Hemoglobinopathy as a Rare Differential Disease for Low Oxygen Saturation by Pulse Oximetry: A Case Report and Literature Review

Abstract

Pulse oximetry is used to screen for respiratory failure in dyspnea patients. However, pulse oximetry can yield false-positive results in certain situations. Unstable hemoglobinopathy is a disease in which mutations in the globin-encoding gene result in abnormal globin chain production, causing low percutaneous oxygen saturation (SpO₂) levels due to changes in hemoglobin absorbance and oxygen affinity. We identified a new family lineage of Hb Hirosaki in an adult patient with chronic obstructive pulmonary disease, dyspnea, and low SpO₂. According to our literature review, only a few cases of unstable hemoglobinopathy have been reported in adults. Most patients with unstable hemoglobinopathy are asymptomatic, and those with dyspnea often have respiratory diseases or severe anemia. To differentiate unstable hemoglobinopathy, an appropriate assessment of the discrepancy between SpO₂ values and arterial blood gas analysis results is important.

Introduction

Dyspnea is a common and nonspecific symptom associated with a wide variety of differential diseases. In cases of dyspnea, pulse oximetry is a simple tool that can be used to screen for respiratory failure and is frequently used in clinical practice. However, care must be taken when interpreting these results because there are situations in which pulse oximetry can yield false readings (1).

Unstable hemoglobinopathy is a disease in which mutations in a globin-encoding gene result in the production of abnormal globin chains (2). Percutaneous oxygen saturation (SpO₂) and arterial oxygen saturation (SaO₂) values have been reported to be dissociated in some unstable hemoglobinopathies (low SpO₂ but normal SaO₂) due to differences in hemoglobin absorbance (3-6). Furthermore, many of these patients are asymptomatic and can be diagnosed with hemoglobinopathies based on screening for respiratory and cardiovascular disease, confirmation of response to oxygen therapy, and results of an arterial blood gas analysis (7). However, these are rare conditions and are more difficult to diagnose when patients present with dyspnea due to a concomitant respiratory disease. A better understanding is required to correctly diagnose this rare disease.

We herein report a new case and review previous reports of low SpO₂ due to hemoglobinopathy.

Case Presentation

The patient was a 59-year-old man who had been found to have low SpO₂ since his youth. He had been diagnosed with asthma five years earlier and had been receiving a fluticasone/umeclidinium/vilanterol combination and montelukast; however, his dyspnea on exertion worsened chronically. He was diagnosed with chronic obstructive pulmonary disease (COPD) based on his smoking history (50 pack-years), obstructive ventilation disorder (forced expiratory volume per second, 50.3%), and mild emphysema on chest computed tomography (CT). However, he was referred to our hospital because of his medical history of low SpO₂ and increased alveolar-arterial oxygen difference (A-aDO₂; 27.88 mmHg) on an arterial blood gas analysis, leading us to suspect shunt disease.

His modified Medical Research Council dyspnea scale score was 2, and his SpO₂ level was 86% on ambient air. Our interviews revealed that the patient's mother and daughter also had low SpO₂, although they were asymptomatic. An arterial blood gas analysis showed that the arterial oxygen partial pressure (PaO₂) was 77 mmHg and SaO₂ was 96.3% on ambient air (Table 1). Furthermore, the color of arterial blood collected in ambient air was dark red (Figure). Blood tests revealed normal brain natriuretic peptide levels but low levels of haptoglobin, suggesting hemolysis (Table 1). Peripheral blood smears revealed fragmented red blood cells (RBCs). Pulmonary function tests revealed moderate obstructive ventilatory disorder (percent predicted forced expiratory volume in one second, 53.5%) and mild diffusion impairment (percent predicted diffusing capacity of the lungs for carbon monoxide, 72.2%). Pulmonary ventilation/perfusion scintigraphy suggested the presence of a minor right-left shunt, with a shunt rate of 8.0% detected. However, transthoracic echocardiography and chest contrast CT showed no obvious shunt disease. Abdominal ultrasonography did not reveal liver disease or portal hypertension.

