חומר רקע
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Clin Case Rep. 2021;9:2048–2052.
wileyonlinelibrary.com/journal/ccr3
1 |
INTRODUCTION
We report a 56-year-old man with methemoglobinemia
and hemolytic anemia, secondary to fava bean ingestion.
Methylene blue administration worsened the hemolysis as he
was G6PD deficient but not diagnosed before. We have dis-
cussed the mechanism of hemolysis in such patients and the
management of such cases.
Hemolytic anemia, a form of anemia that causes premature
rupture of erythrocytes, accounts for five percent of anemias.1
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a
well-known cause of hemolysis and currently affects around
400 000 000 individuals globally. It has a notable prevalence
in African, Asian, and Mediterranean countries.2 Favism is a
common trigger of oxidative stress in G6PD deficient people,
which can lead to hemolysis. Additionally, fava bean ingestion
can cause methemoglobinemia.3 Methemoglobin is an abnormal
variation in the hemoglobin in which the ferrous (Fe2+) iron in
heme is oxidized to the ferric (Fe3+) state. The condition is usu-
ally acquired, secondary to oxidative stress in the body such as
favism or infections, but can rarely be congenital.4 The first-line
treatment for methemoglobinemia is methylene blue. However,
in G6PD deficient patients, methylene blue can potentiate hemo-
lysis because of its oxidative effects.3 It is vital to take a detailed
history of patients presenting with hemolysis to identify the po-
tential causes and avoid any additional oxidative stress.
Received: 7 October 2020 |
Revised: 3 February 2021 |
Accepted: 4 February 2021
DOI: 10.1002/ccr3.3941
C A S E R E P O R T
Favism-induced methemoglobinemia in a G6PD deficient male
with a subsequent hemolytic cascade, a therapeutic challenge:
Case report and review of literature
Fateen Ata1
| Saad Javed2
| Bassam Muthanna1
| Ines dakhlia1 |
Ammara Bint I Bilal3
| Motwakil Musa1 | Mashuk Uddin1 | Mohamed A. Yassin4
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
1Department of Internal Medicine, Hamad
Medical Corporation, Doha, Qatar
2Department of Internal Medicine, Jinnah
Hospital, Allama Iqbal Medical College,
Lahore, Pakistan
3Department of Radiology, Hamad Medical
Corporation, Doha, Qatar
4Department of Hematology, National
Center for Cancer Care & Research, Hamad
Medical Corporation, Doha, Qatar
Correspondence
Bassam Muthanna, Internal Medicine,
Hamad General Hospital, PO box 3050,
Doha, Qatar.
Email: [email protected]
Funding information
The publication of this manuscript is
supported by Qatar National Library (QNL)
Abstract
The co-occurrence of acute hemolysis and methemoglobinemia secondary to favism
in G6PD deficient individuals is rare. Identifying it promptly is of high clinical signif-
icance as treating methemoglobinemia (with methylene blue) can worsen hemolysis.
K E Y W O R D S
fava beans, Favism, G6PD, glucose-6-phosphate dehydrogenase, Hemolysis, methemoglobinemia
|
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2 |
CASE PRESENTATION
A 56-years-old Qatari man, known to have type-II diabetes
mellitus and hypertension, presented with a 5-day history
of progressive dyspnea and dizziness. He also had a 3-day
history of mild hematuria and one episode of minimal non-
bloody vomiting. The patient had no recent infection and no
exposure to new medications. He is married (nonconsanguin-
eous), a smoker (5 cigarettes per day) but nonalcoholic with
no history of illicit drug use.
Upon examination, he was vitally stable (afebrile, Blood
pressure 136/76 mm Hg, heart rate 93 beats per minute)
other than an oxygen saturation (SPO2) of 70% on room air.
