Post on 31-Oct-2014
description
SALVADOR Patricia P.
To discuss the different genetic aberrations leading to G6PD deficiency
To discuss the relationship of Malaria resistance with having G6PD deficiency
I. Brief History II. Mutations involving G6PD deficiencyIII. Clinical and Laboratory findingsIV. G6PD resistance in relation to having
Malaria
Pythagoras – danger of eating
FAVA BEANS Hemolytic effect of anti- malarial
drug PRIMAQUINESensitive individuals had low levels
of G6PD activity in their RBC
G6PD deficiency – one of the most common inherited disorders.
Epidemiological and in vitro studies – advantageous during Plasmodium falciparum infection
Affected individuals are asymptomatic
Possess risk of acute hemolysis
located on the long (q) arm of the X chromosome at position 28Hemophilia A, color visionFragile X and dyskeratosis congenita
X-linked recessive
MaleNormal
Hemizygote (XY)
Deficient Hemizygote
(XaY) with variant gene
Affected
FemaleNormal Homozygote
(XX)Carrier
Heterozygote(XaX)
Female carriers can also be affected by the disease if:Two copies of the
gene in the genome is defective
Five (5) classes by World Health Organization
(WHO)Residual enzyme activitySeverity of hemolysis
Severe clinical symptoms Chronic hereditary non-sperocytic
hemolytic anemia Has < 20% G6PD activity Hemolysis in the absence of stressor
Mild clinical expression with intermittent hemolysis
Most common <10% G6PD activity Stress is present
Mild clinical expression with intermittent hemolysis
Associated with infections or drugs With 10% - 60% G6PD activity
Not deficient at all 100% G6PD activity Has no clinical manifestation
Greater than 100% activity Has increased activity than normal
located on the long (q) arm of the X chromosome at position 28
Generally in males Females can also be affected provided both X gene is variant
Asymptomatic Symptomatic
Triggered by:
•bacterial and viral infections•painkillers and fever-reducing drugs•antibiotics (especially those that have "sulf" in their names)•antimalarial drugs (especially those that have "quine" in their names)
Hemolytic anemia• paleness • extreme tiredness• rapid heartbeat• rapid breathing or shortness of breath
• jaundice, or yellowing of the skin and eyes, particularly in newborns
• an enlarged spleen• dark, tea-colored urine
Complete blood count
• Hematocrit• Hemoglobin• RBC count
Reticulocyte count
Heinz bodies in PBS
Lactate dehydrogenase
Haptoglobin
Indirect bilirubin
Urinalysis – Hemogloburia
Beutler fluorescent spot test• Inexpensive test• Identifies NADPH produced by G6PD under UV light
Beutler fluorescent spot testPrinciple: Reduction of oxidized pyridine nucleotide (NADP – NADPH)
• (+) : Blood spot do NOT fluoresce• False (+): Active hemolysis• Performed several weeks after hemolytic episode
Ascorbate Cyanide test• Specimen: EDTA or Heparin
• Test the ability of normal cells to detoxify H202 when incubated with ascorbate.
• Cyanide: catalase inhibitor
• Specifically measures the Glutathione peroxidase system
• (+): brown color• ( - ): color unchanged
Plasmodium falciparum
Blood conditions that may affect malaria ineffectivity Sickle cell anemia PABA deficiency Duffy factor
Glucose-6-Phosphate dehydrogenase deficiency
Plasmodium oxidizes RBC NADPH from the Pentose Phosphate pathway for its metabollism
Deficiency of RBC reduced gluthathione (GSH)
Infected RBC dies before the parasite is ready, the malarial parasite dies High susceptibility to
oxidative stress
Plasmodium oxidizes RBC NADPH from the Pentose Phosphate pathway for its metabollism
G6PD deffient individual may have resistance to malaria due to impaired growth the of parasite
•Case 1• JR, 26 y/o, black male
• 1 week before admission-signs of respiratory infection and a low-grade fever-self-medication of OTC cold preparation failed to alleviate his symptoms
• 1 day before admission -chills and hacking cough-at 40.6 °C his mother brought him to the ER-acutely ill, dyspneic and coughing-was admitted to the hospital
• Physical Exam
-slight icterus-bronchial breathing over the left lower lung field with scattered rales; moderate degree of dyspnea-Temp - 40 °C-Pulse - 120 bpm
• Lab Finding
-Hemoglobin - 8.4 g/dl-WBC - 18,000/µl with 80% polymorphonuclear leukocytes -Bilirubin - 3.2 mg/dL-Reticulocyte - 1.2%. -Gram positive diplococci in the sputum
• Penicillin therapy
• Next day-considerable improvement-cultures confirmed the presence of pneumococci in both sputum and blood-maximum temperature was 38.2 °C-his dyspnea is less pronounced.
