Biermer’s disease unveiled: Bilateral macular hemorrhage as a rare manifestation—A case report

Abstract

The patient, a 30-year-old woman, presented with a sudden, painless, and severe decrease in vision in both eyes. The ophthalmological examination revealed a normal anterior segment and intraocular pressure, but a fundus examination showed bilateral macular hemorrhage. In the absence of a known history, a metabolic and hematological biological assessment was conducted. The assessment revealed megaloblastic anemia with a significantly reduced serum vitamin B12 level. Further examination confirmed Biermer’s disease as the cause of her anemia. The patient was started on a regimen of monthly vitamin B12 supplementation, which she will continue for life. This case report highlights the importance of recognizing megaloblastic anemia as a potential cause of spontaneous bilateral retinal hemorrhages. Moreover, it underscores the urgency for healthcare practitioners to promptly investigate and determine the root cause of megaloblastic anemia.

Introduction

A spontaneous macular hemorrhage can originate from several conditions, including diabetes, hypertension, blood clotting disorders (such as autoimmune hemolytic anemia and thrombocytopenia), and vasculitis. It can also be induced by certain medications or manifest as a component of anemic retinopathy. Bilateral macular hemorrhages, as a consequence of megaloblastic anemia, are rare. We present a case of anemic retinopathy in the setting of Biermer’s disease.

Case description

We describe the case of a 30-year-old woman who consulted for a sudden, painless, and severe decrease in vision in both eyes 1 week ago (best corrected visual acuity in the right eye was 5/10 and was limited to counting fingers at 1 m in the left eye). The patient had no history of bleeding tendencies, easy bruising, recent fever, or travel to dengue-endemic regions. She reported dyspnea and asthenia but had no history of trauma, surgery, or pregnancy (never been pregnant before). Her dietary habits were normal (not vegetarian), and she never consumed alcohol. The family history was negative for any similar conditions. Additionally, she had no known diabetes, hypertension, or hematopathy and was not taking any medications.

The ophthalmological examination revealed a normal anterior segment and intraocular pressure. The fundus examination (Figure 1(a) and (b)) revealed bilateral macular hemorrhage. In the right eye, there were two small rounded, brownish, punctate parafoveal hemorrhages. In the left eye, the hemorrhage was more extensive, making ½ papillary diameter, foveal, rounded, and brownish. There were no cotton wool spots, tortuous veins, Roth’s spots, exudates, or other vascular anomalies. The optic disk appearance was normal with no optic disc edema. An optical coherence tomography was performed, which showed a subinternal limiting membrane hematoma in the macula in both eyes (Figure 1(c) and (d)).

Figure 1.

(a, b) Fundus pictures of the right and left eyes, respectively, showing macular hemorrhage without any other manifestation of anemic retinopathy. (c, d) Show a subinternal limiting membrane hematoma in the macula in both eyes.

Given this clinical picture and in the absence of known history, we considered several diagnoses and first proceeded to a metabolic and hematological biological assessment to guide the diagnostic approach. A spontaneous macular hemorrhage can originate from several conditions, including diabetes (fasting blood glucose was 0.9 g/L, HbA1c was 5%), hypertension (blood pressure was 110/70 mmHg), blood clotting disorders such as autoimmune hemolytic anemia (direct Coombs test negative) and thrombocytopenia (normal platelet count: 200,560/µL), and vasculitis. The erythrocyte sedimentation rate was within normal limits. Thyroid function tests, urea, and electrolytes were also performed and found to be within normal limits. Normal ferritin level (106 ng/mL) and normal serum iron levels were also observed. Hemoglobin (Hb) electrophoresis was normal. HIV screening was negative.

The biological assessment revealed megaloblastic anemia (hemoglobin level of 4.9 g/dL, mean corpuscular volume 109 fl, mean corpuscular Hb-30.2 pg, white cell count 6.2 g/dL) with a collapsed serum vitamin B12 level (36 pg/mL). Following this result, a more thorough general examination was carried out showing severe pallor. The rest of the somatic examination revealed no abnormalities, particularly no neurological signs or complaints with correct vitals. As part of the etiological assessment of her anemia, the blood autoantibody assay was positive (anti-intrinsic factor antibodies and anti-parietal cell antibodies), and gastric endoscopy with biopsy confirmed Biermer’s disease with a typical atrophic appearance of the mucosa (atrophic gastritis). Other causes of severe anemia were ruled out.

The patient was put on monthly vitamin B12 supplementation, which she will continue for life. Three months after the treatment, she reported that her vision in both eyes had nearly returned to normal, and her complete blood count was within the normal range. Additionally, the fundus examination showed that the bilateral macular hemorrhages had completely resolved.

The patient was followed up monthly, and she adhered regularly to her vitamin B12 supplements. No recurrence of hemorrhage or other vascular abnormalities was detected during these visits.

