G6PD and heme pigmentinduced ATN AM Report

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G6PD and heme pigment-induced ATNAM Report

• Emily Chang
• September 5, 2008

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What is it?
An inherited condition in which patients are
excessively susceptible to the development of
hemolytic anemia.  It is the most common
enzymatic disorder of RBCs in humans.   Affected
individuals lack the ability to tolerate
biochemical oxidative stress, and red cell
hemolysis is the most important clinical
consequence. First noted in African-American
soldiers who developed acute hemolytic anemia
with hemoglobinuria following primaquine
ingestion.
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WHO working groups

• Class I severely deficient, associated with
  chronic nonspherocytic hemolytic anemia
•  
• Class II severely deficient (1-10 residual
  activity), associated with acute intermittent
  hemolytic anemia (G6PD Mediterranean)
•  
• Class III moderately deficient (10-60 residual
  activity) - intermittent hemolysis usu assoc with
  infection or drugs (G6PD A)
• Class IV normal activity (60-150)
• Class V increased activity (gt150)

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Who gets it?
An X-linked disorder that therefore typically
affects men. Over 400 million people worldwide
affected with highest prevalence in individuals
of African, Mediterranean and Asian
heritage.   Since this is an X-linked gene,
prevalence among females is higher but they are
generally asymptomatic. Confers anti-malarial
protection - unknown mechanism
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How does it present?

• Usually asymptomatic but can also vary from
  episodic anemia to chronic hemolysis.  The
  presentation depends on the biochemistry of the
  variant.  There are over 500 different mutations
  identified thus far.
• acute hemolytic anemia
• congenital nonsperocytic hemolytic anemia
• neonatal hyperbilirubinemia
• favism

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Acute hemolytic anemia

• Asymptomatic at steady state without anemia or
  abnormal morphology.
• Sudden destruction of deficient erythrocytes 2-4
  days after offending "event" leads to jaundice,
  pallor, dark urine, /- back pain.  Abrupt drop
  in H/H to lt4 g/dL and PBS with microspherocytes,
  cell fragments or bite cells.  Sequestration of
  damaged red cells in liver and spleen.
• Increase in reticulocytes within 5 days, maximal
  at 7-10 days with reversal of anemia even without
  removal of offending drug.
• In G6PD Mediterranean, hemolysis more severe and
  can continue even after drug d/c'd.

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Congenital nonspherocytic hemolytic anemia

• Class I variants in whom lifelong hemolysis
  occurs in absence of preceding event.
• Functional defect is so severe that RBCs cannot
  withstand normal stresses in the circulation.
• Anemia and jaundice usually noted in newborn
  period.
• Mild to moderate anemia (8-10 g/dL) with rare
  pallor, SM and intermittent icterus. 
  Erythropoietic capacity compensates.
• In severely deficient, neutrophil dysfunction due
  to G6PD deficiency leads to impaired neutrophil
  activity and recurrent infections with
  catalase-positive organisms.

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Favism

• Results from ingestion of fava beans.
• Peak incidence April/May coincident with harvest
  time.
• Usually male children, ages 1-5.
• 5-24 hours after ingestion - HA, nausea, back
  pain, chills, fever, jaundice and
  hemoglobinuria.  Acute fall in hemoglobin
  requiring transfusion.
• Most commonly seen with G6PD Mediterranean
  variant.

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How does it work?
G6PD is required by all cells to protect from
damage by oxidation. It catalyses the first step
in the HMP pathway (glucose-6-P oxidized to
6-phosphogluconate) which is linked to the
reduction of NADP to NADPH, which is used to
generate reduced glutathione.    For the red
cell, this is the sole source of protection
against oxidant damage in the form of free
radicals generated by the conversion of oxy- to
deoxyhemoglobin and by peroxides generated by
phagocytosing granulocytes.   
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cont'd

• Normal red cells generate NADPH in response to
  oxidant stress this capacity is impaired in
  patients with G6PD deficiency. Failure to
  withstand oxidant stress damage to sulphydryl
  groups in hemoglobin and the red cell membrane
  causes hemolysis. 
•  
• Cells in other tissues and organs have alternate
  pathways for the generation of NADPH and can
  withstand such oxidant stress. But not so in the
  simple RBC. 
•  
• The activity of all red cell enzymes, including
  G6PD, is highest in young red cells
  (reticulocytes), and progressively declines as
  the cell ages.

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Biochemical pathway the Hexose monophosphate
shunt
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Precipitants

• Infections (salmonella, E.coli, beta-hemolytic
  strep, rickettsiae, viral hepatitis) 
• Medications
• anti-malarials (primaquine)
• anti-bacterials (dapsone, furazolidone,
  nitrofurantoin, sulfonamides, quinolones)
• others (acetenalide, methylene blue, naphthalene
  in moth balls and henna, toluidine blue,
  trinitrotoluene, rasburicase, vitamin k
  derivatives)
• possible association (phenazopyridine, ASA,
  doxorubicin, flutamide, probenecid,
  sulfasalazine, aminopyrine, aminosalycilic acid,
  acetylphenylhydrazine)
• Metabolic abnormalities (DKA) 

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Laboratory diagnosis

• CBC
• retic profile
• urinalysis
• LDH/haptoglobin
• fractionated bilirubin
• blood smear with stains for Heinz bodies
•  
• G6PD fluroescent spot test
• Detects deficient production of NADPH from NADP.
  In this test NADPH is fluorescent and its absence
  (due to G6PD deficiency) results in lack of
  fluorescence.
• G6PD spectrophotometry to detect level of
  activity
• genetic test for variants 

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Peripheral Blood Smear
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How do you treat it?

• avoid offending medications
• supportive care 
• hydration to protect against renal failure
• transfusions, folic acid
• splenectomy and vitamin E (anti-oxidant) have
  been suggested but not been proven effective
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• because hemolysis is usually mild, drugs may
  be given if there is important indication 
•  

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A word about Heme-pigment induced ATN
 AKI from heme pigment, either from myoglobinuria
(rhabdo) or hemoglobinuria (intravascular
hemolysis) can cause ATN. Urine microscopy shows
pigmented granular casts.  Urine is red-brown in
color. Results from obstruction with
intratubular heme pigment casts, concurrent
volume depletion and ischemia.   FeNa is often
lt1 in contrast to typical ATN reflecting tubular
obstruction more than necrosis. 
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What doesnt fit . . .

• Expect his H/H to be lower, especially with lack
  of reticulocyte response
•  
• Expect recovery
•  
• Expect greater indirect bilirubin  (initially
  elevated but then predominance of direct
  bilirubin) 
•  
• Retic profile was not elevated, but this may have
  been related to drug-induced marrow suppression 

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References
Rose, Burton David.  Pathophysiology of Renal
Disease.  McGraw-Hill, Inc.  1987,
1981. Beutler, E. Study of glucose-6-phosphate
dehydrogenase history and molecular biology.
Am J Hematol. 1993 Jan42(1)53-8. Sarkar, S,
Prakash, D, Marwaha, RK, et al. Acute
intravascular hemolysis in blucose-6-phosphate
dehydrogenase deficiency. Ann Trop Paediatrics.
1993 13391. utdol.com