Intestinal amyloidosis: manifestations and diagnosis

Intestinal amyloidosis is the deposition of amyloid fibrils in the gastrointestinal (GI) wall and/or mesenteric structures in systemic or (less commonly) isolated forms of amyloidosis. The clinical picture varies from asymptomatic findings to severe diarrhea, malabsorption, bleeding, and intestinal obstruction. Gastrointestinal involvement is more commonly observed in AL amyloidosis (immunoglobulin light chain) and AA amyloidosis; in ATTR amyloidosis, intestinal manifestations are less common and typically milder. [1]

Contemporary reviews emphasize that the endoscopic picture is polymorphic (granular, elevated, hemorrhagic, ulcerative and “non-specific” types of lesions), and confirmation of the diagnosis is based on Congo red staining with “apple-green” birefringence and subsequent amyloid typing (immunohistochemistry/mass spectrometry) - this is critical for the selection of treatment at the systemic level. [2]

It's important for gastroenterologists to remember that gastrointestinal manifestations often mask systemic processes (cardiomyopathy, nephrotic syndrome, polyneuropathy). Early referral to an amyloidosis center improves outcomes thanks to etiotropic therapy (antiplasma regimens for AL, inflammation suppression for AA, targeted agents for ATTR, etc.). [3]

ICD-10 and ICD-11 codes

In ICD-10, systemic forms of amyloidosis are coded in block E85.* (E85.3 - secondary systemic, E85.4 - organically limited, E85.8/E85.9 - other/unspecified). Stomach and intestinal lesions as a localization are indicated by additional gastrointestinal tract codes (for example, K55-K63 for complications) and in the diagnosis text. [4]

ICD-11 uses post-coordination: a basic code for amyloidosis (e.g., 4A40.* "Systemic amyloidoses") with expanders such as fibrils (AL/AA/ATTR/other), localization (small/large intestine, stomach), and complications (bleeding, obstruction). This "cluster" more accurately reflects the clinical situation. [5]

Table 1. Practical coding

Clinical formulation	ICD-10 (example)	ICD-11 (example)	Comment
AL amyloidosis with small bowel involvement	E85.4 + K63.8	4A40.0 (AL) + XA0V (small intestine involvement)	Amyloid type is required
AA-intestinal amyloidosis in the presence of IBD	E85.3 + K52.9	4A40.1 (AA) + “colon involvement”	Specify the underlying inflammation
Hereditary ATTR, diarrhea	E85.0 + R19.7	4A40.2 (ATTR) + gastrointestinal involvement	Supplement the cardio-neuro-status
Amyloid-associated gastrointestinal bleeding	E85.* + K92.2	4A40.* + “GI bleeding”	Etiology is more important than the symptom

Epidemiology

AL amyloidosis has an incidence of approximately 10.8–15.2 cases per 1,000,000 person-years; gastrointestinal involvement is less common than cardiac/renal involvement but significantly impairs quality of life. AA amyloidosis is associated with chronic inflammation (rheumatoid arthritis, chronic infections, inflammatory bowel disease). Hereditary ATTR affects the gastrointestinal tract in some patients (diarrhea, weight loss, autonomic dysfunction). [6]

Systemic series show that AL is the predominant type in "digestive amyloidosis"; the lesion can involve the entire gastrointestinal tract, and endoscopic findings are extremely variable. In large series, suspicion of amyloidosis often arises retrospectively, based on the results of biopsies taken during "non-specific" clinical examinations. [7]

Table 2. Epidemiological landmarks

Indicator	Meaning
AL amyloidosis, general incidence	10.8-15.2 per 1,000,000 person-years
The type that most often produces digestive manifestations	AL > AA >> ATTR
Endoscopic phenotypes	elevations, granularity, hemorrhages, ulcers, "nonspecific"

Reasons

• AL amyloidosis: monoclonal plasma cell production of immunoglobulin light chains (often outside of overt myeloma).
• AA amyloidosis: chronic inflammation (autoimmune/infectious diseases), excess serum amyloid A.
• ATTR amyloidosis: wild-type (senile) or inherited mutations of transthyretin; GI symptoms are often associated with autonomic neuropathy and dysmotility.
• Rare forms: Aβ2M in patients on dialysis, local intestinal amyloidosis. [8]

Risk factors

Long-term systemic inflammation (rheumatic diseases, chronic infections), long-term dialysis, plasma cell dyscrasias, familial TTR mutations. For intestinal manifestations - additionally NSAIDs/anticoagulants (aggravate bleeding), motility disorders and bacterial overgrowth (aggravate diarrhea/malabsorption). [9]

Pathogenesis

Amyloid is deposited in the submucosa, vascular walls, and muscular layer, leading to vascular fragility (bleeding), impaired motility (stasis, pseudo-obstruction), thickening of folds, and decreased absorption. In AA, diarrhea/malabsorption predominates; in AL, bleeding, polypoid/nodular lesions, and increased mucosal fragility are more common. [10]