Table 1.

Arterial Blood Gas Analysis in Ambient Air and Blood Test Findings.

BGA and blood tests	Value
pH	7.43
PaO2, mmHg	77
PaCO2, mmHg	38
HCO3-, mmol/L	25.2
A-aDO2, mmHg	25.5
SaO2, %	96.3
WBC, /μL	7,300
RBC, 104/μL	451
Hemoglobin, g/dL	13.9
Hematocrit, %	42.9
MCV, fL	95.1
MCH, pg	30.8
MCHC, %	32.4
Reticulocyte, %	4.0
Total bilirubin, mg/dL	0.8
Direct bilirubin, mg/dL	0.3
Haptoglobin, mg/dL	≤10
Serum iron, μg/dL	267
TIBC, μg/dL	343
Ferritin, ng/mL	1,542.4
Isopropanol test	Positive
BNP, pg/mL	≤5.8

A-aDO₂: alveolar-arterial oxygen difference, BGA: blood gas analysis, BNP: brain natriuretic hormone, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, MCV: mean corpuscular volume, PaCO₂: arterial carbon dioxide partial pressure, PaO₂: arterial oxygen partial pressure, TIBC: total iron binding capacity, RBC: bed blood cell, WBC: white blood cell, SaO₂: arterial oxygen saturation

Figure.

Appearance of arterial blood fluid. Arterial blood samples were collected in ambient air. An arterial blood gas analysis did not reveal respiratory failure (PaO₂, 77 mmHg); however, the color was dark red.

To exclude shunt disease, the shunt rate was calculated using the 100% oxygen method (8) and right heart catheterization was performed. At 100% oxygen, an arterial blood gas analysis revealed a PaO₂ of 609 mmHg, SaO₂ of 100%, and shunt rate of 4.0%. The findings of right heart catheterization were normal (mean pulmonary artery pressure, 18 mmHg; cardiac index, 2.86 L/min/m²; pulmonary vascular resistance, 1.74 wood unit) with no oxygen step-up and no micro-pulmonary arteriovenous fistulas observed on pulmonary angiography.

Based on these findings, the existence of a right-left shunt was ruled out, and hereditary hemoglobinopathies were strongly suspected. Genetic tests performed with the patient's consent revealed α2-globin codon 43 TTC (Phe) → TTG (Leu) [Hb Hirosaki (heterozygote)], and this patient was diagnosed with unstable hemoglobinopathy. Furthermore, the methemoglobin level was elevated (4.1%), which may have contributed to the falsely abnormally low SpO₂. However, the methemoglobin level was causing no symptoms (9). Thus, dyspnea was considered a symptom of obstructive pulmonary disease, and exercise therapy was encouraged while continuing previous treatment.

Methods

A literature review was conducted to identify cases of low SpO₂ due to hemoglobinopathy. Literature in English or Japanese listed in Medline and Igaku Chuo Zasshi before January 1, 2024, were included, with keywords of hemoglobinopathy, unstable hemoglobin, pulse oximetry, and pulse oximeter. The additional literature cited in previous reviews was also validated. Patients with hemoglobinopathy and SpO₂ ＜95% were selected from the literature. Clinical information on patient background, symptoms, SpO₂, arterial blood gas analysis findings (SaO₂ and PaO₂), blood tests (hemoglobin and methemoglobin), and hemoglobin gene abnormalities was extracted from selected cases.

Results

A literature search was conducted to extract clinical information on 53 cases from 38 eligible references, and 54 cases, including self-examined cases, were analyzed. The results are summarized in Table 2. Eighteen (33%) patients were adults (≥18 years old), and only 8 (15%) were diagnosed at ≥50 years old, as in the present case. Of the patients who complained of dyspnea (six cases), three had coexisting respiratory diseases (asthma, two; COPD, one), and two had severe anemia. The median SpO₂ was 85% (range: 36-93%), with 46 cases (85%) showing values ＜90%. Of the 34 cases for which SaO₂ values were provided, 21 (14 genetic variants) showed discrepancies between the SpO₂ and SaO₂ values. Of the 42 patients for whom PaO₂ values were provided, only 3 met the definition of respiratory failure. The median hemoglobin value was 11.2 (range: 7.0-16.3) g/dL, including some cases that did not meet the definition of anemia. Of the 18 cases in which methemoglobin values were provided, 5 were considered to have methemoglobinemia (methemoglobin ≥3.0%).

