Abstract
Background
Gastrointestinal amyloidosis (GIA) is a rare manifestation of amyloidosis, characterized by amyloid fibril deposition in the gastrointestinal tract, leading to a range of clinical symptoms. Early diagnosis is challenging due to the nonspecific nature of endoscopic and clinical findings.
Objective
To analyze the clinical, endoscopic, and pathological characteristics of GIA and identify potential diagnostic markers for earlier detection.
Methods
A retrospective study was conducted on 36 patients diagnosed with GIA based on histopathological findings, including Congo Red staining. Clinical, endoscopic, and pathological data were analyzed to identify correlations between lesion morphology, clinical symptoms, and amyloid deposition.
Results
The cohort consisted of 22 males (61.1%) and 14 females (38.9%), with a mean age of 61.7 years. Endoscopic findings were diverse, with elevated lesions (57.1%) most common in the esophagus, stomach, and small intestine, and white patches (66.7%) prevalent in the duodenum. Histopathological analysis confirmed amyloid deposits in 62.8% of biopsy specimens. The small intestine exhibited the highest detection rate (100%), while the colorectum had the lowest (37.5%). Patients with elevated lesions may be asymptomatic, and among those with symptoms, abdominal pain is most common. Flat lesions are primarily associated with multiple symptoms, with abdominal discomfort, pain, distension, and acid reflux being the most frequent. The infiltration depth varied across different gastrointestinal tract segments, with the mucosal layer predominantly affected in the esophagus and stomach, whereas the submucosal layer more significantly involved in the duodenum and colon.
Conclusion
Gastrointestinal amyloidosis presents with a wide range of clinical symptoms and endoscopic manifestations. Histopathological diagnosis through standardized biopsy is crucial, and attention should be given to the depth of tissue sampling, as it may play a significant role in reducing misdiagnosis.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-025-03670-z.
Keywords: Gastrointestinal amyloidosis, Endoscopic features, Pathological features, Diagnosis
Highlights
• GIA can occur not only in affected areas, but also in normal mucosa.
• The detection rate of GIA was highest in the duodenum, particularly in the mucosal area of the descending part, with villous atrophy being the most common morphology.
• The lesion infiltration depth in GIA varies across different gastrointestinal tract segments.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12876-025-03670-z.
Introduction
Amyloidosis is a heterogeneous group of disorders characterized by the extracellular deposition of amyloid fibrils, which disrupt normal organ function [1]. These fibrils are composed of protein fragments that adopt a distinctive β-pleated sheet conformation, and when stained with Congo Red dye, they display green birefringence under cross-polarized light, a hallmark of amyloid deposits [2]. Amyloidosis can be classified into systemic and localized forms, depending on the site of amyloid precursor protein production and deposition, with both types potentially affecting the gastrointestinal tract. While amyloidosis most commonly affects the cardiovascular system (75%), followed by the urinary system, liver, and nervous system (10–15%), gastrointestinal amyloidosis (GIA) remains relatively rare, with an estimated prevalence of approximately 5% [3, 4].
Both systemic and localized forms of amyloidosis can involve the gastrointestinal tract, contributing to a variety of clinical manifestations, including esophageal motility dysfunction, gastrointestinal bleeding, malabsorption, and bowel obstruction [5–8].
The diagnosis of GIA is particularly challenging due to the nonspecific nature of its clinical and endoscopic manifestations. Although endoscopic features such as mucosal thickening, edema, ulcers, erythema, and villous atrophy are common, they are not pathognomonic of amyloidosis and may overlap with a variety of other gastrointestinal disorders [9]. Therefore, the definitive diagnosis of GIA relies on histopathological examination, with Congo Red staining being the gold standard for detecting amyloid deposits [10]. However, studies indicate that only about 3% of patients with gastrointestinal involvement are confirmed through biopsy [11]. The difficulty in obtaining adequate biopsy specimens and the variability in lesion morphology further complicate the diagnosis, especially in the absence of systemic signs or prior diagnoses of amyloidosis.
Endoscopic findings often precede the diagnosis, and although certain lesions may suggest GIA, the disease’s diverse clinical presentation necessitates a high degree of suspicion for accurate identification. The small intestine is considered the most commonly affected site, with the duodenum also frequently involved, while the colorectum shows relatively lower detection rates. Histopathologically, amyloid protein deposition can vary in both location and depth, commonly involving the mucosal and submucosal layers, depending on the type of amyloid protein deposited [12]. This study aims to provide a detailed analysis of the clinical, endoscopic, and pathological characteristics of GIA, emphasizing the importance of histopathological diagnosis, and to explore the correlations between lesion morphology, clinical symptoms, and the extent of amyloid infiltration.
