G6PD and heme pigment-induced ATN

AM Report

Emily Chang September 5, 2008

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.

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 (>150%)

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

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

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 <4 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.

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.

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.

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.

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.

Biochemical pathway the Hexose monophosphate shunt

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)

Laboratory diagnosis
CBC retic profile urinalysis LDH/haptoglobin fractionated bilirubin blood smear with stains for Heinz bodies
o

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

Peripheral Blood Smear

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

***because hemolysis is usually mild, drugs may be given if there is important indication

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 <1% in contrast to typical ATN reflecting tubular obstruction more than necrosis.

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

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 Jan;42(1):53-8. Sarkar, S, Prakash, D, Marwaha, RK, et al. Acute intravascular hemolysis in blucose-6-phosphate dehydrogenase deficiency. Ann Trop Paediatrics. 1993; 13:391.

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