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MLSCI 230 > RBC Enzymopathies > Flashcards

RBC Enzymopathies Flashcards

1
Q

Abnormalities of hexose-monophosphate shunt

A

G6PD Deficiency

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2
Q

Abnormalities of the Embden-Meyerhof Pathway

A

PK Deficiency

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3
Q

G6PD on males vs female populations

A

Variant is on X chromosome = Male hemizygotes can have full disease expression. Females with the disease can by homozygous or heterozygous with one X chromosome inactivated

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4
Q

The role of G6PD in RBC metabolism

A
  • it converts G6P into 6-phosphogluconate
  • this process turns NADP to NADPH which releases glutione reducatse
  • this reductase turns GSSG and GSH which enables gluthione peroxidase to convert an oxidant -> H2O2 into a water molecule
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5
Q

The most common enzymatic deficiency of RBCs

A

G6PD deficiency

  • first step in the pathway
  • decrease in NADPH = increase in ribulose-5-phosphate
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6
Q

G6PD Subtypes

A
  • many variants of the enzyme and each have varying levels of enzyme activity
  • G6PD B (wild type) is normal
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7
Q

The severity of Anemia in G6PD depends on:

A
  • type of defect
  • the level of enzyme activity in erythrocytes
  • severity of the oxidant challenge
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8
Q

T or F. The vast majority of individuals with G6PD deficiency are asymptomatic throughout their whole lives

A

T

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9
Q

Possible disease presentations of G6PD deficiency

A
  • acute hemolytic anemia (most common we see these patients)
  • neonatal jaundice (huperbilorubinemia)
  • chronic hereditary non-spherocytic hemolytic anemia (very rare)
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10
Q

T or F. G6PD deficiency (A2 variant) in hemizygous males confers protection against life-threatening Plasmodium falciparum malaria

A

T, what studies have shown!
- this protective effect is not observed in heterozygous females because of their mosaicism of normal G6PD-deficient RBCs

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11
Q

GP6PD A variant

A
  • does not manifest anemia until they are exposed to an oxidant drug or other oxidant challenge
  • triggers could provoke an acute hemolytic episode with intravascular hemolysis
  • adequate retic response in restoration of the hemoglobin conctn even if the offending drug is continued bc the newly formed retics are relatively resistant to oxidant stress given their higher G6PD levels
  • women heterozygous for G6PD A = usually experience only mild anemia upon exposure to oxidant stress because a population of G6PD sufficient (normal) cells coexists
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12
Q

G6PD B variant

A
  • Mediterranean variant
  • more severe than the African G6PD A–variant
  • More severe hemolytic episodes
  • Men and heterozygous women with the G6PD-Mediterranean variant can experience severe hemolysis in the face of oxidant stress, and the offending agent must be removed because the reticulocytes have low enzyme levels and are prone to hemolysis
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13
Q

hereditary nonspherocytic hemolytic anemia

A
  • A small percentage of G6PD-deficient patients have chronic HNSHA, as evidenced by persistent hyperbilirubinemia, decreased serum haptoglobin level, and increased serum lactate dehydrogenase level. Most of these patients are diagnosed at birth as having neonatal hyperbilirubinemia, and the hemolysis continues into adulthood
  • They usually do not have hemoglobinuria, which suggests that the ongoing hemolysis is extravascular as opposed to intravascular. RBC morphology is unremarkable.
  • These patients also are vulnerable to acute oxidative stress from the same agents as those affecting other G6PD-deficient individuals and may have acute episodes of hemoglobinuria
  • severity is extremely variable, likely related to the type of mutation in the G6PD gene
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14
Q

Hemolytic anemia in patients with G6PD defiiency

A
  • may first be recognized during an acute clinical event that induces oxidant stress:
    > infection
    > diabetic ketoacidosis
    > severe liver injury
    NOTE: in children, infection is a common precipitating event
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15
Q

Lab findings in people deficient in G6PD

A
  • normocytic, normochromic anemia
  • anisocytosis
  • poikilocytosis
  • bite cells and blister cells (KEY)
  • Heinz bodies (only be detected using a supravital stain)
  • DAT neg
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16
Q