Given the growing recognition of GIA and its impact on patient quality of life, early diagnosis and intervention are crucial. In this study, we retrospectively analyzed the clinical features, endoscopic findings, and pathological results of 36 patients with GIA, seeking to identify potential diagnostic patterns and markers. Our goal is to assist clinicians in recognizing gastrointestinal amyloidosis earlier, enhancing their endoscopic diagnostic capabilities, and improving the timely management and intervention for affected patients.
Methods
Patient sample collection
The study included patients who underwent endoscopic and pathological examinations at the Department of Gastroenterology, Peking University Third Hospital, from January 2007 to December 2021, and were definitively diagnosed with amyloidosis based on pathological findings. The inclusion criteria also required the patients’ complete basic clinical, endoscopic, and pathological data.
Baseline and laboratory parameters
A retrospective analysis was conducted on the patients’ basic clinical, endoscopic, and pathological data. The basic clinical information included the patients’ sex, age and clinical symptoms. Endoscopic data comprised the location, morphology, and detection rate of the lesions. Pathological data primarily included the site and depth of amyloid protein deposition, which facilitated a comprehensive analysis of the endoscopic and pathological characteristics of the lesions.
Immunohistochemistry analysis of tissues
For histological analysis, tissue samples underwent hematoxylin and eosin (H&E) staining to visualize cellular morphology and Congo Red staining to identify amyloid deposits.
Statistical analysis
Data analysis was conducted using SPSS Version 25.0. Continuous variables were expressed as means ± standard deviations and analyzed using the t-test. Categorical data were presented as percentages and analyzed using the chi-square test or Fisher’s exact test. For risk factor analysis, factors with statistically significant differences identified by the chi-square test were included in a multivariate logistic regression analysis using the Enter method. The results were expressed as odds ratios (OR) and 95% confidence intervals (CI), with a p-value < 0.05 considered statistically significant.
Results
Basic information
339,887 endoscopic procedures in our hospital from 2007 to 2021, and 36 cases of GIA were diagnosed with the observed detection rate of 0.01%. Among these, 29 underwent gastroscopy, 5 underwent colonoscopy, 1 underwent both gastroscopy and colonoscopy, and 1 underwent gastroscopy and enteroscopy. The cohort consisted of 22 males (61.1%) and 14 females (38.9%), with a mean age of 61.7 ± 11.3 years. The average age for males was 64.4 ± 10.0 years, and for females, it was 57.4 ± 12.2 years. No significant age difference was observed between the sexes (t = 1.875, p = 0.069).
Immunohistochemical staining
Hematoxylin and eosin (H&E) staining revealed a pale pink, homogeneous, and structureless substance in the deep tissue, indicative of amyloidosis. This finding was further confirmed through Congo Red staining, as shown in Fig. 1, with green birefringence observed under polarized light microscopy (Fig. 2).
Fig. 1.
Endoscopic images and corresponding histopathological images of gastrointestinal amyloidosis at various sites. Scale bars = 200 μm and 500 μm
Fig. 2.
Histological and immunohistochemical features of amyloid deposition. Amyloid deposition was observed in the stomach and duodenum. Scale bars = 100 μm and 200 μm
Endoscopic manifestations and clinical diagnoses
Out of 36 patients, only 1 patient was definitively diagnosed with GIA through enteroscopy; however, this diagnosis had already been confirmed via gastroscopy and pathology prior to the enteroscopy. A further 15 patients were given descriptive diagnoses, including mucosal thickening, edema, ulcers, erythema, bleeding, protuberance, leukoplakia, and villous atrophy. Additionally, 20 patients were diagnosed with other conditions: 2 were diagnosed with gastric cancer (Borrmann IV type) through endoscopy, and 18 were diagnosed with gastric polyps, chronic gastritis, and reflux esophagitis. These diagnoses led to standardized biopsies or treatments, resulting in a pathological confirmation of GIA.
