Key clinical message:
Congenital methemoglobinemia is rarely diagnosed and reported as a cause
of cyanosis, especially in adults. It is a treatable cause of cyanosis
that should be kept in our differential diagnosis.
Abstract:
Cyanosis and dyspnea are common complaints in adults and have broad
differential diagnoses, of which rare ones as congenital
methemoglobinemia should always be kept in mind. Methemoglobinemia might
be acquired or congenital. Patients’ symptoms vary from severe shortness
of breath, mental status changes, cyanosis to none.
Here we present a rare case of a 33-year-old Indian non-smoker female,
who had a long history of recurrent episodes of cyanosis, headache, and
fatigue. After excluding cardiopulmonary causes, methemoglobin levels
were measured and found to be high, without exposure to any offending
agent. Consequently, we suspected a diagnosis of congenital
methemoglobinemia and started treatment with ascorbic acid, and she
improved.
In this article, we summarized our patient’s presentation and did a
literature review about congenital methemoglobinemia.
Introduction:
Methemoglobinemia, a form of hemoglobinopathies, is defined as an
increased methemoglobin level, where the ferric form of iron is attached
to heme instead of ferrous. This will reduce tissue
oxygenation1. A percentage of hemoglobin will be
oxidized to methemoglobin under any oxidative stress, but this is
regulated by special enzymes to keep it in normal individuals less than
1.5%. Usually, cyanosis appears when methemoglobin levels exceed 1.5
g/dl, around 15% of total hemoglobin; most adults with
methemoglobinemia have the acquired type due to exposure to an offending
agent. Whereas having unexplained methemoglobinemia in an adult should
raise the possibility of the congenital type, which is extremely rare.
Three genetic causes lie behind congenital
methemoglobinemia2:
1.CYB5R3 gene pathogenic variations lead to autosomal recessive
cytochrome b5 reductase deficiency. This genetic phenotype causes two
types of methemoglobinemia; type 1, RBC type, might be asymptomatic and
type 2, other cells, were patients will have neurologic manifestations.
2. Point mutation in alpha-globin gene causing hemoglobin M, an
autosomal dominant disease.
3. Cytochrome b5 deficiency, extremely rare.
Our patient presented with shortness of breath of 3 days duration with
bluish discoloration of her fingers and lips. Her complaint was not
associated with chest pain, cough, wheezes, or any other symptoms. she
had recurrent similar episodes since childhood but milder. A mismatch
between oxygen saturation by pulse oximetry and blood gases raised the
possibility of methemoglobinemia. We suspected the congenital
methemoglobinemia type 1 and initiated treatment with a high dose of
ascorbic acid; after ruling out the causes of acquired
methemoglobinemia, and the patient improved clinically.
Case presentation:
This is a case 33-year-old Indian lady seen in the emergency room for
difficulty breathing with bluish discoloration gradually increased over
days, with no fever or cough. She mentioned having recurrent similar
episodes since childhood, exacerbated by infections, but usually milder.
No previous surgical or medical history, except for one admission last
year for shortness of breath with cyanosis, required oxygen support for
one day and then discharged home with no diagnosis, and chronic
headache.
One sister has similar cyanosis symptoms, who had surgery complicated
with low saturation and severe cyanosis during anesthesia. Both have
never been investigated. Her other three siblings and parents do not
have any symptoms.
Physical examination was normal except for central and peripheral
cyanosis; the chest was clear, with no wheezes, no crackles. Cardiac
examination, no murmurs or abnormal heart sounds. Abdominal examination,
no organomegaly appreciated.
Height: 167 cm, weight: 66 kg, BMI: 23.7 kg/m2, SpO2: 90% sometimes
dropping to 88% on room air, HR: 77 beat/minute, BP: 105/80 mmHg, RR:
20 breath/min
Investigations:
Patient had normal liver function tests results, G6PD scan: normal other
laboratory results and ABG result in table (1).
Peripheral blood smear demonstrated mild
erythrocytosis with no other abnormalities. Electrocardiography showed
normal sinus rhythm. Chest radiography showed clear lung fields and a
heart of normal size and contour. There were no abnormalities of
the hilar, mediastinal, pleural, or bony structures.
The patient’s clinical picture of cyanosis with no evidence of
cardiovascular or pulmonary diseases and the discrepancy between PaO2
and O2 saturation on oximeter required thinking of methemoglobinemia as
a possible diagnosis despite the patient’s age and the absence of any
exposures. Methemoglobin level 20.9% (0-1.5%). Hemoglobin
electrophoresis did not detect any abnormal hemoglobin.
The activity of NADH cytochrome b 5 reductase or
the level were not done.
Discussion:
Methemoglobinemia is a result of defective regulation of the
methemoglobin level by the responsible pathways after oxidative stress.
In normal individuals, methemoglobin results from oxidation of ferrous
iron that binds to heme to ferric iron, which decreases its ability to
bind to oxygen, leading to less oxygen delivery to tissues and left
shift in oxygen dissociation curve11/17/2020 5:33:00
PM. Affected individuals can have cyanosis, but clinically significant
tissue hypoxia is unusual as compensatory erythrocytosis improves oxygen
delivery.
Methemoglobinemia might be acquired or congenital. For acquired
methemoglobinemia, a myriad of causes has been described in the
literature of which: medication as dapsone, lidocaine, nitrates, sulfa
drugs 3,4,5. The clinical consequences
depend upon methemoglobin levels in the blood; symptoms will start at a
level >10%, then nausea, tachycardia occurs with
level<30%, while 50% level leads to neurological
deterioration. Higher levels can cause arrhythmia, while more than 70%
of methemoglobin is considered fatal2,3. The acquired
form’s symptoms are affected by the speed of the increase in the levels
and the half-life of the causative agent. Mostly those patients require
treatment with intravenous methylene blue.
Conversely, congenital methemoglobinemia causes milder presentation as
it is a chronic elevation in methemoglobin with a physiologic
compensatory erythrocytosis. NADH cytochrome b5 reductase deficiency
congenital methemoglobinemia is further classified into two
subcategories. Type 1, enzyme deficiency in the erythrocytes, those
patients are usually asymptomatic or will present late with cyanosis,
fatigue, some shortness of breath—treatment for cosmetic reasons
mostly10,23. Type 2, generalize deficiency of
cytochrome b5 in all body tissues, is accompanied by neurological
disabilities; however, it is not amenable to treatment at this time.
While acquired methemoglobinemia, triggered by oxidative means, is
common, congenital causes are uncommon and rarely documented in the
literature10.
Here we tried to summarize the English published literature about
congenital methemoglobinemia in table (2)