Download hexose monophosphate `shunt` pathway

The glycolytic pathway is the main source of energy (ATP)
The hexose monophosphate ‘shunt’ pathway provides the
main source of reduced nicotinamide adenine dinucleotide phosphate
(NADPH), which maintains reduced glutathione (GSH) and protects
haemoglobin and the membrane proteins against oxidant damage.
Genetics
1. Sex-linked recessive mode of inheritance by a
gene located on the X chromosome (similar to
hemophilia).
2. Disease is fully expressed in hemizygous males
and homozygous females.,there is an advantage of
resistance to falciparum malaria in heterozygous
females.
Pathogenesis
- Red cell integrity impaired, especially on exposure to
oxidant drugs, oxidant response to infection and chemicals.
- Oxidation of hemoglobin and of sulfhydryl groups in the
membrane.
- Oxidized hemoglobin precipitates to form Heinz bodies
which are plucked out of the red cell leading to hemolysis
and “bite cell” and “blister cell” morphology.
WHO Classification of G6PD Variants
Clinical Features
Episodes of hemolysis may be produced by:
• Drugs.
• Fava bean (broad bean): ingestion or exposure to pollen
from the bean’s flower (favism)
• Infection.
symptoms develop 24–48 hr after a patient has ingested a
substance that has oxidant properties, The degree of
hemolysis varies with( the inciting agent, the amount
ingested, and the severity of the enzyme deficiency).
The enzyme is abundant and more stable in younger RBCs.
The associated reticulocytosis produces a compensated
hemolytic process.
PRECIPITATING FACTORS
• Antimalarials: primaquine, quinine, chloroquine
• Antibiotics - nitrofuantoin, furazolidine,
cotrimoxazole, Nalidixic acid,
Chloramphenicol,
• Others :
• Vitamin K – large doses
• Naphthalene (moth balls)
• Benzene, Methylene blue
• Probenecid
• Acetyl salicylic acid (aspirin)
• Fava beans
• Septicemia and viral hepatitis
• Diabetic ketoacidosis
1. Drug-induced hemolysis
a. Typically in African-Americans but also in
Mediterranean types
c. Acute self-limiting hemolytic anemia with
hemoglobinuria
d. Heinz bodies in circulating red cells
e. Blister cells, fragmented cells
f. Reticulocytosis
g. Hemoglobin normal between episodes.
2. Favism
This results from oxidative products derived from
2 glycosidic compounds, vicine and convicine, which
are hydrolyzed to divicine and isouramil, ultimately
producing hydrogen peroxide and other reactive
oxygen products.
Acute life-threatening hemolysis, often leading to
acute renal failure, associated with Mediterranean.
Blood transfusion is required.
3. Neonatal jaundice
Infants may present with pallor, jaundice (can be
severe and produce kernicterus)and dark urine.
When a pregnant woman ingests oxidant drugs, they
may be transmitted to her G6PD-deficient fetus,
and hemolytic anemia and jaundice may be apparent
at birth.
Occasionally exposure to naphthalene (mothballs),
aniline dye, marking ink, or a drug.
Chronic nonspherocytic hemolytic anemia
Occurs mainly with sporadic inheritance
it variable but can be severe with transfusion
dependence and intense neonatal
presentation(NNJ)
Persons with G6PD B‾(Mediterranean) enzyme
deficiency occasionally have chronic hemolysis, and
the hemolytic process may worsen after ingestion
of oxidant drugs.
Splenectomy is of little value in these types of
chronic hemolysis.
LABORATORY FINDINGS.
-Blood film:RBCs reveal Heinz bodies (precipitated
hemoglobin.
Because cells containing these inclusions are rapidly removed
from the circulation, they are not seen after the first 3–4
days of illness.
The blood film reveals a few fragmented and
polychromatophilic cells (bluish, large RBCs), representing
reticulocytosis(5–15%).
DIAGNOSIS
The diagnosis depends on direct or indirect
demonstration of reduced G6PD activity in RBCs.
By direct measurement,
enzyme activity in affected persons is ≤10% of
normal. Immediately after a hemolytic episode,
reticulocytes and young RBCs predominate. These
young cells have significantly higher enzyme
activity than do older cells. Testing may therefore
have to be deferred for a few weeks before a
diagnostically low level of enzyme can be shown.
Satisfactory screening tests are based on
- decoloration of methylene blue,
- reduction of methemoglobin
- fluorescence of NADPH
G6PD variants also can be detected by
electrophoretic analysis.
Management
1. Avoidance of agents that are deleterious in G6PD
deficiency.
2. Education of families and patients in recognition of food
prohibition (fava beans), drug avoidance, heightened vigilance
during infection and the symptoms and signs of hemolytic
crisis (orange/dark urine, lethargy, fatigue, jaundice).
3. Indication for transfusion of packed red blood cell in
children presenting with acute hemolytic anemia:
a. Hemoglobin (Hb) level below 7 g/dl
b. Persistent hemoglobinuria and Hb below 9 g/dl.
4. Chronic nonspherocytic hemolytic anemia (NSHA):
• In patients with severe chronic anemia: transfuse red
blood cells to maintain Hb level (8–10 g/dl) and iron chelation
when needed.