Table 2.

Literature Review Results.

Items	Results
Total cases, n	54
Age, median (range)	14 (0-63)
Adult patients (age≥18), n (%)	8 (15)
Male/female, n (%)	31 (57)/23 (43)
Region, n (%)
East Asia	14 (26)
Europe	15 (28)
Middle East	1 (2)
North America	24 (44)
Complaints of dyspnea, n (%)	6 (11)
SpO2, median (range)	85 (36-93)
Cases with SaO2 ≥90% in ambient air*, n (%)	21 (62)
SaO2 in room air*, median (range)	92.4 (65.2-100)
Cases with PaO2 ≥60 mmHg in ambient air†, n (%)	39 (93)
PaO2 in room air (mmHg)†, median (range)	90.8 (47.0-117.0)
Hemoglobin value (g/dL)§, median (range)	11.2 (7.0-16.3)
Cases with methemoglobin ≥3.0%**, n (%)	5 (28)

^*The number of cases with SaO₂ value available were 34.

^†The number of cases with PaO₂ value available were 42.

^§The number of cases with hemoglobin value available were 40.

^**The number of cases with methemoglobin value available were 18.

PaO₂: arterial oxygen partial pressure, SaO₂: arterial oxygen saturation

Discussion

Hb Hirosaki is a rare abnormal hemoglobin caused by a genetic abnormality in α2-globin discovered in Japan. In this disease, the oxidation of unstable hemoglobin results in the formation of Heinz bodies attached to the red blood cell membrane. These abnormal red blood cells are removed by the spleen and cause hemolytic anemia (10). Although these mutations are often detected in severe hemolytic anemia, mild anemia has also been reported (5,10-12), but no association between this syndrome and methemoglobinemia has been reported. However, hyperoxidation associated with hemoglobin abnormalities has also been reported in other genetic mutations, suggesting that a similar mechanism may lead to methemoglobinemia (13). In addition, in the present case, no social history or adverse medication had caused methemoglobinemia.

In particular, the relationship between SpO₂ and SaO₂ varied with the mutation type. SpO₂ by irradiating the skin with light at 2 wavelengths [660 nm (red light) and 940 nm (near-infrared light)] and measures the change in the optical absorption of oxyhemoglobin and reduced hemoglobin (14). SaO₂ was calculated as the percentage of oxygenated hemoglobin from individually measured oxyhemoglobin, reduced hemoglobin, carboxyhemoglobin, and methemoglobin. In unstable hemoglobinopathies, in which SpO₂ appears low despite normal SaO₂, as in our case and in previous reports, interference of the absorbance of red and/or near-infrared light by abnormal Hb levels accounts for the spurious reduction in SpO₂ (4,5,15-26). In addition, methemoglobin absorbs red and near-infrared light equally, so that SpO₂ approaches 80-85% as methemoglobin increases (27). Meanwhile, in genetic mutations in which both SpO₂ and SaO₂ are low, reduced oxygen affinity for abnormal hemoglobin has been reported (28-34). Only one case of Hb Milwaukee has been reported with SaO₂ below SpO₂, which is explained by the combination of decreased hemoglobin oxygen affinity and methemoglobinemia (35).

Conclusion

In rare cases, unstable hemoglobinopathy is diagnosed in adults based on falsely low SpO₂ values. Unstable hemoglobinopathy rarely causes dyspnea. Therefore, respiratory complications or severe anemia should be suspected when respiratory symptoms are present in patients with hemoglobinopathy. To distinguish unstable hemoglobinopathy, it is important to properly assess the discrepancy between SpO₂ values and arterial blood gas analysis results.

Informed consent was obtained from all patients.

The authors state that they have no Conflict of Interest (COI).