Clinical symptoms of the patients
Regarding the clinical symptoms, 4 patients were excluded from the clinical symptom analysis due to early presentation, which prevented retrospective tracking of their symptoms. Therefore, 32 patients were analyzed for clinical symptoms. 3 patients (9.4%) were asymptomatic and were diagnosed incidentally during evaluations for multiple myeloma, chronic atrophic gastritis follow-up, and routine gastroscopy. For the remaining 29 symptomatic patients, gastrointestinal symptoms were more common than systemic symptoms. The most frequent gastrointestinal symptoms were acid reflux (31.0%), abdominal pain (27.6%), bloating (24.1%), and abdominal discomfort (24.1%), while weight loss (10.3%) was the most common systemic symptom.
Correlation between clinical symptoms and lesion morphology
Among the 32 symptomatic patients, 14 (43.8%) had elevated lesions, 8 (25.0%) had flat lesions, 2 (6.3%) had depressed lesions, and 8 (25.0%) exhibited a combination of two or more lesion morphologies. Notably, no patients had lesions consisting entirely of normal gastric mucosa; those with normal mucosa also had other lesion types. There were no significant differences between lesion morphology and the frequency of clinical symptoms, gastrointestinal symptoms, or systemic symptoms. However, patients with elevated lesions were more likely to be asymptomatic or present with a single symptom (Table 1).
Table 1.
Association between lesion morphology and clinical symptoms
| Lesion Morphology | Number of Patients (n) | Asymptomatic (n, %) | Single Symptom (n, %) | Multiple Symptoms (n, %) | P Value | Digestive Symptoms (n, %) | P Value | Systemic Symptoms (n, %) | P Value |
|---|---|---|---|---|---|---|---|---|---|
| Normal Mucosa | 0 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0.594 | 0 (0.0) | 0.266 | 0 (0.0) | 0.915 |
| Elevated Lesions | 14 | 3 (21.4) | 4 (28.6) | 7 (50.0) | 7 (50.0) | 4 (28.6) | |||
| Flat Lesions | 8 | 0 (0.0) | 2 (25.0) | 6 (75.0) | 6(75.0) | 1 (12.5) | |||
| Depressed Lesions | 2 | 0 (0.0) | 0 (0.0) | 2 (100.0) | 2 (100.0) | 0 (0.0) | |||
| Multiple Types | 8 | 0 (0.0) | 1 (12.5) | 7 (87.5) | 7 (87.5) | 2 (25.0) |
Further analysis of the relationship between lesion type and clinical symptoms showed that abdominal pain (36.4%) was the most common symptom in patients with elevated lesions, whereas abdominal discomfort (50.0%) was most frequent in patients with flat lesions. Heartburn and acid reflux are the most common symptoms in patients with depressed lesions. Abdominal distension (37.5%) was most common in patients with multiple lesion types (Table 2).
Table 2.
Frequency of gastrointestinal and systemic symptoms in patients with gastrointestinal amyloidosis
| Symptom | Elevated Lesions (n, %) | Flat Lesions (n, %) | Depressed Lesions (n, %) | Multiple Types (n, %) |
|---|---|---|---|---|
| Frequency (n, %) | 11 (37.9) | 8 (27.6) | 2 (6.9) | 8 (27.6) |
| Digestive Symptoms | ||||
| Abdominal pain | 4 (36.4) | 3 (37.5) | 0 (0.0) | 1 (12.5) |
| Abdominal Distension | 1 (9.1) | 3 (37.5) | 0 (0.0) | 3 (37.5) |
| Abdominal Discomfort | 1 (9.1) | 4 (50.0) | 0 (0.0) | 2 (25.0) |
| Decreased Appetite | 3 (27.3) | 1 (12.5) | 0 (0.0) | 0 (0.0) |
| Acid Reflux | 3 (27.3) | 3 (37.5) | 2 (100.0) | 1 (12.5) |
| Heartburn | 1 (9.1) | 2 (25.0) | 2 (100.0) | 1 (12.5) |
| Nausea | 1 (9.1) | 2 (25.0) | 0 (0.0) | 2 (25.0) |
| Vomiting | 0 (0.0) | 2 (25.0) | 1 (50.0) | 2 (25.0) |
| Belching | 2 (18.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Bitter Taste | 1 (9.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Diarrhea | 1 (9.1) | 2 (25.0) | 0 (0.0) | 2 (25.0) |
| Constipation | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) |
| Melena | 0 (0.0) | 0 (0.0) | 1 (50.0) | 0 (0.0) |
| Hematochezia | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) |
| Systemic Symptoms | ||||
| Weight Loss | 3 (27.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Lower Limb Edema | 0 (0.0) | 1 (12.5) | 0 (0.0) | 1 (12.5) |
| Taste Reduction | 0 (0.0) | 1 (12.5) | 0 (0.0) | 1 (12.5) |
| Dry Mouth | 1 (9.1) | 0 (0.0) | 0 (0.0) | 1 (12.5) |
| Dizziness | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) |
| Fatigue | 1 (9.1) | 0 (0.0) | 0 (0.0) | 1 (12.5) |
| Anemia | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (12.5) |
Correlation between clinical symptoms and lesion location and mucosal layer involvement
We also analyzed the correlation between clinical symptoms and the involvement of different gastrointestinal locations and mucosal layers. Although no significant associations were found (p = 0.228), patients with involvement of the upper gastrointestinal tract were more likely to present without clinical symptoms, while those isolated lower gastrointestinal tract involvement had a higher proportion of single symptoms. In contrast, patients with multi-site involvement tended to exhibit multiple symptoms. No significant differences were found between the depth of lesion involvement and the presence of gastrointestinal or systemic symptoms (Table 3).
