Refractory Iron-Deficiency Anemia and Vascular Malformation Concomitant with Aortic Stenosis: Heyde Syndrome

Introduction

Iron-deficiency anemia is globally recognized as a prevalent pathological condition [1], and identifying its underlying causes is crucial for effective treatment. Regarding the etiology of iron-deficiency anemia, malnutrition is frequent in children, and menstruation-related bleeding is common in women of reproductive age, while in men and postmenopausal women, chronic gastrointestinal bleeding is more prevalent [2]. Chronic gastrointestinal bleeding is often attributed to malignancies of the gastrointestinal tract, such as stomach and colon tumors, as well as conditions such as erosive gastritis, hemorrhoids, or colonic diverticula [2]. In cases of idiopathic iron-deficiency anemia, bleeding due to malignancies, ulcers, and vascular dilatation was associated with 43% of them, while 51% were due to conditions such as atrophic gastritis and celiac disease [3]. However, in older patients, malnutrition, vascular ectasia, and nonsteroidal anti-inflammatory drug-induced ulcers are often implicated as the common causes [4,5]. These causes can also simultaneously occur in some older patients. Heyde syndrome is a unified explanation for this mixed pathophysiology, characterized by anemia due to angiodysplasia, aortic valve stenosis, and acquired von Willebrand syndrome [6]. As the prevalence and severity of aortic stenosis (AS) increase with age [7], Heyde syndrome must be considered when gastrointestinal vascular malformations or anemia are observed [8]. The pathogenesis of Heyde syndrome involves structural changes in the von Willebrand factor (vWF) that occur during its passage through the narrowed aortic valve induced by shear stress [6]. While 1.8% of patients undergoing catheter treatment for aortic valve stenosis have Heyde syndrome [9], this condition is potentially prevalent among a larger population. Nevertheless, awareness of Heyde syndrome in actual clinical practice is low.

Herein, we report a case of an older woman presenting with severe refractory iron-deficiency anemia and severe AS, who subsequently received a diagnosis of Heyde syndrome.

Case Report

A 70-year-old woman undergoing treatment for hypertension and dyslipidemia began experiencing exertional dyspnea 3 months prior to presentation. Microcytic hypochromic anemia, with a hemoglobin level of 69 g/L (116–148 g/L), was detected during routine blood testing at her primary care physician’s office, raising suspicion of iron-deficiency anemia and leading to iron supplementation. Subsequent upper gastrointestinal endoscopy conducted within the following month revealed atrophic gastritis, suggesting Barrett esophagus and Helicobacter pylori infection; lower gastrointestinal endoscopy identified a sigmoid diverticulum but did not reveal any bleeding source. Despite ongoing symptoms, a repeat upper endoscopy conducted 3 weeks before she visited her primary care physician’s office showed consistent findings. Her hemoglobin level declined to 46 g/L despite continued iron supplementation, prompting referral to our hospital. She did not experience any episodes of bleeding, such as nosebleeds, gum bleeding, abnormal bleeding, or melena.

Physical examinations revealed a blood pressure of 120/71 mmHg, pulse rate of 72 beats per min, and oxygen saturation of 97% on room air. The patient had the pallor of the conjunctiva, normal breath sounds, and a widely radiating systolic ejection murmur. Blood tests revealed the following: hemoglobin level of 41 g/L (116–148 g/L), mean corpuscular volume of 93.5 fL (83.6–98.2 fL), mean corpuscular hemoglobin concentration of 28.7% (31.7–35.3%), platelet count of 123×109/L (158–348×109/L), prothrombin time-international normalized ratio of 0.99 (0.90–1.10), activated partial thromboplastin time of 24.2 s (25.0–40.0 s), iron level of 3.58 µmol/L (7.16–33.7 µmol/L), total iron binding capacity of 72.70 µmol/L (44.05–73.42 µmol/L), unsaturated iron binding capacity of 69.12 µmol/L (19.34–58.20 µmol/L), and ferritin level of 38.20 pmol/L (13.48–310.11 pmol/L) (Table 1). The platelets were aggregated, and it was determined to be pseudothrombocytopenia. Electrocardiography indicated left ventricular hypertrophy, and chest radiography revealed a cardiothoracic ratio of 62%, indicating cardiac enlargement. A red blood cell transfusion (6 units) was administered for severe anemia. Chest and abdominal contrast-enhanced computed tomography did not show evidence of active gastrointestinal bleeding or a large malignant tumor; however, significant calcification of the aortic and mitral valves was observed (Figure 1). Transthoracic echocardiography revealed severe aortic valve stenosis, with a peak velocity of 5.3 m/s, mean pressure gradient of 62 mmHg, and aortic valve area of 0.75 cm2 (Figure 2). Upper and lower gastrointestinal endoscopy did not reveal an obvious bleeding source. Capsule endoscopy of the small intestine showed capillary dilation primarily in the jejunum (Figure 3). Heyde syndrome was suspected; post-transfusion vWF activity was 127%, and vWF antigen was 147%, with both within the normal range. However, a deficiency in large vWF multimers led to the diagnosis of Heyde syndrome.

