An African American Woman with Fever and Painless Jaundice
A 61-year-old African American woman presents to the emergency room 1 week after resection of a Bartholin’s cyst complaining of fever to 104°F at home. She reports having had slight discharge with bloody mucous and pain at the site and having been given a prescription for nitrofurantoin the day prior to presentation.
History
The patient has a history of allergy to penicillin, causing itching and an allergy to trimethoprim-sulfamethoxazole (TMP/SMX), causing fevers, chills, and jaundice. She also has noninsulin dependent diabetes mellitus and hyperlipidemia. She has had a cholecystectomy and hysterectomy in the past.
Physical Examination
Physical examination reveals temperature of 100.1°F. Heart rate and blood pressure are initially 113 and 89/52 mm Hg, respectively. After a 1 L normal saline bolus, her heart rate and blood pressure are 95 and 123/70 mm Hg, respectively. Her emergency department exam is otherwise unremarkable, with clear lungs, no murmurs, or arrhythmias. Her abdomen is soft, nontender and nondistended. Her gynecological exam shows a well-healing, left-sided Bartholin gland marsupialisation, without drainage, erythema, or bleeding. She only has minimal tenderness at the time of examination. Of note, on the morning after her initial presentation to the hospital, she is found to have jaundice on exam, but is otherwise in her normal state of health.
Laboratory tests
Her white blood cell count is 8.1 K/mm3, with 20% bandemia noted on manual differential. Her hemoglobin is 12.8 g/dL. Platelet count is 278. A chest x-ray is negative for infiltrates or masses and urinalysis is nitrate positive, but leukocyte esterase negative without any white cells. On the morning after her initial presentation, her liver function testing shows a direct bilirubin of 2.2 mg/dL and total bilirubin of 4.2 mg/dL. Alkaline phosphatase is 94 U/L. International normalized ratio is 1.2. Hemoglobin was 10.2 g/dL and platelets 236K.
Which of the following is the correct statement regarding the presented patient’s illness?
A. The patient likely has ascending cholangitis and a more appropriate antibiotic should have been selected.
B. A thorough history by the nitrofurantoin-prescribing physician may have prevented her presentation.
C. The patient has disseminated intravascular coagulopathy secondary to sepsis.
D. The diagnosis can be made by serologic testing.
(Answer and discussion on next page)
Correct Answer: B. A thorough history by the nitrofurantoin-prescribing physician may have prevented her presentation.
A thorough history and physical revealed that not only did this patient have an identical drug reaction with TMP/SMX in the past, but that her daughter also had an identical reaction.
This patient has glucose-6-phosphate dehydrogenase deficiency (her acute G6PD level was 1.1 U/g, with a reference range of 4.6-13.5), an X-linked genetic condition affecting approximately 400 million people worldwide. The most frequent presentation of G6PD deficiency is neonatal jaundice and acute hemolytic anemia. The condition manifests itself within red blood cells, because the pentose phosphate pathway is the only source of nicotinamide adenine dinucleotide phosphate (used to counterbalance oxidative stressors), as red cells lack mitochondia.
Prevalence
As stated, the condition is believed to affect approximately 400 million individuals worldwide, predominantly central and Western Africa, Southeast Asia, Eastern Mediterranean, and Middle East. However, due to recent history and population migration, the disease can now be seen in previously uncommon areas such as North and South America and Northern Europe. Interestingly enough, the story of the disease appears to be related to the distribution of the blood borne disease, malaria. This coincidence has been the basis of the theory surrounding G6PD deficiency conferring resistance against malaria.
Diagnosis and Treatment
Clinical symptoms of acute hemolysis due to G6PD deficiency include fever, back pain, abdominal pain, jaundice, transient splenomegaly, hemoglobinuria, jaundice, and scleral icterus.
The diagnosis of G6PD should be considered by any clinician who receives a history of atypical drug reactions, as is the case in this patient. In the acute setting, the diagnosis can be difficult, as the gold standard requires quantitative measurement of enzyme activity. A high reticulocyte count can lead to false negatives. This is because reticulocytes have a higher G6PD activity. A Coombs’ test, if sent, should be negative as the process is not immune mediated. A peripheral smear may show Heinz bodies, which results from precipitation of denatured hemoglobin due to electron transfer or reactive oxygen species. G6PD deficiency can be further classified into 5 classes of enzyme activity, with only Class I and II (<10% activity) being associated with hemolysis.
Causes of acute hemolysis have been definitively associated with primaquine, sulfamethoxazole, dapsone, and nitrofurantoin, in addition to other less commonly used drugs. The oxidizing akaloids vicine and covicine in fava beans (broad beans) have also been implicated.
The treatment of G6PD deficiency is focused on withdrawal and avoidance of stressors.
Clinical Picture
This patient’s presentation is somewhat dramatic and many cases of hemolysis due to G6PD deficiency may be subtler. Because the disease is X-linked and this patient was female, she most likely has a homozygous genetic mutation to explain her presentation and the fact that her daughter also is afflicted by this condition. We were fortunate to make the diagnosis by quantitative assay on her initial presentation, as many patients may be falsely negative. Due to the life cycle of red blood cells, repeat laboratory testing is suggested after 90 days from the suspected insult.
Acute hemolysis is generally self-limited and occurs within 24 to 72 hours of onset after ingestion of offending agents. The condition generally does not continue further than 8 to 10 days as younger red cells generally have sufficient quantities of the enzyme to resist hemolysis.
It is important to consider the possibility of G6PD deficiency in adults, because it affects antimicrobial choices.
Outcome of the Case
The diagnosis of G6PD deficiency was made on the morning after the patient’s emergency room presentation when her clinical history became clearer in addition to the appearance of painless jaundice (with mixed hyperbilirubinemia) in conjunction with a high reticulocyte count. Her enzyme activity was sent during the acute episode at the suggestion of our hematology department. We were confident enough in the diagnosis to inform the patient prior to the result, which only further confirmed our suspicion.
David Berman, MD, is a hospitalist at Temple University School of Medicine in Philadelphia, PA.
Ronald Rubin, MD, is a professor of medicine at Temple University School of Medicine and chief of clinical hematology in the department of medicine at Temple University Hospital, both in Philadelphia, PA.
References:
1. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64-74.
2. Frank J. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005;72(7):1277-1282