Endoscopic phenotypes are classified into 5 types: protrusive, granular, hemorrhagic, ulcerative, non-specific; often several types are combined in one patient. [11]

Symptoms

The most common complaints are chronic diarrhea, weight loss, bloating, abdominal pain, iron deficiency anemia and/or overt bleeding (melena, hematochezia), and symptoms of malabsorption. Early satiety, nausea/vomiting (gastro- and duodenal dysmotility), and episodes of subobstruction are also possible. [12]

In ATTR amyloidosis, intestinal complaints often overlap with autonomic neuropathy (orthostatic hypotension, gastroparesis, diarrhea/constipation). Any gastrointestinal symptoms in the presence of confirmed systemic amyloidosis require an active search for intestinal involvement. [13]

Classification, forms and stages

In practice, the following are distinguished: 1) systemic forms (AL, AA, ATTR) with varying degrees of gastrointestinal involvement; 2) localized gastrointestinal amyloidosis (rare). The degree of damage is described based on a combination of clinical presentation, endoscopy, histology, and the impact on nutrition (malabsorption, weight loss, need for nutritional support). [14]

Table 3. Clinical profiles by amyloid type

Type	More frequent gastrointestinal manifestations	Comments
AL	Bleeding, polypoid/nodular lesions, mucosal fragility	Often combined with cardiopathy/nephrotic syndrome
AA	Diarrhea, malabsorption, ulcerative-hemorrhagic forms	Background: chronic inflammation
ATTR (herited/wild)	Diarrhea/constipation, weight loss, dysmotility	Often autonomic neuropathy

Complications and consequences

Bleeding (even massive), perforations, strictures and pseudo-obstruction, severe malabsorption with deficiencies, hypoalbuminemia, and sarcopenia are possible. Some patients develop biliary-pancreatic and hepatic complications as part of the systemic lesion. Untreated systemic disease determines the prognosis. [15]

When to see a doctor

Immediate: hematemesis/melena, dark or scarlet stools, signs of dehydration with intractable diarrhea, severe abdominal pain with muscle tension (perforation/ischemia). Urgent: progressive anemia, weight loss, persistent diarrhea for >4 weeks, recurrent episodes of sub-obstruction. Elective: GI symptoms in a patient with known systemic amyloidosis. [16]

Diagnostics

Step 1. Clinical examination and basic tests. Complete blood count (anemia), iron/ferritin, albumin, electrolytes; stool occult blood test; inflammatory markers. Identify systemic clues (edema, shortness of breath, polyneuropathy). [17]

Step 2. Endoscopy with targeted biopsies. Esophagogastroduodenoscopy and/or colonoscopy; take multiple biopsies from abnormal and "appearingly normal" areas, including submucosa where possible. Congo red stain → "apple-green" birefringence - morphological confirmation. [18]

Step 3. Amyloid typing. Immunohistochemistry and/or mass spectrometry for precise determination of the type (AL/AA/ATTR, etc.) is the key to etiotropic therapy. In parallel, if AL is suspected, serum/urine immunofixation and free light chains are tested. [19]

Step 4. Advanced imaging and evaluation of complications. CT/MR enterography if stenosis/bleeding/pseudo-obstruction is suspected; if malabsorption is present, standard panel screening for deficiencies, bile acid diarrhea tests, and bacterial overgrowth tests as indicated. [20]

Table 4. Diagnostic roadmap

Question	First test	The next step
Is there amyloid in the mucosa?	EGDS/colonoscopy + biopsies	Congo red + polarization
What type is this?	Immunohistochemistry	Mass spectrometry (if in doubt)
Is there an AL clone?	Immunofixation + free light chains	Hematologist's consultation
Are there any gastrointestinal complications?	CT/MR (entero)graphy	Local tactics/endotherapy

Differential diagnosis

Gastrointestinal amyloidosis mimics inflammatory bowel disease, ischemic/radiation colitis, enteropathies (including drug-induced), angiodysplasia and coagulopathy (with bleeding), and infections. In colitis-like presentations, AA amyloidosis can "mask" as IBD; biopsy with Congo red and typing are crucial. [21]

Treatment

The main principle is etiotropic systemic therapy + local control of gastrointestinal symptoms and complications. Without determining the amyloid type, an adequate strategy is impossible. Therefore, after morphological confirmation, a multidisciplinary consultation is activated (gastroenterologist, hematologist/cardiologist/rheumatologist, pathologist, surgeon/interventionalist). [22]

