INTRODUCTION
Amyloidosis represents a diverse group of diseases characterized by the abnormal extracellular deposition of misfolded proteins, known as amyloid fibrils. These insoluble proteins accumulate in tissues, disrupting their normal structure and function. With approximately 27 out of 60 identified amyloidogenic proteins associated with human diseases, amyloidosis is recognized as a rare condition with varied causes and clinical presentations. Accurate epidemiological data remains elusive due to its heterogeneity and rarity. Systemic amyloidosis, where protein deposition affects multiple organs, is more prevalent than localized forms. Gastrointestinal (GI) involvement can occur in both systemic and localized amyloidosis, posing diagnostic and therapeutic challenges.
Gastrointestinal amyloidosis is defined by the presence of GI symptoms alongside histological confirmation of amyloid deposits in GI tissues. However, direct biopsy confirmation from the GI tract can be infrequent, highlighting the need for a comprehensive understanding of this condition. This review aims to provide an in-depth analysis of gastrointestinal amyloidosis, encompassing its classification, epidemiology, pathogenesis, clinical manifestations, and crucially, the diagnostic approaches and current treatment strategies available. This is particularly important for enhancing the diagnostic accuracy for “Gastrointestinal Amyloidosis Diagnosis” in clinical practice.
METHODS
This review is based on an extensive literature search conducted to identify relevant articles on gastrointestinal amyloidosis and its clinical presentations. Databases including PubMed, Google Scholar, and Ovid MEDLINE were searched for publications from 1960 to 2020. A manual review of references from identified articles was also performed. Data from reputable national organizations like the Genetic and Rare Disease Information Center (GARD) were consulted. Search keywords included “amyloidosis,” “gastrointestinal amyloidosis,” “localized amyloidosis,” “systemic amyloidosis,” “amyloid pathogenesis,” “hepatic amyloidosis,” “amyloidosis diagnosis,” “gastrointestinal amyloidosis diagnosis”, “amyloidosis treatment,” “gastrointestinal amyloidosis treatment,” and “gastrointestinal amyloidosis prognosis.” Inclusion criteria encompassed English language articles published between 1960 and 2020, data from national organizations, and guidelines related to the management of GI amyloidosis. Exclusion criteria included duplicate articles, abstracts only, pre-1950 publications, non-English articles, and unpublished research. After applying these criteria, 3197 articles were reviewed, and 65 were selected for this narrative review.
DISCUSSION
Amyloidosis, at its core, is marked by the extracellular accumulation of fibrillar proteins, leading to tissue disruption. Under electron microscopy, amyloid fibrils measure approximately 10 nm in diameter. A hallmark diagnostic feature is their apple-green birefringence under polarized light after Congo Red (CR) staining[5]. The International Society of Amyloidosis has identified approximately 27 amyloidogenic proteins linked to human diseases out of around 60 heterogeneous proteins[7].
CLASSIFICATION OF GASTROINTESTINAL AMYLOIDOSIS
Amyloidosis is broadly classified into systemic and localized types based on the origin and deposition of amyloidogenic precursor proteins (Table 1). Gastrointestinal involvement can be a feature of both.
Table 1. Systemic vs. Localized Gastrointestinal Amyloidosis
| Feature | Systemic Gastrointestinal Amyloidosis | Localized Gastrointestinal Amyloidosis |
|---|---|---|
| Prevalence | More common | Less common |
| Amyloid Production | Remote site, deposition in GI tract | GI tract, local deposition |
| Precursor Proteins in Blood | Present | Absent |
| Associated Conditions | Plasma cell dyscrasia, chronic inflammation, dialysis, hereditary conditions | Not associated with underlying disease pathology |
| Common Amyloid Proteins | AL, AA, Aβ2M, ATTR | AL (most common) |
| Management | Treat underlying etiology, symptomatic management | Observation or surgical excision of localized deposits |
| Prognosis | Variable, depends on amyloid type and extent | Generally good, no systemic progression |
AL: Monoclonal light chain; AA: Serum amyloid A; Aβ2M: β2-microglobulin amyloid; ATTR: Familial transthyretin-associated amyloidosis; GI: Gastrointestinal.
Systemic Gastrointestinal Amyloidosis
Systemic amyloidosis is the more prevalent form, characterized by amyloidogenic precursor proteins produced at a distant site from the affected organ, such as the GI tract. This can arise from acquired conditions like plasma cell disorders or hereditary conditions linked to mutations in the transthyretin (TTR) gene. Table 2 outlines common forms of systemic amyloidosis and their organ involvement. Primary systemic amyloidosis (AL) is particularly relevant to GI involvement.