Table 3.
Correlation between clinical symptoms and gastrointestinal involvement
| Parameter | Cases (n) | Asymptomatic (%) | Single Symptom (%) | Multiple Symptoms (%) | P-Value | With GI symptoms (n, %) | Without GI symptoms (n, %) | P-Value | With Systemic symptoms (%) | Without Systemic symptoms (%) | p-Value |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Affected Region | |||||||||||
| Upper GI tract | 23 | 3 (13.0) | 4 (17.4) | 16 (69.6) | 0.228 | 19 (95.0) | 1 (5.0) | 1.000 | 6 (30.0) | 14 (70.0) | 1.000 |
| Lower GI tract | 5 | 0 (0.0) | 3 (60.0) | 2 (40.0) | 5 (100.0) | 0 (0.0) | 1 (20.0) | 4 (80.0) | |||
| Multiple sites | 4 | 0 (0.0) | 0 (0.0) | 4 (100.0) | 4 (100.0) | 0 (0.0) | 1 (25.0) | 3 (75.0) | |||
| Affected Layer | |||||||||||
| Mucosal layer | 16 | 1 (6.3) | 3 (18.8) | 12 (75.0) | 0.754 | 15 (93.8) | 1 (6.3) | 0.600 | 4 (25.0) | 12 (75.0) | 1.000 |
| Submucosal layer | 16 | 2 (12.5) | 4 (25.0) | 10 (62.5) | 13 (81.3) | 3 (18.7) | 4 (25.0) | 12 (75.0) | |||
GI refers to gastrointestinal
Morphological characteristics of amyloidosis in the gastrointestinal tract
Biopsies were performed at 191 sites across 36 patients, yielding 120 positive biopsy specimens. The mucosal morphology of all positive specimens is shown in Table 4. The most common presentations in the esophagus, stomach, small intestine, and colorectum were elevated lesions, such as mucosal elevations, nodules, or polyps, which accounted for 57.1%, 31.9%, 64.3%, and 100.0% of the lesions, respectively. In the duodenum, the predominant feature was white patches, representing 66.7% of the lesions. In certain areas of the esophagus, stomach, and small intestine, positive histopathological results were obtained despite a normal mucosal appearance. Gastric lesions exhibited diverse morphologies, with rough and mucosal thickening occurring in 29.0% and 11.6% of cases, respectively, following polypoid lesions. Villous atrophy was particularly prevalent in duodenal and small intestinal amyloidosis, accounting for 12.5% and 21.4%, respectively.
Table 4.