AL amyloidosis. The basis is antiplasma therapy (e.g., daratumab-containing and/or bortezomib-containing regimens, autologous transplantation if indicated) under the guidance of a hematologist; the goal is to rapidly reduce free light chains. Management of gastrointestinal symptoms includes correction of anemia/deficiencies, antidiarrheal agents, and treatment of bleeding (endotherapy, transfusions). [23]

AA amyloidosis. The key is suppression of the underlying inflammation/infection (optimization of IBD/rheumatic disease therapy, targeted anti-inflammatory drugs). In this setting, intestinal manifestations often regress; in severe diarrhea, symptomatic support and nutritional measures are recommended. [24]

ATTR amyloidosis. TTR stabilizers (tafamidis for cardiac forms) and suppressors (patisiran/vutrisiran for polyneuropathy) are used systemically, depending on indications and availability. Gastrointestinal symptoms are treated as manifestations of autonomic neuropathy/dysmotility: fractional meals, motility modulators, antidiarrheals, and correction of orthostatic hypotension. [25]

Bleeding. Endoscopic hemostasis according to standards (injection, mechanical, and thermal methods) taking into account tissue fragility; low threshold for clipping and combined techniques. In case of recurrent bleeding, angiographic methods and surgical tactics are discussed. Anticoagulants/antiplatelet agents are reviewed individually. [26]

Diarrhea and malabsorption. Stepwise: rehydration and electrolytes → loperamide/diphenoxylate; consider bile acid diarrhea - trial therapy with bile acid sequestrants; assess bacterial overgrowth (breath tests/empirical therapy). Maintain nutrition (energy/protein, medium-chain triglycerides in steatorrhea), parenteral support - as indicated. [27]

Dysmotility/pseudo-obstruction. Gentle nutrition, prokinetics (depending on regional availability/risks), avoid drugs that slow transit. In refractory episodes - hospitalization, decompression, electrolyte correction; exclude the mechanical component. [28]

Ulcerative-erosive lesions. PPI/mucosal protection, eradication of Helicobacter pylori if present, monitoring of NSAIDs. Biopsies during follow-up - only if clinically necessary (tissue fragility). [29]

Nutritional support. Systemic screening for deficiencies (iron, B12, folate, A/D/E/K, albumin). In cases of severe malabsorption, high-calorie/low-osmolarity enteral formulas; in cases of chronic intestinal failure, referral to a home parenteral nutrition center. [30]

Monitoring. Assessment of symptoms, body weight, anemia/ferritin/albumin, repeat endoscopy if indicated (bleeding, new "alarm"). Monitoring of systemic processes is mandatory (hematological responses in AL, inflammatory activity in AA, cardiac/neurological status in ATTR). [31]

Surgery. Indicated for complications (perforation, uncontrolled bleeding, obstruction). Given the fragility of tissues and vessels, organ-preserving and limited interventions are preferable; the tactics are determined by a consultation. [32]

Table 5. "Amyloid type → treatment priority"

Type	System priority	Gastrointestinal accents
AL	Darutumab/bortezomib-containing regimens ± AHSCT	Hemostasis, correction of deficiencies
AA	Inflammation control (biological/targeted)	Diarrhea/malabsorption, nutritional support
ATTR	TTR stabilizers/silencers	Dysmotility, autonomic symptoms

Prevention

Primary prevention is the control of underlying conditions: timely treatment of chronic inflammatory diseases (for AA), early diagnosis of plasma cell dyscrasias (for AL), genetic counseling for families with inherited ATTR. Secondary prevention is the early recognition of gastrointestinal involvement (anemia, unexplained diarrhea, weight loss) in patients with known amyloidosis. [33]

Forecast

It is determined by the type of amyloid and the systemic burden of target organs. Local endoscopic interventions improve complication control, but survival in AL/AA primarily depends on the hematological response/inflammatory control; in ATTR, on the effectiveness of targeted therapy and management of neuro-/cardiac manifestations. Gastrointestinal involvement impairs quality of life but can be controlled with the right strategy. [34]

Additional tables for practice

Table 6. Endoscopic phenotypes in gastrointestinal amyloidosis

Type	Description	Clinical significance
Protrusive	Polypoid/nodular elevations	Bleeding, imitation of a tumor
Granular	Fine grain, brittleness	Hidden blood loss
Hemorrhagic	Petechiae, submucosal hematomas	Acute/chronic bleeding
Ulcerative	Erosions/ulcers	Pain, anemia, risk of perforation
Non-specific	Swelling, pallor, thickening of folds	Requires a biopsy for verification

Table 7. Red flags and first steps

Situation	Action
Melena/hematochezia in a patient with amyloidosis	Urgent endoscopy + hemostasis
Diarrhea >4 weeks, weight loss, anemia	EGD/colonoscopy with multiple biopsies
Suspicion of AL clone	Immunofixation + free light chains, hematologist
Recurrent subobstruction	CT/MR enterography, consultation with a gastroenterologist