An amyloid is a fibrillar protein characterized by a β-sheet secondary structure (known as cross-β) that readily forms aggregates [1]. Amyloidosis is a disease characterized by the extracellular deposition of amyloid proteins [2]. To date, 36 proteins have been identified as amyloidogenic. Of these, 14 are exclusively associated with systemic amyloidosis, reflecting their potential to affect multiple organs, whereas 19 are primarily implicated in localized diseases, where deposition is restricted to a single organ or tissue [3].

Amyloid light-chain (AL) amyloidosis is the most common form of this disease, with an estimated incidence of 3–13 cases per million people per year. In contrast, amyloid A (AA) amyloidosis occurs at a rate of approximately 2 cases per million per year. The typical age of onset for both types is between 55 and 60 years [4]. Amyloidosis may be either hereditary or acquired, and late-onset disease does not preclude a hereditary origin [5]. Approximately one-third of cases are hereditary, while acquired forms represent about half of all cases. The latter typically occurs at an older age and likely reflects an age-related decline in protein homeostasis mechanisms [6].

Gastrointestinal involvement is relatively common in systemic amyloidosis, whereas isolated gastrointestinal amyloidosis is rare [7]. According to a recent systematic review, the median age of patients with isolated gastrointestinal amyloidosis was 64.4 years, with a male-to-female ratio of 2:1. The stomach is the most frequently involved organ, followed by the small intestine and the colon [8]. Gastrointestinal amyloidosis may present with a wide spectrum of clinical manifestations, including bowel dysmotility, weight loss, gastrointestinal bleeding, ulceration or perforation, and malabsorption [2].

The endoscopic features of gastrointestinal amyloidosis are diverse and may include depressed lesions, submucosal tumorlike masses, nodular changes, and thickened folds [1,7]. Active ulcers or ulcer scars can also be observed as manifestations of amyloid deposition [9,10]. Vascular dilatation is another common finding, and magnified observation using narrow-band or blue laser imaging often reveals distortion of the microvasculature [1]. Because these lesions are frequently misinterpreted as other conditions, it is crucial to recognize endoscopic findings suggestive of amyloidosis. Therefore, this study aimed to characterize the endoscopic features and the clinical course of patients with isolated upper gastrointestinal (UGI) amyloidosis.

Proteins can adopt a wide range of conformational states within living organisms. Under certain conditions, they may undergo structural alterations that lead to the formation of nonfunctional and potentially pathogenic protein aggregates [11]. Ultimately, highly ordered assemblies known as amyloid fibrils form and are closely associated with numerous human diseases [6]. Several types of amyloidosis are clearly hereditary, with genetic factors playing a pivotal role in their pathogenesis [12]. Point mutations or deletions in precursor proteins can promote structural rearrangements that predispose to fibril formation [13]. In addition, systemic conditions such as multiple myeloma, lymphoma, or chronic dialysis can trigger the development of amyloidosis [14]. Histopathological examination of amyloidosis reveals a characteristic green–yellow–orange birefringence under cross-polarized light following Congo red staining [15]. Immunohistochemical analysis is performed using antibodies against AA amyloid, amyloid P components, and κ or λ light chains [16]. Our patients demonstrated consistent findings (Fig. 2).

Amyloidosis has the potential to affect virtually every organ system [17]. When the gastrointestinal tract is involved, the amyloid deposits exhibit type-specific demographic characteristics. For instance, patients with AA amyloidosis typically have a median age of 64 years, which is younger than that of patients with other types [16]. In our study, the AA amyloidosis group had a slightly older median age of 74 years (range, 63–82 years) compared with patients with nonspecific types, a finding inconsistent with previous reports. The remaining patients were not classified as having a specific amyloid type. These findings may be explained by the fact that our study included only patients with isolated gastrointestinal amyloidosis, whereas other forms such as AL and amyloid Transthyretin (ATTR) account for most cases of systemic amyloidosis [18].

The endoscopic features of gastrointestinal amyloidosis are highly variable and often atypical [19]. Erosions, ulcers, and even lesions that mimic malignancy can be observed, and in some cases, endoscopically normal-appearing mucosa have been histologically confirmed as amyloidosis through biopsy [20,21]. Several attempts have been made to classify these endoscopic findings. Said et al. [20] categorized lesions into groups such as normal appearance, erythema, and erosion, whereas Niu et al. [22] proposed a classification based on mucosal morphology, including normal, elevated, and thickened mucosa, emphasizing the mucosal status. A recent Korean study classified endoscopic findings into five types: protruding, granular, hemorrhagic, ulcerative, and nonspecific [23].