On examination, he had pallor and jaundice. The rest of the
physical examination was unremarkable. Arterial blood gas
(ABG) analysis revealed SPO2 of 101% and a methemoglobin
(MetHB) level of 5.6% (Table 1). The patient was initiated on
supplemental oxygen, but his SPO2 remained low. Because
of a high MetHgb level, a provisional diagnosis of methemo-
globinemia was made, and he received methylene blue intra-
venously (IV) 80 mg while in the emergency department. A
complete blood analysis revealed low hemoglobin (Hgb) of
9.9 gm/dL, secondary to hemolysis (Table 1, Figure 1). Chest
x-ray and electrocardiogram were unremarkable. A urine dip-
stick analysis did not reveal significant blood or protein.
A repeated Hgb level after 24 hours showed a further drop
to 7 gm/dL. As he was symptomatic, two units of packed red
blood cells (RBC) were transfused. Unexpectedly, his Hgb
continued to drop further (Figure 1). Ongoing hemolysis was
evident, and a detailed history was retaken to identify the
cause of hemolysis. The patient revealed an intake of large
amounts of fava beans, which preceded his symptoms. He
had a history of eating fava beans in small amounts before
without experiencing any symptoms. However, this time,
the intake was considerably larger (six fava beans containing
sandwiches). Because of suspicion of favism-induced hemo-
lysis, a G6PD level was sent, which came low (Table 1). At
this point, he was diagnosed with G6PD deficiency, aggra-
vated by the ingestion of a large number of fava beans. His
hemolysis was worsened by methylene blue, which was evi-
dent by a progressive drop in Hgb.
The patient was kept in the medical ward under close obser-
vation. He received a total of 3000 mg of IV Vitamin C in two di-
vided doses. After 2 days, his SPO2 improved to 100% on room
air, and Hgb improved gradually to 11 gm/dL on the fifth day
(Figure 1). He was discharged as he became asymptomatic on
day five with a follow-up in the acute medical assessment clinic.
3 |
FOLLOW-UP
Follow-up lab work showed near-normal Hgb (12 gm/dL),
normal bilirubin, and liver enzymes. The patient did not have
any residual dyspnea. There was no jaundice, and his hema-
turia had resolved. He was discharged from the clinic with
clear instructions about his diagnosis. He was also counseled
to avoid fava beans in the future. He was using aspirin as pri-
mary prevention of cardiovascular disease and was advised
to discontinue it to avoid oxidative stress. The patient was
offered genetic testing of G6PD at the follow-up visit in the
genetics clinic, which he refused.
4 |
DISCUSSION
Glucose-6-phosphate
dehydrogenase
(G6PD)
deficiency
is the most prevalent blood cell disorder in humans.5 It is an
X-linked genetic disorder caused by a chromosome X defect
(band X q28).6 It is usually diagnosed when patients present
TABLE 1
Clinical features of the patient
Hematological
parameters
Patient
code
Normal range
WBC count
31000
4.5-11 *103/μL
Platelets
515
150-400 ×103/μL
MCV
98.7
83-101 fL
MCHC
32.9
31.5-34.5 gm/dL
RI
2.47
>2
PO2 on ABG
524
83-108 mm Hg
MetHgb
5.6%
<1.6%
Indirect bilirubin
60
<13 μmol/L
LDH
Hemolyzed
135-225 U/L
Haptoglobin
15
30-200 mg/dL
G6P6D quantity
23
224-
517 mU/109RBC
PS
Bite cells,
blister
cells, left
shift
–
Carboxy Hgb
3.3%
Nonsmoker: <1.5%
of Hgb
Smokers: <1.5%-
5.0% of Hgb
HgbE
HBA:96,
HBA2:2.6,
HBS:0,
HBF:1,
HBH:
absent
HBA:95.8-98,
HBA2:2-3.3,
HBS:0,
HBF:0-0.9, HBH:
absent
CRP
67
0-5 mg/L
Abbreviations: CRP, c-reactive protein; Hgb, hemoglobin; HgbE, hemoglobin
electrophoresis; LDH, lactate dehydrogenase; MCHC, mean corpuscular
hemoglobin concentration; MCV, Mean corpuscular volume; MetHgb,
methemoglobin; PS, peripheral smear; RI, reticulocyte index; WBC, white blood
cell.
