Question 26

Last updated 27/11/2021 - 17:00
 Topic: Acid-Base Disorders
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A 23-year-old male of Southeast Asian descent is admitted to the Emergency Department following an episode of syncope. He is currently resident in a medical research facility, taking part in a phase 1 trial of a novel anti-inflammatory agent. An extensive pre-trial health questionnaire did not reveal any concerns.

In the Emergency Department he is alert and comfortable with no respiratory distress, and noted to have an SpO2 of 83% on 15L O2 via a non-rebreathe mask.

His initial arterial blood gas results are shown below:

Parameter          Patient Value Adult Normal Range
FiO2 0.9  
pH 7.52* 7.35 – 7.45
pO2 200 mmHg (26.3 kPa)  
pCO2 31.0 mmHg (4.1 kPa)*         35.0 – 45.0 (4.6 – 6.0)
SaO2 100%  
Hb 118 g/L* 135 – 170
FO2Hb 90.6%* 94.0 – 97.0
FMetHb 7.8%* 0.0 – 1.5
FCOHb 2.1%* 0.0 – 1.5

He has a baseline and repeat full blood count (at 24 hours), shown below:

Parameter Patient Value Adult Normal Range
  On admission              At 24 hours  
Hb 122 g/L 77 g/L* 120 – 160
MCV 91 92 80 – 100
Platelets 262 214 150 – 350
WCC 15.5 x 109/L* 18.9 x 109/L* 4.0 – 11.0
Reticulocytes - 192 x 109/L* 20 – 100
Mega/myelocytes          0.19 x 109/L* 0.7 x 109/L* 0.00 – 0.06
Nucleated RBC 1.1 6.4  
Film   Blister (helmet) cells ++,
bite cells ++,
polychromasia
Occasional Howell-Jolly
bodies		  


a)    List three potential causes of the discrepancy between SpO2 and SaO2 in this patient.
(15% marks)

b)    List the likely diagnosis and underlying aetiology suggested by his investigations.
(30% marks)

c)    List the additional tests you would order. List the results you would expect from these tests.
(25% marks)

d)    List three potential causes for the elevated MetHb.    (15% marks)

e)    List three potential causes for the elevated COHb.    (15% marks)
 

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College answer

Not available.

Discussion

a)

  • Leukostasis
  • Polycythaemia
  • Methaemoglobinaemia
  • Poor perfusion of the limb from which the pulse oximeter is measuring
  • Nail polish
  • Electrical interference

b)

Southeast Asian? Haemolysis? Surely this must G6PD deficiency, the most common hereditary enzymopathy among people from that part of the world. How did this happen?

  • The experimental drug they fed him clearly must have caused some sort of oxidative stress
  • Failure to produce enough NADPH in the context of oxidative stress has the tendency to deplete glutathione through its conversion to glutathione disulfide.
  • With ongoing oxidative stress, the sulfhydryl groups of haemoglobin and various other proteins are oxidized to disulfides or sulfoxides. 
  • These denatured products precipitate into Heinz bodies.
  • This sort of molecular garbage damages red cell membranes and marks red cells to be destroyed by the reticuloendothelial system, hence the acute haemolytic reaction and jaundice.

c) Additional tests you would order:

  • Rapid fluorescent spot test, qualitatively detecting the generation of NADPH from NADP (the test is positive if the blood spot fails to fluoresce under ultraviolet light)
  • Quantitative spectrophotometric analysis of NADP-NADPH conversion, where a sample of the patient's red cells is added to a mixture of glucose-6-phosphate NADP, and then the fluorescence is measured (it should be lower than normal)
  • Specific genetic testing then follows

d) Three potential causes for the elevated MetHb are asked for, but it is not clear whether they asked for causes in this patient or in general. Noting that the first part of this question specifies "in this patient", one can only conclude that generic causes of methaemoglobinaemia are asked for. But then, it asks for three potential causes for the elevated MetHb, not just an elevated MetHb. What are we to make of this?.. To be safe, the following differentials were tailored to the case scenario:

  • Drugs (eg. the experimental drug; but also numerous others)
  • Congenital (eg. NADH cytochrome B5 reductase deficiency, haemoglobin M disease)
  • Accelerated autooxidation of haemoglobin (due to haemolysis)

e) Three potential causes for the elevated COHb:

  • Haemolysis and accelerated haem metabolism
  • Cigarette smoking
  • Increased metabolic production of carbon monoxide as a side effect of drug metabolism, eg. this experimental anti-inflammatory drug - this is a known thing, and occurs as the result of methylene chloride (dichloromethane) metabolism, as one example.

References

Beutler, Ernest. "G6PD deficiency." Blood 84.11 (1994): 3613-3636.

Frank, Jennifer E. "Diagnosis and management of G6PD deficiency." American family physician 72.7 (2005): 1277-1282.

Howes, Rosalind E., et al. "G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: a geostatistical model-based map." PLoS medicine 9.11 (2012): e1001339.

Luzzatto, Lucio, and Elisa Seneca. "G6 PD deficiency: a classic example of pharmacogenetics with on‐going clinical implications." British journal of haematology 164.4 (2014): 469-480.

 Clark, Byron B., Robert W. Morrissey, and Dorothy Blair. "Relation of methemoglobin to hemolysis." Blood 6.6 (1951): 532-543.

Ata, Fateen, et al. "Favism Induced Methemoglobinemia in G6DP Deficient Patients: Case Series and Review of Literature." Blood 136.1 (2020): 11-12.

Jaffe, Todd A., et al. "Acute and delayed toxicity from co-ingestion of methylene chloride and methanol." Toxicology communications 3.1 (2019): 79-84.

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