On day 14, minimally invasive cardiac surgery was performed for aortic valve replacement to manage severe AS, and she subsequently underwent blood transfusions twice. At postoperative day 44, the patient’s hemoglobin level improved to 111 g/L, and she was progressing without any symptoms.

Discussion

The present case involves the coexistence of iron-deficiency anemia with aortic valve stenosis; upon thorough investigation, Heyde syndrome was diagnosed. Considering aortic valve stenosis and iron-deficiency anemia as components of a unified pathophysiology instead of separate conditions, the inclusion of Heyde syndrome in the differential diagnosis can improve the quality of diagnosis. Thus, recognizing Heyde syndrome in the differential diagnosis enables a proactive search for angiodysplasia in the gastrointestinal tract, including the small intestine, facilitating prompt and appropriate diagnosis and treatment.

Heyde syndrome is associated with acquired deficiency of vWF [6]. The vWF, a large glycoprotein, plays a crucial role in hemostasis by mediating platelet adhesion and stabilizing factor VIII. However, the structure of the vWF is believed to be altered because of shear stress during its passage through a narrowed aortic valve, leading to the loss of large vWF multi-mers. This results in decreased hemostatic function and promotes vascular malformation [6]. Since Heyde syndrome is often reported with normal vWF levels [6,10], measuring large vWF multimers is necessary for accurate assessment.

Recognizing the underlying condition and conducting chest auscultation is crucial when considering Heyde syndrome as a potential differential diagnosis, particularly in a primary care setting. Despite the potential coexistence of Heyde syndrome in 1.8% of patients with AS [9], clinicians can overlook this condition, albeit a considerable number of patients with Heyde syndrome. When evaluating patients suspected of having iron-deficiency anemia in clinical settings, it is essential to auscultate the heart sounds to assess heart failure. In typical anemia cases, a systolic functional murmur is commonly heard, particularly in the apical region [11]. However, the strongest ejection murmur is typically heard in AS at the second right sternal border. When the cause of anemia cannot be identified, Heyde syndrome should be considered in the differential diagnosis, and the presence of auscultatory findings suggestive of AS should be verified.

In considering Heyde syndrome in the differential diagnosis, gastrointestinal vascular dilation and vascular malformation are identified as potential causes of iron-deficiency anemia. While vascular malformations in Heyde syndrome are well known for their predilection in the appendix and right-sided colon, they can occur throughout the stomach, small intestine, and entire colon [12]. Therefore, in cases such as the present one, where active bleeding is not observed in upper or lower gastrointestinal endoscopy, it is crucial to confirm the absence of vascular dilation and malformation using techniques such as capsule endoscopy. These findings should be considered potential causes of iron-deficiency anemia if identified. Additionally, surgical intervention can be a viable option for the radical treatment of Heyde syndrome in cases of AS accompanied by refractory iron-deficiency anemia [6,13]. Surgical interventions include surgical aortic valve replacement and thoracic endovascular aortic repair. Surgical intervention allows large vWF multimers to be normalized and bleeding controlled [14]. In the present case, we performed a surgical valve replacement. However, as the older population is expected to increase, thoracic endovascular aortic repair, which is minimally invasive and has a lower incidence of complications, may become more common [15].

Conclusions

In cases in which the cause of iron-deficiency anemia cannot be identified in a primary care setting, careful chest auscultation should be conducted to verify the absence of aortic valve stenosis. If aortic valve stenosis is detected, considering Heyde syndrome in the differential diagnosis and conducting a thorough gastrointestinal tract examination is advisable. When identifying angiodysplasia in the small intestine as the cause of anemia, in addition to measuring vWF, large vWF multimers should be measured.