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ATA et al.
with signs and symptoms of hemolytic anemia, secondary to
oxidative stress. It is usually triggered by infections, fava beans,
and certain medications.7 Various screening tests are available
to detect G6PD deficiency, and the diagnosis is usually con-
firmed by quantitative measurement of nicotinamide adenine
dinucleotide phosphate (NADPH).8 The primary differential
diagnoses of G6PD deficiency are other causes of hemolysis.
In malaria-endemic areas, malaria is one of the differentials of
G6PD hemolysis. Other causes of inherited and acquired hemo-
lytic anemias need to be considered while diagnosing G6PD
deficiency-induced hemolytic anemia.9 Genetic testing can be
carried out via polymerase chain reaction; however, it is usually
not routinely performed and limited to challenging situations
and atypical presentations.9 Treatment of acute episodes of he-
molysis is by transfusion and, more importantly, eliminating
the cause of oxidative stress.10
On the other hand, methemoglobinemia is a hemoglobin
disorder where ferrous (Fe2+) iron in heme is oxidized to
the ferric (Fe3+) state. It is usually acquired, secondary to
oxidative stress in the body, but can rarely be congenital.4
Physiologically, various enzyme systems such as NADH
methemoglobin reductase, NADPH methemoglobin reduc-
tase, ascorbic acid, and glutathione reductase systems keep a
check on the accumulation of methemoglobin in the blood.11
FIGURE 1
Trend of hemoglobin of the
patient throughout the hospital stay
FIGURE 2
Mechanism of reduction of methemoglobin to hemoglobin by methylene blue; concept taken from Percy MJ et al15
|
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ATA et al.
However, there are instances where these mechanisms are in-
sufficient to counter the conversion of hemoglobin to methe-
moglobin, consequently promoting an oxidative state in the
body. This can be either due to the overproduction of methe-
moglobin or under conversion to hemoglobin due to unavail-
able enzyme mechanisms. The former can be secondary to
exposure to certain drugs, chemicals, or food items but can
sometimes be hereditary.12 The inability of enzyme systems
to counteract methemoglobin can be secondary to enzyme
deficiencies, such as G6PD deficiency.
Usually, the patients typically have a low SPO2 on pulse
oximeters but a falsely high SPO2 on arterial blood gas-
ses (ABG).13 The treatment depends on the level of met-
hemoglobin in the body and symptoms. The first step is
to remove any possible precipitator if present immediately.
The treatment of choice for symptomatic or asymptom-
atic patients with a level of methemoglobin >30 percent is
methylene blue (1-2 mg/kg).14 Methylene blue is reduced
to leuko-methylene blue via NADPH-dependent methe-
moglobin reductase. This, in turn, reduces methemoglobin
back to hemoglobin, hence correcting the abnormality 15
(Figure 2).
Rarely, patients can present with co-occurrence of met-
hemoglobinemia and G6PD deficiency.3,16-19 In such cases,
extreme caution is required while administering methylene
blue as they do not have sufficient NADPH levels to reduce
it. Otherwise, a cascade of oxidative hemolysis ensues sec-
ondary to underlying G6PD deficiency, resulting in a vicious
cycle of further methemoglobinemia.11
The most frequent cause of this co-occurrence reported
in the literature is the ingestion of fava beans, which can in-
duce methemoglobinemia and potentiate G6PD deficiency
simultaneously.3,16-19 All the reported cases in the litera-
ture are male, with a median age of 6 years (range 1-56).
All of them were newly diagnosed with G6PD deficiency
upon presentation with MethHgb. Median Hgb was 8 gm/
dL (4.6-9.9) and median MetHgb was 8% (5.6-35). One pa-
tient (our patient) received methylene blue, and 3 received
Vitamin C. All of them recovered and were discharged. Our
patient was also male and had taken a full meal consisting
of fava beans before presenting. Although his methemo-
globin level was 5.6 percent, he was given methylene blue
due to his symptoms, which worsened his hemolytic ane-
mia (Table 2).
