- If not treated, it may lead to kernicterus and mental retardation.
- It is rare in neonates with the A– variant but more common in Mediterranean and various Asian variants.
Ascorbic acid does not cause hemolytic anemia in normal doses, but can produce severe, even fatal, hemolysis at doses of ________ g or more intravenously
80 g or more intravenously