Discussion

Anemia has been reported as a significant risk factor for the development of retinopathy in many case series, with a prevalence of 20%–28.3%.^1,2 Retinopathy has been described in the context of several types of anemia such as iron deficiency anemia, ¹ aplastic anemia, ³ sickle cell anemia, ⁴ beta-thalassemia, ⁵ autoimmune hemolytic anemia, ⁶ and drug-induced anemia. ⁷

Vitamin B12 is essential for DNA synthesis, and its deficiency can lead to various symptoms affecting the hematologic, neurologic, psychiatric, cutaneous, gastrointestinal, and cardiovascular systems. A deficiency in vitamin B12 results in megaloblastic anemia. ⁸ The primary causes of vitamin B12 deficiency are autoimmune conditions like pernicious anemia (Biermer’s disease), malabsorption due to conditions such as atrophic chronic gastritis or damage to the terminal ileum, alcohol abuse, ⁹ and dietary insufficiency, particularly in those following a strict vegan diet for an extended period.^8,10 Biermer’s anemia, also called pernicious anemia, is an autoimmune condition, is marked by a lack of vitamin B12. This shortage stems from an autoimmune condition known as atrophic chronic gastritis, which leads to the malabsorption of vitamin B12 due to reduced production of the intrinsic factor. This results in severe megaloblastic anemia, which, if not supplemented with vitamin B12, can pose significant health risks. ¹¹

The manifestations of anemic retinopathy are nonspecific and can mimic hypertensive or diabetic retinopathy.^1,12 In anemic retinopathy, the retina undergoes alterations such as the appearance of cotton wool spots, tortuous veins, and hemorrhages that can be observed throughout the retina and choroid. Retinal hemorrhages can manifest when the Hb level drops below 8 g/100 mL or when the platelet count decreases to less than 50,000 per cubic millimeter. ¹ On the other hand, megaloblastic anemia retinopathy can manifest as a spontaneous macular hemorrhage limited to the foveal region ¹ as in our case. Alternatively, it may present as blot or flame-shaped hemorrhages, Roth spots, optic disc edema, or superficial and deep intraretinal hemorrhages.^8,9,13

Two previous case reports of retinal manifestation linked to pernicious anemia have been documented. The first case report was authored by Gupta et al. ¹⁴ in 2001, where they described a 38-year-old man who presented with sudden onset of reduced vision in both eyes, and the examination found widespread superficial and premacular hemorrhages present in both fundi. After that in 2011, Macauley and Nag ¹⁵ reported a case of a 44-year-old man who presented with Roths spots as a manifestation of pernicious anemia. Our case describes a 30-year-old woman with a spontaneous bilateral macular hemorrhage limited to the foveal region.

Roth spots, characterized by white-centered retinal hemorrhages, are observed in patients with conditions such as leukemia and bacterial endocarditis. ¹³ These spots result from the disruption of capillaries followed by the formation of hemostatic fibrin plugs.^13,16 While Roth spots are typically associated with these conditions, they are considered rare in cases of megaloblastic anemia,^9,13 with only a few instances reported in literature, often in the context of alcohol abuse ⁹ or pernicious anemia. ¹⁵ Moreover, Derouich et al. ¹⁷ reported a case of Biermer’s disease presenting as optic neuropathy. The authors attributed this association to the fact that vitamin B12 deficiency, one of the causes of optic neuropathy, leads to optic atrophy through a process of demyelination.

Bilateral macular hemorrhages resulting from anemia are rare occurrences.^1,13 The precise mechanism behind retinal hemorrhages in anemic patients, particularly in the absence of thrombocytopenia, remains unclear. ⁷ Thrombocytopenia is a more established factor in the development of fundus lesions. However, the contribution of anemia to these lesions is not well understood, except in certain diseases like sickle cell anemia, where the abnormal shape of erythrocytes hinders perfusion to the peripheral retina, potentially leading to neovascularization.^18,19 Anemia-induced tissue hypoxia is thought to cause vasodilation and abnormal vessel leakage, which may lead to fundus abnormalities.^20,21

In addition to its direct impact on erythropoiesis and red blood cell fragility, cobalamin deficiency contributes to hemolysis through secondary mechanisms, notably hyperhomocysteinemia. Elevated levels of homocysteine, a by-product of methionine metabolism, have been implicated in endothelial damage and oxidative stress. This endothelial dysfunction and oxidative stress may weaken vascular integrity, making retinal vessels more susceptible to hemorrhage.^22,23

The tendency for hemorrhage in the macular region may be linked to the inherent fragility of vessels in this area. The association between macular hemorrhages and megaloblastic anemia, specifically due to vitamin B12 deficiency, is still poorly understood, and the exact mechanism behind these hemorrhages is yet to be elucidated.

In reported cases of megaloblastic anemia, treatment typically involved injectable cyanocobalamin (vitamin B12) and, if necessary, transfusion of packed red blood cells. In all cases, favorable outcomes were observed following the treatment of the underlying cause of the anemia, as seen in our case.

Conclusion

This case underscores the need for medical practitioners to consider megaloblastic anemia as a potential cause of spontaneous bilateral retinal hemorrhages, especially in patients presenting with sudden vision loss. The case also emphasizes the importance of a thorough examination and biological assessment in guiding the diagnostic approach. Timely diagnosis and treatment of the underlying cause, in this case, Biermer’s disease, can help manage the condition and prevent further complications. This case serves as a reminder of the diverse etiologies of retinal hemorrhages and the critical role of vitamin B12 in ocular health.