Table 2. Common Forms of Systemic Amyloidosis and Organ Involvement
| Type of Systemic Amyloidosis | Causative Protein | Organ Involvement |
|---|---|---|
| Primary Systemic Amyloidosis (AL) | Monoclonal light chain (AL) | Heart, Kidneys, Liver, Peripheral nervous system, Autonomic nervous system, GI tract |
| Senile Systemic Amyloidosis (ATTRwt) | Wild-type transthyretin (ATTR) | Heart |
| Hereditary Systemic Amyloidosis (ATTRm, AApoA1, AFib, ALys) | Mutant transthyretin (ATTR); Apolipoprotein 1 (AApoA1); Mutant fibrinogen A alpha (AFib); Lysozyme (ALys) | Heart; Heart, Kidneys, Liver, Peripheral nervous system, Skin; Kidneys, Liver; Kidneys, Liver |
| Isolated Atrial Systemic Amyloidosis | Atrial natriuretic factor (AANF) | Heart |
| Secondary Systemic Amyloidosis (AA) | Serum amyloid A (AA) | Kidneys, Heart, GI tract |
| Dialysis-Related Systemic Amyloidosis (Aβ2M) | β2-microglobulin (Aβ2M) | Osteoarticular tissue, Circulatory system, GI tract |
| Finnish-type Systemic Amyloidosis (AGel) | Gelsolin (AGel) | Lattice dystrophy of cornea, Corneal neuropathy |
Localized Gastrointestinal Amyloidosis
Localized amyloidosis is defined by the production and deposition of amyloidogenic proteins within the same location. It less frequently affects the GI tract compared to other sites like the respiratory tract, urinary bladder, breast, and skin. Studies suggest that only a small percentage of biopsy-proven amyloidosis cases are restricted to the GI tract, highlighting its rarity.
EPIDEMIOLOGY OF GASTROINTESTINAL AMYLOIDOSIS
Amyloidosis, including its gastrointestinal form, is considered a rare disease. The wide range of etiologies and clinical presentations makes accurate epidemiological assessment challenging. Geographic variations in environmental factors, prevalence of infections, autoimmune diseases, and genetic predispositions can influence disease incidence.
In Western countries, AL amyloidosis incidence is estimated at 1 case per 100,000 person-years, with approximately 1,275 to 3,200 new cases annually in the United States[4]. Systemic amyloidosis predominates over localized forms, with primary systemic amyloidosis (AL) accounting for 78% and secondary systemic amyloidosis (AA) for only 6% of new systemic cases in the US each year[4]. Familial transthyretin-associated amyloidosis is less common, representing 10% to 20% of diagnosed cases at tertiary centers in the US[4].
Global incidence trends are similar. A UK study reported a global amyloidosis incidence of 5 cases per million person-years, with AL and AA subtypes contributing 3 and 1 case per million person-years, respectively[10]. A Swedish study estimated an incidence of 8 cases per million person-years, with AL at 3 and AA at 2 cases per million person-years[11]. Amyloidosis typically manifests later in life, predominantly affecting older adults (mean age for AL subtype is 63 years)[12], and is more common in males than females[12]. Mortality related to amyloidosis in the US increased from 1.77 to 3.96 per million between 1979 and 2015, with higher rates in the African-American population[13].
Gastrointestinal involvement occurs in both localized and systemic amyloidosis (especially AL subtype). GI amyloidosis is defined by GI symptoms and biopsy confirmation[14], and is more frequently observed in older males. A retrospective study of 583 amyloid patients found that 16.8% had GI symptoms, but only 45% of those undergoing endoscopy had biopsy-proven GI amyloidosis[15]. Another study evaluating 2337 patients over 13 years reported biopsy-proven GI amyloidosis in only 3.3%[6]. Duodenal biopsies had the highest diagnostic yield, followed by stomach, colon, rectum, and esophagus[6,15]. These findings confirm that GI amyloidosis with direct biopsy verification is a rare occurrence. The limited data, primarily from small, retrospective studies and case reports, underscores the need for large, multi-center prospective studies to better understand the global impact and healthcare burden of GI amyloidosis.