To simplify and standardize endoscopic characterization, we propose a classification system comprising four categories for gastric amyloidosis and three categories for duodenal amyloidosis (Fig. 3). Diffuse, flat, and yellowish lesions were defined as the yellowish patch-like type, representing the characteristic endoscopic appearance of duodenal amyloidosis in our cohort, whereas they were less frequently observed in the stomach. This type typically exhibits vascular dilatation, with central areas lacking visible vasculature, resulting in a yellowish mucosal appearance. The flat-depressed and flat-elevated types were characterized by a complete loss of mucosal vascularity and a homogeneous surface texture, which distinctly demarcated the lesion margins. These two types were differentiated based on their morphology, appearing either depressed or elevated, and the involved mucosa showed a whitish discoloration due to a lack of visible vascularity. The ulcerative-type showed heterogeneous endoscopic findings. In one patient, a large deep ulcer with easy-touch bleeding mimicked advanced gastric cancer, whereas in another patient, shallow ulcers with hematin deposits suggested benign ulcerative changes.

The proposed classification has the advantage of being simple, intuitive, and easy to apply in clinical practice. Regular endoscopic follow-up is warranted for isolated UGI amyloidosis, and a straightforward and easily recalled classification system is particularly useful during serial examinations. This system enables endoscopists to accurately recognize previously diagnosed lesions and compare them consistently with prior findings, thereby improving the continuity and quality of patient management.

It remains unclear whether the endoscopic features and clinical manifestations of isolated gastrointestinal amyloidosis differ from those of systemic amyloidosis involving the gastrointestinal tract. In the present study, the isolated amyloidosis group tended to include older patients, possibly because patients with systemic amyloidosis might have died before being diagnosed with gastrointestinal involvement. In patients with the isolated form, yellowish patch-like lesions were the most common finding in the duodenum, consistent with previous reports [17,22]. In contrast, the stomach exhibited more diverse morphological patterns without a dominant trend. These findings suggest that endoscopic manifestations are broadly similar irrespective of systemic involvement [17]. In our study, among patients with systemic involvement, the ulcerative type was the most common, which may reflect deeper submucosal invasion. Regarding the amyloid subtypes, AA-type amyloidosis was more frequent in the systemic group, although this difference was not statistically significant. This finding is consistent with previous observations that AA amyloidosis is typically associated with systemic diseases, as the AA protein tends to deposit more readily in the gastrointestinal tract [19].

However, the diagnostic role of EUS in gastrointestinal amyloidosis has not yet been fully clarified. Amyloid deposition may involve either the mucosal or submucosal layer, with duodenal lesions more frequently demonstrating submucosal infiltration than gastric lesions [22]. Previous studies have also reported that AL and ATTR amyloid proteins tend to accumulate predominantly within the submucosa, whereas AA proteins are more commonly confined to the mucosal layer [24,25]. On EUS, amyloid deposits typically appear as hypo- to isoechoic areas [1]. In our series, EUS revealed linear hypoechoic lesions with submucosal invasion, which were consistent with these observations.

The mainstay of the management of isolated gastrointestinal amyloidosis is careful observation and regular endoscopic follow-up. As reported in previous studies, most cases of isolated disease remain stable without progressing to systemic amyloidosis and generally exhibit a favorable prognosis [26,27]. However, if disease progression occurs, there is a potential risk of systemic involvement, and systemic chemotherapy, which is commonly used to treat systemic amyloidosis, may be warranted. In systemic AL amyloidosis, a combination regimen of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (the Dara-CyBorD regimen) is regarded as the treatment of choice [28]. In our series, only one patient (Case 1) received chemotherapy because of disease progression from the duodenum to the stomach, accompanied by abdominal pain and diarrhea. The patient was treated with the CyBorD regimen, resulting in marked symptomatic improvement. Apart from this case, no other patient showed disease progression, suggesting that isolated gastrointestinal amyloidosis generally follows a benign clinical course.

Gastrointestinal hemorrhage occurs in approximately 25%– 45% of patients with gastrointestinal amyloidosis, and the main bleeding sources include ulceration, ischemia, and mucosal friability [29]. Gastrointestinal amyloidosis can occasionally lead to life-threatening massive bleeding, in which case surgical resection should be considered [17,30]. In our cohort, Case 3 presented with melena, and duodenoscopy revealed large, deep gastric ulcers. Despite three sessions of successful endoscopic hemostasis, bleeding recurred, and surgical resection was recommended; however, the patient declined. After two weeks of supportive care alone, the patient died of a spontaneous intracranial hemorrhage, which was not directly related to amyloidosis but may have been influenced by uncontrolled hypertension.

This study had several limitations. Owing to the rarity of this condition, the sample size was small, which precluded a meaningful statistical analysis. In addition, some patients were lost to follow-up 12 months after diagnosis, limiting the assessment of the long-term disease course. Moreover, a few patients declined systemic evaluations such as 2D echocardiography or bone marrow biopsy, raising the possibility of underdiagnosed systemic amyloidosis. Future studies should aim to delineate the differences between isolated and systemic gastrointestinal amyloidosis and determine whether isolated UGI amyloidosis represents a distinct clinical entity.

In conclusion, isolated UGI amyloidosis appears to be a distinct clinical entity characterized by diverse endoscopic features. The awareness of amyloidosis as a potential underlying cause is crucial when interpreting duodenoscopic findings. Although the overall prognosis is generally favorable, careful long-term follow-up is warranted because of the potential for disease progression and systemic involvement. Familiarity with characteristic endoscopic appearances and the natural disease course is essential for accurate diagnosis and optimal management.