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Test ID: GSH Glutathione, Blood


Specimen Required


Collection Container/Tube:

Preferred: Yellow top (ACD solution B)

Specimen Volume: 6 mL

Collection Instructions: Send specimen in original tube. Do not transfer blood to other containers.


Useful For

Evaluation of neonatal hyperbilirubinemia, favism or chronic or episodic hemolysis or jaundice

 

Evaluation for gamma-glutamylcysteine synthetase deficiency (OMIM 230450)

 

Evaluation for glutathione synthetase deficiency causing hemolytic anemia (OMIM 231900)

 

Evaluation for generalized glutathione synthetase deficiency with 5-oxoprolinuria (OMIM 266130)

Method Name

Kinetic Spectrophotometry

Reporting Name

Glutathione, B

Specimen Type

Whole Blood ACD-B

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Whole Blood ACD-B Refrigerated 20 days

Clinical Information

Hemolytic anemia may be associated with deficiency of erythrocyte enzymes. Red blood cell (RBC) enzymes linked to hemolysis are those important in the energy generation of glycolysis or protection from oxidative stress such as the hexose monophosphate shunt.

 

The hexose monophosphate pathway depends primarily upon the glucose 6-phosphate dehydrogenase (G6PD) enzyme for the generation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) with 6-phosphogluconate dehydrogenase (6PGD) providing an additive effect. Both reactions require adequate levels of reduced glutathione (GSH). Because RBCs lack the citric acid cycle, this is an important source of NADPH, and a deficiency of G6PD or GSH results in the inability to neutralize oxidative insults. GSH is synthesized from amino acids by two enzymatic steps and is present in liver, kidney, brain, muscle, and RBCs. It plays widely versatile and important roles in the synthesis of proteins and DNA, the processing of medications and toxins, and other redox reactions.

 

Similar to G6PD deficiency, glutathione deficiency can have an episodic acute time course of hemolysis or jaundice, be triggered by fava beans, and cause neonatal hyperbilirubinemia. Five enzymes impact GSH availability and therefore are potential candidates for abnormalities leading to glutathione deficiency:

-Two enzymes, gamma-glutamylcysteine synthetase (GCLC) and glutathione synthetase (GSS), are required for GSH synthesis

-Two enzymes, glutathione reductase (GSR) and glutathione peroxidase (GPX1), are required for reduction-oxidation cycling of oxidized glutathione (GSSG) to reduced glutathione (GSH)

-A family of enzymes, glutathione S-transferases (GSTs), utilizes GSH in the detoxification and preparation of substances for excretion into the bile or urine

 

Enzyme deficiencies have been reported in all of these enzymes, albeit very rarely. The best characterized are GSS and GCLC deficiencies. GSS deficiency is associated with two clinical presentations; a mild form causing isolated chronic hemolytic anemia (OMIM 231900), and a more severe form marked by urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system disorders (5-oxoprolinuria, OMIM 266130). GCLC deficiency is associated with moderate to severe chronic hemolytic anemia present from neonatal or early childhood, or compensated hemolysis with sporadic but recurrent anemia or jaundice. Some cases have shown learning disabilities, severe and progressive ataxia with myopathy and spinocerebellar degeneration. GSR deficiency has been confirmed in three siblings with favism (episodic hemolysis after fava bean ingestion) and cataracts in early adulthood, and an unrelated infant with marked neonatal hyperbilirubinemia. GSR activity can be decreased in riboflavin deficiency, but whether this results in hemolysis is not clear. Although patients have been reported with anemia in the context of decreased GPX1 activity (OMIM 614164) and decreased GST activity was found in a person with hemolytic anemia, splenomegaly, hyperbilirubinemia, and cholelithasis, neither have been characterized sufficiently as the definitive cause of hemolysis. All described cases have shown autosomal recessive inheritance pattern.

 

A deficiency of either of the synthetic enzymes, GCLC or GSS, results in GSH levels less than 25%, but many show a virtual absence of measurable GSH. Heterozygotes usually show normal GSH levels. Elevated concentrations of GSH are found in patients with myelofibrosis and in those with pyrimidine-5'-nucleotidase deficiency.

Reference Values

≥12 months: 46.9-90.1 mg/dL RBC

Reference values have not been established for patients who are <12 months of age.

Interpretation

Measurement of reduced glutathione (GSH) is used as a surrogate for the activity of the enzymes that contribute to normal levels of GSH within the red blood cell. GSH is associated with less than 25% of mean normal in individuals with deficiencies of gamma-glutamyl cysteine synthetase or glutathione synthetase.

 

Elevated concentrations of GSH are of uncertain significance. This finding can be nonspecific and is seen in normal neonates, pyrimidine-5’-nucleotidase deficiency, lead poisoning, dyserythropoietic disorders (inherited and acquired), myelofibrosis (possibly due to chromosome 8 duplication), or riboflavin supplementation. Consistently elevated glutathione levels have been reported in a family with mild hemolytic anemia of uncertain cause (1); however, whether this was causative or incidental was not determined.

Clinical Reference

1. Valentine WN, Paglia DE: Syndromes with increased red cell glutathione (GSH). Hemoglobin. 1980;4(5-6):799-804. doi: 10.3109/03630268008997748

2. Manu Pereira M, Gelbart T, Ristoff E, et al: Chronic non-spherocytic hemolytic anemia associated with severe neurological disease due to gamma-glutamylcysteine synthetase deficiency in a patient of Moroccan origin. Haematologica. 2007 Nov;92(11). doi: 10.3324/haematol.11238

3. Ristoff E, Mayatepek E, Larsson A: Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr. 2001 Jul;139(1):79-84. doi: 10.1067/mpd.2001.114480

4. Konrad PN, Richards F, Valentin WN, et al: Gamma glutamyl cysteine synthetase deficiency. N Engl J Med. 1972;286:557

5. Mehta A, Mason PJ, Vulliamy TJ: Glucose-6-phosphate dehydrogenase deficiency. Baillieres Best Pract Res Clin Haematol. 2000 Mar;13(1):21-38

6. Beutler E, Dunning D, Dabe IB, Forman L: Erythrocyte glutathione S-transferase deficiency and hemolytic anemia. Blood. 1988;72:73-77

7. Kamerbeek NM, van Zwieten R, de Boer M, et al: Molecular basis of glutathione reductase deficiency in human blood cells. Blood. 2007 Apr 15;109(8):3560-3566. doi: 10.1182/blood-2006-08-042531

8. Tomoda A, Noble NA, Lachant NA, Tanaka KR: Hemolytic anemia in hereditary pyrimidine 5'-nucleotidase deficiency: nucleotide inhibition of G6PD and the pentose phosphate shunt. Blood. 1982 Nov;60(5):1212-1218

9. van Solinge WW, van Wijk: Enzymes of the red blood cell. In: Rifai N, Horvath AR, Wittwer CT: eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:chap 30

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

82978

LOINC Code Information

Test ID Test Order Name Order LOINC Value
GSH Glutathione, B 2383-8

 

Result ID Test Result Name Result LOINC Value
608409 Glutathione, B 2383-8
Mayo Clinic Laboratories | Hematology Catalog Additional Information:

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