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In order to discuss chronic granulomatous disease (NADPH oxidase deficiency), we need to introduce a process known as “respiratory burst,” which is a series of reactions through which phagocytes – most notably neutrophils – create reactive oxygen intermediates (ROI) to kill invading microbes.
NADPH oxidase is the critical enzyme in this system (probably because it’s the most upstream in the reaction pathway).
For whatever magical reason, the USMLE likes to ask the substrate for this enzyme, and the answer is molecular oxygen.
People easily memorize NADPH oxidase deficiency for their boards, but then when they’re asked, “Ok, but whats the enzyme act on? In other words, what’s the substrate of the enzyme?” They’re like, “Uhh..yeah..”
| So once again, what is the substrate for NADPH oxidase? Molecular oxygen. Craziness. |
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As you can see, the respiratory burst ultimately leads to H2O2 and bleach (HOCl–) production, which kill microbes.
H2O2 that is not converted into bleach exits the phagocyte and is neutralized to H2O by catalase and glutathione peroxidase. Reduced glutathione and NADPH are what allow this neutralization to occur.
| Reduced glutathione has an –SH group. –SH groups, NADPH, and NADH = reducing agents on the USMLE
In contrast, oxidized glutathione has a disulfide bond (–S–S–). –S–S–, NADP+, and NAD+ = oxidizing agents on the USMLE Tangential but HY: N-acetylcysteine (for acetaminophen toxicity) and Mesna (for cyclophosphamide toxicity) also both have –SH groups. |
The NADPH used for the respiratory burst is produced from the hexose monophosphate shunt (HMP shunt) via glucose-6-phosphate dehydrogenase.
This is why patients with G6PD deficiency are susceptible to oxidizing drugs (e.g., dapsone, primaquine) and hemolytic anemia, because their NADPH production is less efficient, so they can’t neutralize H2O2 and other oxidizing agents as readily, leaving their RBC membranes more prone to lysis.
Now we can introduce the crux of why the respiratory burst is important for the USMLE:
Chronic granulomatous disease (CGD)
Chronic granulomatous disease = NADPH oxidase deficiency
This disease is characterized by increased susceptibility to catalase-positive organisms. Catalase is the enzyme that breaks down H2O2.
| Humans without CGD: Production of H2O2 via respiratory burst is >>> catalase produced by organisms → organisms are overwhelmed + die
Human with CGD: Production of H2O2 via respiratory burst is < catalase produced by organisms → organisms can tolerate phagocyte environment + survive |
Organisms that produce catalase are able to neutralize small amounts of H2O2, but not large amounts. So in a typical person who does not have NADPH oxidase deficiency, the amount of hydrogen peroxide he or she produces far exceeds what catalase (+) organisms can handle, so therefore there’s no innate susceptibility to these organisms.
| A general mnemonic for catalase-positive organisms is C SHAPES:
Candida, Serratia, H. pylori, Actinomyces, Pseudomonas, E. coli, S. aureus |
You’ll either get a vignette that is overwhelmingly CGD based on Serratia, Candida, and/or E. coli showing up in a child, OR
The vignette will mention a fairly non-specific Hx of mere Staph infections, but you’ll easily be able to eliminate the other answer choices to choose CGD anyway – i.e., “Ok, well this is clearly not SCID, or Leukocyte-adhesion deficiency, or Chediak-Higashi syndrome, etc.” And you just eliminate to get there.
Rarely, questions might throw in supporting details like mouth ulcers, since up to 50% of patients with CGD have Crohn-like symptoms.
CGD patients frequently have:
- Aphthous ulcers (mouth ulcers)
- Urogenital tract obstruction due to granulomas
- 50% have Crohn-like symptoms (bleeding per rectum / malabsorption)
But in general, merely knowing the catalase (+) organisms is sufficient.
| Neutropenia on Step1 frequently presents as mouth ulcers. Notice that in CGD, although there isn’t neutropenia, neutrophil function is impaired. |
USMLE questions also might rarely mention lymph nodes with “leaking purulent material” as synonymous with CGD.
| Diagnosis is made via a positive dihyrorhodamine test.
Nitroblue-tetrazolium test is now obsolete and the wrong answer. If they give both as answer choices, choose dihydrorhodamine test. |
| USMLE-favorite treatment for CGD is IFN-γ. |
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Myeloperoxidase
As you can see from the respiratory burst image, myeloperoxidase is a phagocytic enzyme that converts hydrogen peroxide into bleach.
If they ask you which enzyme is the second most effective bactericidal mechanism in phagocytes, the answer is myeloperoxidase. If they list NADPH oxidase, the reason that’s wrong is because that’s the most effective.
But the USMLE actually doesn’t care so much about myeloperoxidase deficiency. If you were to be asked that on your actual exam, that would in fact be quite low-yield. The question writers are more interested in seeing if you know how the enzyme relates to acute myelogenous leukemia (AML).
| Auer rods are most often seen on blood smear in the M3 subtype of AML, aka acute promyelocytic leukemia (APL). If they ask you what Auer rods are composed of, the answer is myeloperoxidase.
The release of myeloperoxidase into the blood during the Tx of leukemia can lead to disseminated intravascular coagulation (DIC). |
Because myeloperoxidase composes Auer rods, it should be articulated that it is a heme-containing pigment with a blue-green color. Why is this important?
Because it is myeloperoxidase that primarily gives sputum its color, NOT shed epithelial cells, leukocytes, or dead bacteria.
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