PATHOGENESIS OF GASTROINTESTINAL AMYLOIDOSIS
The fundamental pathogenic mechanism of amyloidosis involves the extracellular deposition of insoluble protein fibrils derived from amyloid precursor proteins in tissues[16]. These fibrils are composed of low molecular weight subunits arranged in antiparallel ß-pleated sheets[16]. In GI amyloidosis, these misfolded proteins infiltrate different layers of the GI tract.
Mucosal Infiltration in GI Amyloidosis
The duodenum is the most common site of mucosal infiltration, followed by the stomach, colorectum, and esophagus[17]. The type of amyloid protein dictates the clinical presentation[18,19].
- AL amyloid deposition: Typically found in the muscularis mucosa, submucosa, and muscularis propria, often leading to protrusions and potential bowel obstruction symptoms.
- AA amyloid deposition: Predominantly in the mucosa, causing increased friability and erosions, potentially manifesting as diarrhea and malabsorption.
- Aβ2M amyloid deposition: Seen in hemodialysis patients, affecting blood vessels, mucosa, submucosa, and muscularis propria, potentially leading to mucosal ulceration.
Neuromuscular Infiltration in GI Amyloidosis
Amyloid deposition in the neuromuscular layer can disrupt the intrinsic nerve plexus (myenteric or submucosal) and muscularis externa, leading to abnormal peristalsis, altered GI transit times, and dysmotility[20–22].
Hepatic amyloidosis, a systemic manifestation, involves extracellular deposition of fibrillar amyloid protein (AL) in the liver parenchyma[23]. It presents a diagnostic challenge due to overlapping symptoms with other chronic liver diseases and carries a poor prognosis, particularly with jaundice[23].
CLINICAL MANIFESTATIONS OF GASTROINTESTINAL AMYLOIDOSIS
Clinical presentations of GI amyloidosis depend on the extent and location of amyloid deposits, regardless of whether it’s primary or secondary systemic amyloidosis[17]. Localized amyloidosis can mimic systemic disease symptoms. Common general symptoms include fatigue, light-headedness, anorexia, and weight loss[24]. GI-specific abnormalities include:
Gastrointestinal Bleeding
Occurring in up to 57% of patients, bleeding can originate from any site of amyloid deposition[25]. Causes include mucosal lesions (amyloidoma ulcers, erosions, polyps, hematomas), vascular fragility, or bowel ischemia[25,26]. Dialysis-related amyloidosis is often associated with massive occult GI bleeding[27].
Malabsorption Syndrome
Manifesting as diarrhea, weight loss, steatorrhea, anorexia, or dizziness, malabsorption results from mucosal infiltration, pancreatic insufficiency, or bacterial overgrowth[28,29].
Protein-Losing Gastroenteropathy
Characterized by diarrhea, edema, and ascites, this condition is due to protein loss from mucosal lesions in the GI tract[30].
Chronic Gastrointestinal Dysmotility (Stasis Syndrome)
Symptoms include nausea, vomiting, dysphagia, gastroparesis, reflux, appetite loss, constipation, abdominal pain, bloating, or chronic intestinal pseudo-obstruction[20,21,25]. Dysmotility arises from myopathic and neuropathic dysfunction[25]. Paradoxically, some patients experience persistent diarrhea due to rapid transit times from dysmotility, inflammation, and bacterial overgrowth[25,31,32].
Hepatic Amyloidosis Manifestations
Often clinically silent due to mild symptoms[33]. Hepatomegaly and mild alkaline phosphatase (ALP) elevations are common findings[34]. Other symptoms include weight loss (72%), fatigue (60%), abdominal discomfort (53%), and anorexia (26%)[25]. Elevated direct bilirubin (> 2 mg/dL) indicates poor prognosis[25,34].
Uncommon Symptoms
Rarely, patients may present with cholangitis, pneumatosis intestinalis, or bowel perforation[35–37].
Physical examination findings vary depending on organ involvement[9]. GI-specific findings include macroglossia (enlarged tongue) in up to 50% of cases[25]. Abdominal examination may reveal hepatosplenomegaly and ascites[34,38].
GASTROINTESTINAL AMYLOIDOSIS DIAGNOSIS
A high index of suspicion is crucial for accurate “gastrointestinal amyloidosis diagnosis”. Due to the rarity and non-specific symptoms, patients often undergo extensive and unnecessary testing. GI amyloidosis should be considered in patients with unexplained GI symptoms and predisposing conditions like plasma cell dyscrasia, chronic renal failure on hemodialysis, and chronic inflammatory conditions (e.g., rheumatoid arthritis, inflammatory bowel disease). Family history of amyloidosis should also raise suspicion[9].