Morphological characteristics of amyloidosis in various regions of the gastrointestinal tract
| Morphological Feature | Location | ||||
|---|---|---|---|---|---|
| Esophagus | Stomach | Duodenum | Small Intestine | Colorectum | |
| Normal Mucosa (%), n | 42.9%, 3/7 | 8.7%, 6/69 | -- | 14.3%, 2/14 | -- |
| Elevated Mucosa (%), n | 57.1%, 4/7 | 31.9%, 22/69 | 4.2%, 1/24 | 64.3%, 9/14 | 100.0%, 6/6 |
| Thickened Mucosa (%), n | -- | 11.6%, 8/69 | 8.3%, 2/24 | -- | -- |
| Rough Mucosa (%), n | -- | 29.0%, 20/69 | -- | -- | -- |
| Erythema (%), n | -- | 5.8%, 4/69 | -- | -- | -- |
| White Patch (%), n | -- | -- | 66.7%, 16/24 | -- | -- |
| White Patch (%), n | -- | 4.3%, 3/69 | -- | -- | -- |
| Ulcer (%), n | -- | 8.7%, 6/69 | 8.3%, 2/24 | -- | -- |
| Villous Atrophy (%), n | -- | -- | 12.5%, 3/24 | 21.4%, 3/14 | -- |
“—" indicates no data available or not examined. Values are presented as percentages (%), followed by the count (n) of cases
Detection rates of various gastrointestinal locations
The overall detection rate of GIA was 62.8% (120 out of 191 biopsy sites). The detection rates for different gastrointestinal locations are shown in Table 5. The small intestine exhibited the highest detection rate at 100.0%, followed by the duodenum at 88.9%. In contrast, the colorectum had a lower detection rate of 37.5%. The differences in detection rates across locations were statistically significant (Fisher’s exact test, p = 0.000). The detection rates in various regions of the stomach were not significantly different (Fisher’s exact test, p = 0.550). The gastric angle had the highest detection rate at 71.4% (5 out of 7), followed by the antrum at 62.5% (30 out of 48). The fundus and body of the stomach showed similar detection rates of 55.6% (5 out of 9) and 50.0% (29 out of 58), respectively. All duodenal samples were collected from the descending mucosa, which exhibited a detection rate of 100.0%. The detection rates for the colon and rectum were 33.3% (4 out of 12) and 50.0% (2 out of 4), respectively, though these differences were not statistically significant (Fisher’s exact test, p = 0.604).
Table 5.
Detection rates of amyloidosis in various gastrointestinal locations
| Location | Detection Rate (%), n | p-value |
|---|---|---|
| Esophagus | 58.3%, 7/12 | 0.000 |
| Stomach | 56.6%, 69/122 | |
| Duodenum | 88.9%, 24/27 | |
| Small Intestine | 100.0%, 14/14 | |
| Colorectum | 37.5%, 6/16 |
The p-value for the duodenum was statistically significant at p = 0.000. Values are presented as percentages (%), followed by the number (n) of positive cases out of the total number of cases examined. The p-values for the other locations are not listed in the table
Detection rates of various lesion morphologies in the gastrointestinal tract
Across the entire gastrointestinal tract, only the duodenum showed significant differences in detection rates for various lesion morphologies (χ2 = 13.090, p = 0.009). White patches, villous atrophy, and thickened mucosa had a detection rate of 100%, while no lesions were identified in areas with normal mucosal morphology. Elevated lesions were detected throughout the gastrointestinal tract at high rates, but no significant differences in detection rates were observed between esophagus, stomach, small intestine, and colorectum. Although gastric lesions exhibited diverse morphologies, including rough mucosa, ulcerative elevations, and erythema, the detection rates for these were high and without significant differences. The detection rates for normal mucosa in the esophagus, stomach, and small intestine ranged from 42.9% to 100.0%, while no lesions were found in the normal mucosa of the duodenum and colorectum. Further details are provided in Table 6.
Table 6.
