g6pd

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 antimalarial

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


Antipyretic/analgesicsAcetanilideAcetylsalicylic acid high dose (>3 g/d)Acetylsalicylic acid (<3 g/d)

Phenazopyridine (Pyridium)

Norfloxacinp-Aminosalicylic acidNitrofurantoinNiridazole

AcetaminophenPhenacetin

Antibacterial/AntibioticsCotrimoxazoleCiprofloxacinChloramphenicolNalidixic acid



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g6pd