Interestingly, our patient had a history of favism in the
past without developing any symptoms. Only this time, he
ate a larger amount of fava beans, which led to hemolysis
and methemoglobinemia. Hence, while treating methemo-
globinemia patients, one should be vigilant that a history of
fava beans ingestion without any symptoms does not rule out
G6PD deficiency. It depends upon the number of beans in-
gested over a certain period.20
5 |
CONCLUSION
Favism is a rare cause of the co-occurrence of methemo-
globinemia and hemolysis in G6PD deficient individuals.
The severity of hemolysis in G6PD deficient individuals is
dependent on the number of fava beans ingested. It is vital to
identify the presence of G6PD deficiency in patients present-
ing with methemoglobinemia, as the initiation of methylene
blue in such individuals can result in a cascade of oxidative
hemolysis.
TABLE 2
Reported cases of methemoglobinemia and G6PD deficiency secondary to favism
Case number
Patients' age,
sex
Nationality
G6PD
deficiency
Type
Hgb (gm/dL)
presentation/lowest
MetHgb
Methylene
blue
Vit
C
Outcome
Case 1 16
43 y, male
Albanian
New diagnosis
NA
8/NA
8%
No
Yes
Discharged
Case 2 18
6 y, male
Algerian
New diagnosis
G6PD376G/202A
9.2/6
7.6%
No
No
Discharged
Case 3 19
30 y, male
Nepalese
New diagnosis
NA
8.4/5.9
35%
No
Yes
Discharged
Case 4 3
1 y, male
Afghan
New diagnosis
NA
6.2/6.2
6.2%
No
No
Discharged
Case 5 17
1 y, male
Iraqi
New diagnosis
NA
6.9/NA
11.4%
No
No
Discharged
Case 6 17
6 y, male
Iraqi
New diagnosis
NA
4.6/NA
14.9%
No
No
Discharged
Our case
56 y, male
Qatari
New diagnosis
NA
9.9/6.5
5.6%
Yes
Yes
Discharged
Abbreviations: G6PD, Glucose-6-phosphate dehydrogenase; Hgb, Hemoglobin; MetHgb (normal 0%-1.5%), Methemoglobin.
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ATA et al.
ACKNOWLEDGMENTS
Authors would like to thank Dr Percy MJ for permitting
reproduction of the Figure 2. This article is available as a
preprint with the following link: Favism induced methe-
moglobinemia in a G6PD deficient male with a subsequent
hemolytic cascade, a therapeutic challenge: case report and
review of literature - Authorea
CONFLICT OF INTEREST
All authors declare no potential conflicts of interest to dis-
close related to the publication of this case series.
AUTHOR CONTRIBUTIONS
FA, BM: Conceptualized the data. BM: Consented the pa-
tient. FA, AB, SJ, ID, MM, MU, MY: Reviewed the litera-
ture. FA, BM, AB, SJ, ID: Wrote the manuscript. FA, AB:
Collected the data. AB: Took part in writing and images ra-
diologically. FA, MU, MY: Modified and critically reviewed
the article. FA, AB, SJ, ID, MM, MU, MY: Reviewed finally
and approved the article.
CONSENT
Written informed consent was obtained from the patient for
publication of this case report and accompanying images.
ORCID
Fateen Ata
https://orcid.org/0000-0001-7121-8574
Saad Javed
https://orcid.org/0000-0002-7510-2381
Bassam Muthanna
https://orcid.
org/0000-0002-9594-0964
Ammara Bint I Bilal
https://orcid.
org/0000-0002-0219-1678
Mohamed A. Yassin
https://orcid.
org/0000-0002-1144-8076
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How to cite this article: Ata F, Javed S, Muthanna B, et
al. Favism induced methemoglobinemia in a G6PD
deficient male with a subsequent hemolytic cascade, a
therapeutic challenge: Case report and review of
literature. Clin Case Rep. 2021;9:2048–2052. https://doi.
org/10.1002/ccr3.3941