Detection rates of various lesion morphologies in the gastrointestinal tract
| Morphology | Location | ||||
|---|---|---|---|---|---|
| Esophagus | Stomach | Duodenum | Small Intestine | Colorectum | |
| Normal Mucosa (%), n | 75.0%, 3/4 | 42.9%, 6/14 | 0.0%, 0/2 | 100.0%, 2/2 | 0.0%, 0/3 |
| Elevated Mucosa (%), n | 80.0%, 4/5 | 57.9%, 22/38 | 100.0%, 1/1 | 100.0%, 9/9 | 46.2%, 6/13 |
| Thickened Mucosa (%), n | -- | 50.0%, 8/16 | 100.0%, 2/2 | -- | -- |
| Rough Mucosa (%), n | 0.0%, 0/3 | 69.0%, 20/29 | -- | -- | -- |
| Erythema (%), n | -- | 57.1%, 4/7 | -- | -- | -- |
| White Patch (%), n | -- | -- | 100.0%, 16/16 | -- | -- |
| Erosion (%), n | -- | 33.3%, 3/9 | -- | -- | -- |
| Ulcer (%), n | -- | 66.7%, 6/9 | 66.7%, 2/3 | -- | -- |
| Villous Atrophy (%), n | -- | -- | 100.0%, 3/3 | 100.0%, 3/3 | -- |
| Fisher’s Exact Test, p-value | 0.116 | 0.483 | 0.009 | -- | 0.250 |
“—" indicates no data available or not applicable. Values are presented as percentages (%), followed by the count (n) of cases. The p-values reflect the significance of differences in detection rates among lesion morphologies, as determined by Fisher’s exact test
Infiltration depth and lesion site
Lesion infiltration depth varied across different parts of the gastrointestinal tract. In the esophagus, lesions were confined to the mucosal layer, primarily affecting the lamina propria, with no significant difference in involvement across layers (Fisher’s exact test, p = 0.061). In the stomach, the lamina propria and muscularis mucosa were predominantly affected, with significantly more involvement than the superficial mucosal epithelium and submucosa (χ2 = 56.046, p = 0.000). In the duodenum (χ2 = 11.667, p = 0.009) and colorectum (Fisher’s exact test, p = 0.000), the submucosa was significantly more affected than other layers, though the lamina propria also exhibited considerable involvement. In the small intestine, the lamina propria and submucosa was mainly affected (χ2 = 14.583, p = 0.002). For further details, refer to Table 7.
Table 7.
Depth of infiltration of lesions in different parts of the gastrointestinal tract
| Location | Depth of Infiltration | p-value | |||
|---|---|---|---|---|---|
| Superficial Mucosal Epithelium | Lamina Propria | Muscularis Mucosae | Submucosa | ||
| Esophagus (%), n | 42.9%, 3/7 | 71.4%, 5/7 | 42.9%, 3/7 | 0.0%, 0/7 | 0.061 |
| Stomach (%), n | 14.5%, 10/69 | 68.1%, 47/69 | 46.4%, 32/69 | 18.8%, 13/69 | 0.000 |
| Duodenum (%), n | 41.7%, 10/24 | 45.8%, 11/24 | 33.3%, 8/24 | 87.5%, 19/24 | 0.009 |
| Small Intestine (%), n | 14.3%, 2/14 | 71.4%, 10/14 | 14.3%, 2/14 | 78.6%, 11/14 | 0.002 |
| Colorectum (%), n | 0.0%, 0/6 | 50.0%, 3/6 | 0.0%, 0/6 | 100.0%, 6/6 | 0.000 |
Values are expressed as percentages (%), followed by the count (n) of cases. The p-values indicate the statistical significance of differences in infiltration depth across regions
Lesion morphology and infiltration depth
Gastrointestinal lesions were classified into four categories: normal mucosa, elevated lesions (elevated or thickened mucosa), flat lesions (rough mucosa, erythema, white patches, or villous atrophy), and depressed lesions (erosions or ulcers). Among all lesion types, the lamina propria was most frequently affected. Normal mucosa, however, exhibited the least involvement of the submucosa. Except for the involvement of the lamina propria, elevated lesions were more likely to involve the submucosa, while flat lesions demonstrated comparable involvement of both the muscularis mucosa and submucosa. Depressed lesions, though primarily involving the lamina propria, showed minimal involvement of the muscularis mucosa and no submucosal involvement. For further details, refer to Table 8. There was a significant difference in submucosal involvement across various lesion morphologies (Fisher’s exact test, p = 0.001). Elevated and flat lesions were more likely to involve the submucosa, while depressed lesions and normal mucosa primarily involved the mucosal layer. Depressed lesions primarily affected the lamina propria, whereas normal mucosa primarily involved the mucosal epithelial layer and lamina propria.
Table 8.
