Setting: ED
CC: “My urine is dark.”
VS: R: 25 breaths/minute; BP: 110/70 mm Hg; P: 105 beats/minute; T: 101°F
HPI: A 23-year-old man comes to the ED with complaints of a few hours of dark urine and fatigue. He had been having a cough with sputum and fever for the past 2 days. His condition suddenly got worse after his temperature went up early today. He has not started any new medications recently.
PE:
Chest: rales at right base
Abdomen: nontender liver
Neurological: normal
Skin: yellow
Initial Orders:
CBC
Chest x-ray
LFTs
UA
Oximeter
Fever, cough, and sputum are clearly a respiratory infection. The question is: Why is the patient suddenly fatigued and why the jaundice?
Laboratory Test Results:
CBC: hematocrit 30%; MCV 90 fL; WBC and platelet counts normal
Chest x-ray: right lower lobe infiltrate
LFTs: total bilirubin 6.8 mg/dL; direct bilirubin1.2 mg/dL; LDH elevated, AST and ALT normal
UA: dipstick positive for blood, but no RBCs seen
Oximeter: 92% on room air
High indirect bilirubin, high LDH, and anemia are clear for hemolysis. The chest x-ray and hypoxia on oximeter indicate pneumonia.
Orders and Results:
Reticulocyte count: 4%
Coombs test: negative
Repeat hematocrit: 29%
Start ceftriaxone and azithromycin
Reticulocytes can take several days to increase to their full range. The negative Coombs test only really excludes autoimmune hemolysis. Lack of chronicity excludes PNH. The absence of splenomegaly and recurrences excludes hereditary spherocytosis.
Always do a peripheral smear on cases of hemolysis.
Order and Results:
Peripheral smear: bite cells, no schistocytes, no fragmented cells
As you move the clock forward to get results, you will never lose points by reviewing the chart too much if you are uncertain. Bite cells are indicative of G6PD deficiency.
G6PD catalyzes the initial step in the hexose monophosphate (HMP) shunt.
Which of the following should be tested first to find G6PD deficiency?
a. G6PD level
b. Complement levels
c. Brilliant cresyl blue stain for Heinz bodies
d. Genetic studies
Answer c. Brilliant cresyl blue stain for Heinz bodies
Heinz bodies are not visible on routine peripheral blood smear. You can clearly miss G6PD deficiency by missing Heinz bodies unless you specifically look for them (Figure 2-4). G6PD levels are normal on the day of an acute hemolytic event because only older, deficient cells are destroyed.
Figure 2-4. Heinz bodies. Supravital stain. These bodies are particles of denatured hemoglobin, usually attached to the inner face of the red blood cell membrane. (Reproduced with permission from Lichtman MA, et al. Lichtman’s Atlas of Hematology. 2007, www.accessmedicine.com.)
After acute hemolysis, only cells with a normal G6PD level are left behind.
Why are there no fragmented cells in G6PD deficiency?
a. Cells are taken to the spleen for destruction.
b. Cells “dissolve” or melt rather than fragment.
c. Cell destruction happens in the spleen.
Answer b. Cells “dissolve” or melt rather than fragment.
In G6PD, deficient cells are destroyed by oxidant stress in the vessels, but they do not “fragment” into pieces.
G6PD reduces nicotinamide adenine dinucleotide phosphate (NADP) to coenzyme nicotinamide adenine dinucleotide phosphate (NADPH).
Oxidants, such as superoxide anion (O2−) and hydrogen peroxide, are formed within RBCs, thereby oxidizing Hb.
Move the clock forward until you have the result of Heinz body stain. The presence of Heinz bodies and bite cells are the best you can do to establish a diagnosis of G6PD deficiency on the day of the acute hemolytic event.
Heinz bodies are precipitated oxidized hemoglobin in the RBC membrane.
Which of the following is the most common cause of acute hemolytic events in G6PD deficiency?
a. Fava beans
b. Infection
c. Dapsone
d. Primaquine
Answer b. Infection
Although the original description of hemolysis in G6PD deficiency was in patients with malaria who get primaquine, this is far less common a cause of hemolysis than infection. Infections are simply a far more common occurrence than the use of dapsone, primaquine, and fava beans although all of these cause hemolysis.
NADPH is needed for glutathione reductase to protect the cell from oxidant stress.
The follow-up CBC the next day shows no significant change in hematocrit. What is the treatment?
a. Supportive, no specific therapy
b. Steroids
c. Intravenous G6PD
d. IVIGs
Answer a. Supportive, no specific therapy
Nothing reverses the oxidant stress of infection on cells deficient in G6PD. The most deficient cells are destroyed immediately. The ones with borderline levels will survive with bite cells and Heinz bodies. You have to wait 2 months and recheck the G6PD level.
G6PD deficiency is an X-linked recessive disorder (Figure 2-5).
Figure 2-5. Diagram of redox metabolism in the red blood cell. G6P, glucose-6-phosphate; 6PG, 6-phosphogluconate; G6PD, glucose-6-phosphate dehydrogenase; GSH, reduced glutathione; GSSG, oxidized glutathione; Hb, hemoglobin; MetHb, methemoglobin; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate. (Reproduced with permission from Longo DL, et al. Harrison’s Principles of Internal Medicine, 18th ed. 2012, www.accessmedicine.com.)
X-linked recessive inheritance expresses almost exclusively in male patients.