• Next few days-fever abated completely-hemoglobin however, fell to 7.2 g/dL-reticulocyte count rose rapidly so that 7 days after admission, it had reached 12% (normal, <1%)
• One month after the episode of pneumococcus pneumonia
-hemoglobin was nearly normal at 13.8g/dL-patient fell quite well-was warned to never again to take aspirin-was supplied a long list of unfamiliar drugs and advised him never to take any of them
*Observed intermittently over the next several years, the patient experienced no further hemolytic episode
CASE 1CASE 1
CLASS IIICLASS III
PREVALENCEFound in 11% of black men
PREVALENCEFound in 11% of black men
STRESSInfection
Oxidizing drugs
STRESSInfection
Oxidizing drugs
OXIDATIVE BURSTPhagocytes releases
oxidants
OXIDATIVE BURSTPhagocytes releases
oxidants
• Case 2• Patient D.M.
• 1 day old-bilirubin was 14mg/dL-treated with ultraviolet light
• 2 day old-bilirubin climbed to 17 mg/dL-Preparations for exchange transfusion were made but abandoned when it fell to 13 g/dL-reticulocyte count at 5 to 10%
• Family History
-older brother - anemia and darkening of urine: 1. during a respiratory infection2. when a urinary tract infection was treated
with a sulfonamide of unknown type
-parents - both well
-maternal uncle - had intermittent jaundice & anemia
-The child developed normally-steady-state hemoglobin of 10.5 g/dL-reticulocyte of 10%
•At 6 years old-dark urine in the course of a
respiratory infection-hemoglobin declined to 5.4g/dL-transfusion of 1 U of packed red cells-subsequently, hemoglobin rose to the usual
level
• Following year
-diagnosis of hereditary spherocytosis -splenectomy was performed-no change in the steady-state hemoglobin level-nucleated red cells and red cells with Howell-Jolly bodies-platelet count elevated to 700 x 109/L
• At 14 years old
-anemia was re-evaluated-red cells were profoundly deficient in G6PD activity-has continued to get along quite well clinically-mildly jaundiced at times-during infections:
-hemolytic episode-fall in hemoglobin concentration-darkening of the urine
-has been cautioned to seek medical attention promptly-has dealt well with infections up to now
CASE 2CASE 2
CLASS ICLASS I
Severe G6PD Deficiency
Severe G6PD Deficiency
Hemolysis occur even in
the absence of stress
Hemolysis occur even in
the absence of stressPathologic jaundicePathologic jaundice
Hereditary spherocytosisHereditary
spherocytosisSplenomegalySplenomegalySplenectomySplenectomy
Sulphonamides/Sulphones
SulphametoxazoleSulfasalazineSulfisoxazoleSulfadimidine
SulfadiazineDapsoneOthers
Antimalarials PrimaquineDapsone/ChloroproguanilChloroquineQuinine
Drugs precipitating hemolytic anemia
Drugs precipitating hemolytic anemia
Antipyretic/analgesicsAcetanilideAcetylsalicylic acid high dose (>3 g/d)Acetylsalicylic acid (<3 g/d)
Phenazopyridine (Pyridium)
Norfloxacinp-Aminosalicylic acidNitrofurantoinNiridazole
AcetaminophenPhenacetin
Antibacterial/AntibioticsCotrimoxazoleCiprofloxacinChloramphenicolNalidixic acid
Drugs precipitating hemolytic anemia
Drugs precipitating hemolytic anemia