Depth of infiltration in various morphological lesions of the gastrointestinal tract
| Morphology | Depth of Infiltration | p-value | |||
|---|---|---|---|---|---|
| Superficial Mucosal Layer | Lamina Propria | Muscularis Mucosae | Submucosa | ||
| Normal Mucosa (%), n | 45.5%, 5/11 | 45.5%, 5/11 | 27.3%, 3/11 | 9.1%, 1/11 | 0.204 |
| Elevated Lesions (%), n | 11.5%, 6/52 | 59.6%, 31/52 | 28.8%, 15/52 | 48.1%, 25/52 | 0.000 |
| Flat Lesions (%), n | 30.4%, 14/46 | 63.0%, 29/46 | 54.3%, 25/46 | 50.0%, 23/46 | 0.015 |
| Depressed Lesions (%), n | 0.0%, 0/11 | 100.0%, 11/11 | 18.2%, 2/11 | 0.0%, 0/11 | 0.000 |
Discussion
GIA is a rare but clinically significant disease characterized by the extracellular deposition of amyloid proteins in the gastrointestinal tract, leading to a wide range of clinical symptoms and endoscopic manifestations. This study comprehensively analyzed the endoscopic and pathological features of 36 patients diagnosed with GIA, aiming to improve the diagnostic approach and understanding of this condition. Our findings highlight the challenges of diagnosing GIA due to its nonspecific endoscopic manifestations and diverse clinical presentations. Moreover, the correlation between lesion morphology and clinical symptoms, as well as the involvement of different gastrointestinal locations and mucosal layers, provides valuable insights into the clinical behavior of GIA.
The observed detection rate of 0.01% (36/339,887) in our study is notably lower than that reported in other studies [11, 13]. This discrepancy is likely attributable to the distinct patient populations between studies. Specifically, in our cohort, the patients diagnosed through endoscopy had not previously been diagnosed with amyloidosis, as those amyloid involvement in other organ systems are typically not subjected to endoscopic evaluation for diagnosis. This may explain the lower detection rate observed in our study. We posit that the identification of this group of patients highlights the clinical significance of early detection of GlA, especially in cases where gastrointestinal involvement precedes the involvement of other organ systems, such as the heart or kidneys. Early recognition and diagnosis of GIA could have profound implications for patient management and outcomes.
The diagnosis of GIA is primarily based on histopathological examination, as endoscopic findings are often nonspecific. In our cohort, only one patient was definitively diagnosed with GIA through enteroscopy, while the majority of diagnoses were made through gastroscopy and pathology. These findings are consistent with previous studies, which report that GIA lesions are difficult to identify based solely on endoscopic features, thus requiring biopsy for confirmation [14, 15]. The diverse endoscopic manifestations observed in this study, including mucosal thickening, edema, ulcers, erythema, and villous atrophy, are in line with those reported in the literature [5, 14, 16, 17], but these findings are not unique to GIA, which complicates clinical diagnosis.
The most common clinical symptoms in our cohort were gastrointestinal in nature, with acid reflux, abdominal pain, bloating, and discomfort being the most frequent complaints. These symptoms align with findings by Dias et al., who reported that GIA often presents with nonspecific gastrointestinal symptoms such as dyspepsia and malabsorption [18]. The predominance of gastrointestinal symptoms over systemic symptoms, such as weight loss, is consistent with the literature, which identifies the gastrointestinal tract as the most commonly affected site in GIA [11]. Additionally, the high proportion of asymptomatic patients diagnosed incidentally during endoscopic evaluations further underscores the need for heightened clinical awareness in high-risk populations, such as those with systemic amyloidosis or conditions like multiple myeloma.
The relationship between lesion morphology and clinical symptoms has been debated in previous studies, with conflicting reports on whether certain lesion types correlate with specific symptoms [11, 18]. In our study, no significant differences were found between lesion morphology and the frequency of gastrointestinal or systemic symptoms. However, patients with elevated lesions were more likely to be asymptomatic or present with a single symptom, suggesting that elevated lesions may be less likely to cause severe symptoms. This observation aligns with findings from Krauß LU et al., who noted that elevated lesions in the gastrointestinal tract tend to be less symptomatic compared to flat or depressed lesions [19].
Interestingly, our analysis of the relationship between lesion type and specific symptoms revealed that patients with elevated lesions frequently presented with abdominal pain, acid reflux and decreased appetite, while those with flat lesions most often experienced abdominal discomfort, distension, pain and acid reflux. These findings suggest that the morphology of GIA lesions may influence the type of gastrointestinal symptoms presented, supporting the hypothesis that lesion characteristics are linked to clinical presentation [14, 20–22].
