Enzymopathies

Question 1

Two principal types of hemolysis:

Answer 1

• 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)

Question 2

The normal energy source of the red cell

Answer 2

Glucose

Question 3

Glucose is metabolized by the erythrocyte along 2 major routes:

Answer 3

• 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

Question 4

The primary controlling factor for 2,3-BPG levels

Answer 4

pH

Question 5

RBC inclusion that represents denatured hemoglobin

Answer 5

Heinz bodies

Question 6

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

Answer 6

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

Question 7

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)

The “normal” or wild-type enzyme

Answer 7

G6PD B

Question 8

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)

The principal deficient variant found among people of African ancestry

Answer 8

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

Question 9

Classes of G6PD variants


Answer 9

• 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)

Question 10

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.

Answer 10

Missense mutations

Question 11

The major clinical consequence of G6PD deficiency is ___________ in adults and ___________- in infants, and the anemia is usually episodic

Answer 11

Hemolytic anemia

Neonatal icterus

Some unusual variants may cause nonspherocytic congenital hemolytic disease

Question 12

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)

Typically, drug-induced hemolysis begins _______ days after drug exposure.

Answer 12

1 to 3 days

When severe, it may be associated with abdominal or back pain. The urine may become dark, even black.

Question 13

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD)

Drugs That Can Incite Hemolysis

Predictable Hemolysis

Answer 13

Antiparasitics
* Dapsone
* Primaquine
* Methylene blue

Analgesics/Antipyretic
* Phenazopyridine

Antibacterials
* Cotrimoxazole
* Sulfadiazine
* Quinolones (including nalidixic acid, ciprofloxacin, ofloxacin)
* Nitrofurantoin

Other
* Rasburicase
* Toluidine blue

Question 14

Infections that can precipitate hemolysis

Answer 14

• 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.

Question 15

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

Answer 15

Favism

Not all G6PD-deficient subjects develop hemolysis when they ingest fava beans. The enzyme deficiency is a necessary but not sufficient factor.

Question 16

________ allows for reliable confirmation of G6PD deficiency in female carriers.

Answer 16

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.

Question 17

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

Answer 17

TRUE

The majority of studies conclude that G6PD deficiency in hemizygous males, and probably also homozygous females, confers significant protection against malarial infection

Question 18

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.

Answer 18

HEREDITARY NONSPHEROCYTIC HEMOLYTIC ANEMIA (HNSHA)

Question 18

The most common disorder of red blood cell glycolysis

The most common cause of HNSHA

Answer 18

Pyruvate kinase (PK) deficiency

Question 19

An oral, small-molecule allosteric activator of pyruvate kinase

Answer 19

Mitapivat

Question 20

Second most common cause of HNSHA

Answer 20

Glucose phosphate isomerase deficiency

Anemia is usually relatively mild, but fetal hydrops has been observed several times with this enzyme deficiency.

Question 21

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

Answer 21

Triosephosphate isomerase deficiency

Question 22

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)

Answer 22

Pyrimidine 5′-nucleotidase deficiency

Acquired deficiency of pyrimidine 5′-nucleotidase may result from lead poisoning (lead preferentially occupies the enzyme’s active site).

Question 23

Characterized predominantly by mild to severe myopathy, in particular exercise intolerance, cramps, and myoglobinuria

The associated hemolysis is usually mild but may be absent

Answer 23

PFK deficiency

Question 24

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.

Answer 24

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.

Question 25

TRUE OR FALSE

Folic acid therapy is often given but is without proven hematologic benefit unless a deficiency is found in the red cells.

Answer 25

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

Question 26

TRUE OR FALSE

Iron therapy is contraindicated unless unrelated causes of iron deficiency are present and its diagnosis established.

Answer 26

TRUE

Iron therapy is contraindicated unless unrelated causes of iron deficiency are present and its diagnosis established.

Question 27

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

Answer 27

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.

Question 28

Ascorbic acid does not cause hemolytic anemia in normal doses, but can produce severe, even fatal, hemolysis at doses of ________ g or more intravenously

Answer 28

80 g or more intravenously