Purple-staining Heinz bodies are precipitates of…

A

denatured hemoglobin that tend to attach to the cell membrane

17
Q

Two-stage tests for diagnosis RBC enzyme defects

A
  • first screening

- specific enzyme assay

18
Q

More common tests for Enzyme defects

A
  • ascorbate cyanide test

- fluorescent spot test

19
Q

Fluorescence screening test for G6PD deficiency

A
  • a qualitative screen
  • NADPH in a lysate of RBCs, fluoresces under long-wave UV light
  • in G6PD-D there is inability to produce sufficient NADPH = lack of fluorescence
20
Q

Tor F. Retics have higher G6Pd levels than mature RBCs

A

T! Need to know the retic count before testing for G6PD (false normal if reticulocytosis) (false deficiency if anemic = little fluorescence)

21
Q

reticulocytosis

A

condition where there is an increase in reticulocytes

22
Q

The quantitative assay following a positive screen for G6PD-D

A

quantitative spectrophotometric assays = gold standard!; can assess severity of disease

23
Q

T or F. Most hemolytic episodes, especially in individuals with G6PD-A2 are self-limited

A

T!

24
Q

Treatment for G6PD-Mediterranean

A

more severe so may need RBC transfusions

25
Q

Role of pyruvate kinase in RBC metabolism

A

Pyruvate kinase is an enzyme that helps cells turn sugar (glucose) into energy (called adenosine triphosphate, ATP) in a process called glycolysis. Red cells rely on this process for energy, and so, pyruvate kinase deficiency leads to a deficiency in energy and to premature red cell destruction (hemolysis)

26
Q

In contrast to G6PD deficiency, PK inheritance is ….

A

autosomal recessive

27
Q

the most common congenital nonspherocytic hemolytic anemia caused by a defect in glycolytic RBC metabolism. 1 per 20,000

A

PK deficiency

28
Q

early signs of PK deficiency

A
  • neonatal or early childhood jaundice
  • splenomegaly
  • failure to thrive
  • osmotic fragility of the patient’s RBC is typically normal
29
Q

Two metabolic abnormalities resulting from PK deficiency

A
  • depleted ATP
  • increased 2,3-BPG (shifts curve to the right and decreases the O2 affinity of Hb)
    > promotes greater release of O2 to tissues; enables affected indivs to tolerate lower levels of Hb
    > also affects ability of cell to maintain its shape and membrane integrity
30
Q

Clinical manifestations of chronic hemolysis

A
  • most patients have chronic hemolysis

- increased incidence of gallstones due to production of excessive bilirubin

31
Q

Lab findings for PK deficiency

A
  • distorted and shrunken RBCs (echinocytes due to decreased ATP)
32
Q

Problems with quantitative PK assay

A

A hemolysate is prepared from patient’s anticoagulated blood after careful removal of the WBCs. WBCs have a very high PK level, and contamination of the hemolysate with WBCs falsely increases the result (i.e., in a PK deficiency, the result could be falsely normal)

33
Q

T or F. NAD fluoresces but NADH does not

A

F!

  • NADH fluoresces but NAD does not
  • PK deficiency = persistence of fluorescence
  • screening test
34
Q

Quantitative assay of PK

A
  • The same principle is employed as in the screening test, but the rate of decrease of absorbance at 340 nm is measured.
  • A negative screening test or a normal PK assay (using the standard high substrate [PEP] concentrations) does not rule out PK-deficient hemolytic anemia. Because mutant PK enzymes may have normal activity at high PEP concentrations
  • Decreased activity at low PEP concentrations
  • it is necessary to perform the assay both ways
35
Q

Treatment for PK deficiency

A
  • No specific therapy is available for PK deficiency except supportive treatment and RBC transfusion as necessary.
  • Splenectomy is beneficial in severe cases, and after this procedure the hemoglobin level usually increases enough to reduce or eliminate the need for transfusion.
  • Splenectomy, however, results in a lifelong increased risk of sepsis by encapsulated bacteria.
  • Hematopoietic stem cell transplant may be curative for children with severe hemolytic disease who have an unaffected HLA-identical sibling for a donor
36
Q

Characteristic abnormality of PK deficiency observed on the PBS

A

echinocytes

37
Q

most common defect of the glycolytic pathway

A

PK deficiency

MLSCI 230 (36 decks)

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