Laboratory investigations may reveal anemia, mild ALP elevation, acute phase reactant elevations (related to underlying inflammation), and malabsorption-related deficiencies. Radiological investigations are generally non-specific[39]. CT or MRI findings may include[25,39–41]:
- Diffuse or nodular bowel wall thickening.
- Dilatation due to hypomotility.
- Fluid levels in dilated loops.
- Luminal narrowing from amyloid infiltration or ischemia.
- Attenuation from calcifications or mucosal ulcerations.
- Polyploid protrusions or masses mimicking cancer.
- Loss of haustrations.
- Mesenteric thickening or adenopathy.
- Decreased hepatic attenuation, possibly with calcifications (Ultrasound may show heterogeneous liver texture).
While radiology can suggest the extent of involvement, tissue biopsy followed by Congo Red staining and polarized light microscopy is the gold standard for gastrointestinal amyloidosis diagnosis[42]. Endoscopy (EGD or colonoscopy) should be performed to obtain biopsy specimens based on presenting symptoms. The duodenum offers the highest diagnostic yield in GI biopsies, followed by the stomach, colorectum, and esophagus[6,15]. Liver biopsy, via a transjugular approach to minimize bleeding risk, can confirm hepatic amyloid infiltration[43,44].
However, biopsy results can be negative in a significant proportion of clinically suspected GI amyloidosis cases (e.g., 55% in one study[15]). In such cases, especially with persistent GI symptoms and functional bowel disorder criteria (Rome IV), further diagnostic studies are warranted. These may include functional assessments of the GI tract like esophageal or anorectal manometry, capsule endoscopy, or gastric emptying studies[6]. Therefore, for patients with clinical suspicion of GI amyloidosis but negative biopsies, additional motility studies are recommended.
Amyloid fibrils appear as amorphous, eosinophilic deposits on routine hematoxylin-eosin stains, potentially mimicking hyaline changes or sclerosis[45]. Congo Red staining with apple-green birefringence under polarized light remains the definitive diagnostic test since its introduction[45]. Despite high sensitivity and specificity, false negatives can occur due to amyloid quantity, deposit age, section thickness, tissue fixation, or staining technique[46].
Newer diagnostic adjuncts are emerging. Digitally reinforced hematoxylin-eosin polarization (DRHEP) enhances birefringence detection using digital photography alongside light microscopy, potentially identifying weak birefringence missed by conventional microscopy[45]. While currently primarily used for kidney biopsies, DRHEP’s application in “gastrointestinal amyloidosis diagnosis” is under investigation[45].
TREATMENT STRATEGIES FOR GASTROINTESTINAL AMYLOIDOSIS
Once GI amyloidosis is diagnosed, subtype determination from the biopsy is crucial to guide therapy[47]. Management involves:
Symptomatic Management of GI Amyloidosis
Symptom control is tailored to the clinical presentation. For dysmotility (stasis syndrome), dietary modifications, hydration, prokinetic, and antiemetic agents are recommended. Dietary adjustments include frequent, small-volume liquid or homogenized low-fiber, low-fat foods, with nutritional supplementation if needed[48]. Prokinetics like metoclopramide, erythromycin, or domperidone are central to dysmotility management[48]. Parenteral nutrition is indicated in severe dysmotility cases. Balloon dilation can treat dysphagia[49]. For diarrhea or bloating, antidiarrheals like loperamide are used[50]. Empiric antibiotics are considered for suspected bacterial overgrowth-related diarrhea. Corticosteroids and octreotide have shown benefit in severe diarrhea from protein-losing enteropathy[51,52]. GI bleeding management includes triage, supportive care, volume resuscitation, and source control via ligation. Surgical intervention may be necessary for severe obstruction, uncontrolled hemorrhage, or bowel ischemia[8,53]. Partial tongue resection can alleviate airway obstruction or sleep apnea from macroglossia[54].
Treatment of Underlying Systemic Amyloidosis
Currently, no specific protocols exist solely for GI amyloidosis. Treatment is guided by the amyloid protein type and underlying cause (Table 3).
Table 3. Management Strategies Based on Amyloid Protein in Gastrointestinal Amyloidosis
| Gastrointestinal Amyloidosis Type | AL Amyloidosis | AA Amyloidosis | Hereditary Amyloidosis | Dialysis-Related Amyloidosis