The extent and distribution of amyloid deposits in gastrointestinal tract can vary. In our study, the small intestine exhibited the highest detection rate for GIA, which is consistent with other reports that identify the small intestine as the primary site of amyloid deposition in the gastrointestinal tract [9, 23]. The anatomical structure of the small intestine, with its large mucosal surface area and relatively slow transit time, may predispose it to amyloid protein deposition, facilitating early detection and diagnosis. The duodenum also demonstrated a high detection rate, suggesting that the examination of the upper gastrointestinal tract, particularly the duodenum, using both endoscopy and biopsy techniques, is crucial for the diagnosis of GIA [14, 16].
In contrast, the colorectum demonstrated a lower detection rate. Current research shows the deposition of AA and AL proteins is less prominent in the colorectum [24, 25]. And our research showed amyloid deposits in the colon primarily involve the submucosal layer, which is less readily detectable by standard endoscopic examination compared to the mucosal layer. Moreover, unlike a gastroscopic biopsy to assess gastritis, we do not usually biopsy normal-looking intestinal mucosa and may miss amyloidosis involving the intestine with normal-looking mucosa. These findings emphasize the need for targeted biopsies in suspected cases of GIA, especially in high-risk patients with gastrointestinal symptoms but no clear endoscopic findings.
Our study also revealed significant differences in lesion infiltration depth across different gastrointestinal locations. In the stomach, amyloid deposition primarily affected the lamina propria, while in the duodenum and colon, the submucosa was more commonly involved. This observation is consistent with previous studies suggesting that the type of amyloid protein deposited influences its distribution across different gastrointestinal layers. Specifically, AL and ATTR proteins tend to accumulate in the submucosa, while AA proteins are more commonly found in the mucosal layer [24–26]. The involvement of different layers may also be related to variations in tissue structure, blood supply, and hemodynamic factors, which could influence the extent of amyloid deposition [23, 27–29].
Due to the diverse endoscopic features of gastrointestinal amyloidosis, biopsy accuracy is of critical importance. Depressed or normal mucosa lesions tend to involve the superficial layers, making them more amenable to biopsy, which typically provides an accurate diagnosis. However, for elevated or flat lesions, which often extend into the submucosa, it is crucial to ensure that the biopsy samples are deep enough to avoid misdiagnosis due to superficial sampling.
The results of this study emphasize the importance of performing standardized biopsies, performing to minimize the risk of missing a rare disease even when the mucosal surface appears normal. Given the nonspecific nature of endoscopic findings and the diversity of lesion morphologies, histopathological examination remains the gold standard for diagnosing GIA. As recommended by previous studies, multiple biopsies should be obtained from different areas of the gastrointestinal tract to increase diagnostic yield [15, 25]. Additionally, our findings suggest that lesion morphology and location may be related with clinical presentation, which could affect biopsy strategies.
This study has several limitations. The relatively small sample size may limit the generalizability of our findings. Additionally, the retrospective nature of the study introduces the possibility of bias, and a prospective cohort study would be ideal for further validating our results. Future research should also explore the relationship between lesion morphology and clinical outcomes, such as treatment response and prognosis. Long-term follow-up studies should focus on how early diagnosis and targeted therapy can improve prognosis and quality of life for patients with GIA.
Conclusions
Gastrointestinal amyloidosis presents with a wide range of clinical symptoms and endoscopic manifestations. Histopathological diagnosis through standardized biopsy is crucial, and attention should be given to the depth of tissue sampling, as it plays a significant role in reducing misdiagnosis.
Supplementary Information
Acknowledgements
This study was supported by grants from the China Health & Medical Development Foundation.
Authors’ contributions
Z. Y. and S. D.: Conceptualization; Y. S. and H. Z.: Methodology; Y. X.: Validation; Z. Y. and Y. L.: Writing – Original draft preparation; S. D.: Writing – Reviewing and Editing, Project administration; Z. Y.: Funding acquisition. All authors have read and approved the final version of the manuscript.
Funding
This study was funded by the China Health and Medical Development Foundation (LM2023782).
Data availability
All data generated or analysed during this study are included in this published article and its supplementary information files.
Declarations
Ethics approval and consent to participate
All patient samples in this study were collected with informed consent by the Declaration of Helsinki. This retrospective cohort study was approved by the Peking University Third Hospital Medical Ethics Committee (M2023706).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Zhanyue Niu and Yanfei Lang contributed equally to this work.
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Supplementary Materials
Data Availability Statement
All data generated or analysed during this study are included in this published article and its supplementary information files.