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Web of Medicine
Gastroenterology›Condition·Updated Jul 20, 2026·v1

Gastrointestinal Amyloidosis

Gastrointestinal amyloidosis is a multisystem disorder of protein misfolding causing amyloid deposition in the GI tract. It presents with dysmotility, malabsorption, or bleeding. Diagnosis requires tissue biopsy with Congo red staining and typing. Management is tailored to the amyloid type: chemotherapy for AL, anti-inflammatory agents for AA, and tafamidis for ATTR. Supportive care and avoidance of bleeding risk are essential. Prognosis depends on cardiac involvement and treatment response.

Low Evidence0 references·420 words·2 min read·v1
amyloidosisgastrointestinal amyloidosisAL amyloidosisAA amyloidosisATTR amyloidosisCongo redbortezomibtafamidis
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Quick Reference

RxDrug of choiceFor AL amyloidosis: CyBorD (cyclophosphamide 300 mg/m² PO weekly, bortezomib 1.3 mg/m² SC weekly, dexamethasone 40 mg PO weekly in 28-day cycles). For AA: treat underlying inflammation (e.g., colchicine 0.6 mg BID for FMF). For ATTR: tafamidis 61 mg PO daily.
AltAlternativesDaratumumab + CyBorD for AL; lenalidomide-based regimens for relapsed AL; tocilizumab for AA; patisiran for ATTR polyneuropathy.
⊘AvoidNSAIDs, anticoagulants/antiplatelets (except mandatory), non-dihydropyridine calcium channel blockers (verapamil, diltiazem) in cardiac amyloidosis.
DxTest of choiceEndoscopic biopsy of duodenum or rectum with Congo red staining and apple-green birefringence; amyloid typing by mass spectrometry.
ScKey scoreMayo Clinic staging for AL amyloidosis (NT-proBNP, troponin, free light chain difference), stage III/IV indicates high risk.
→When to referHematology for AL; rheumatology for AA; neurology/cardiology for ATTR; consider amyloidosis specialist center for multidisciplinary management.
Gastrointestinal amyloidosis is a diagnostic clue to systemic disease; confirm with tissue biopsy and typing, then treat the underlying amyloid type urgently to prevent organ failure.
Gastrointestinal amyloidosis is a manifestation of systemic amyloidosis, primarily AL (light chain) or AA (secondary) types, characterized by extracellular deposition of insoluble amyloid fibrils in the GI tract. It causes a spectrum of symptoms from dysmotility and malabsorption to life-threatening bleeding and perforation. Early recognition via tissue biopsy and typing is critical to guide targeted therapy and improve outcomes. This overview provides a framework for diagnosis and management.

Overview and Recommendations

Background

  • •Gastrointestinal (GI) amyloidosis results from systemic deposition of misfolded amyloid fibrils in the GI tract, most commonly in AL (light-chain) amyloidosis (associated with plasma cell dyscrasia) and AA (secondary) amyloidosis (driven by chronic inflammation such as rheumatoid arthritis, inflammatory bowel disease, or familial Mediterranean fever). Hereditary ATTR amyloidosis (transthyretin) also involves the GI tract, though less frequently.
  • •GI involvement occurs in up to of patients with systemic amyloidosis at autopsy, and symptomatic GI disease portends a poor prognosis, median survival in AL amyloidosis with GI involvement is < without treatment. The paradigm shift in management involves early tissue diagnosis with Congo red staining and precise amyloid typing (immunohistochemistry or mass spectrometry) to direct therapy: chemotherapy for AL, anti-inflammatory agents for AA, and tafamidis for ATTR.
  • •The pathophysiology is driven by extracellular amyloid deposition in the submucosa, muscularis propria, and vasculature, leading to ischemia, impaired motility, and mucosal fragility. This explains the three main clinical syndromes: dysmotility (dysphagia, gastroparesis, pseudo-obstruction), malabsorption (diarrhea, weight loss, steatorrhea), and bleeding (from mucosal friability or vascular fragility).
  • •Key clinical variants include nodular amyloidosis (localized GI deposits, often incidental) and diffuse infiltrative disease. AL amyloidosis is the most common type to cause GI symptoms, while AA typically presents with hepatosplenomegaly and diarrhea. The landmark SWOG trial (S0120) and other studies established the use of bortezomib-based therapy for AL amyloidosis, improving organ response rates.

Evaluation

  • •Suspect GI amyloidosis in any patient with unexplained chronic diarrhea, weight loss, early satiety, dysphagia, or GI bleeding, especially in the setting of a known plasma cell dyscrasia, chronic inflammatory condition, or family history of amyloidosis.
  • •Ask about systemic symptoms: orthostatic hypotension (autonomic neuropathy), nephrotic-range proteinuria (renal amyloid), carpal tunnel syndrome (ATTR), and macroglossia (pathognomonic for AL amyloidosis).
  • •Examine for macroglossia, periorbital purpura ("raccoon eyes"), hepatomegaly (often firm and nontender), splenomegaly, and peripheral edema. Perform a comprehensive neurological exam for signs of autonomic or peripheral neuropathy.
  • •Order serum free light chain assay (kappa/lambda ratio), serum and urine protein electrophoresis with immunofixation to detect monoclonal light chains in AL amyloidosis. For AA, measure serum amyloid A (SAA) and inflammatory markers (CRP, ESR).
  • •Obtain tissue biopsy: endoscopic biopsies of the duodenum, stomach, or rectum have high yield (sensitivity > 80%). Biopsy of involved organs (e.g., liver, kidney) is diagnostic but higher risk. Fat pad aspiration is a less invasive alternative (sensitivity ~ 60-70%).
  • •Histopathology: Congo red staining shows apple-green birefringence under polarized light; immunostaining or mass spectrometry identifies the amyloid type (AL vs. AA vs. ATTR).
  • •Assess for cardiac involvement in all patients with AL amyloidosis, order N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin, and perform echocardiography with strain imaging to detect cardiac amyloidosis. Cardiac involvement dictates prognosis and chemotherapy intensity.
  • •Evaluate for renal involvement: urinalysis for proteinuria, serum creatinine, and estimated glomerular filtration rate (eGFR).
  • •Consider genetic testing for hereditary amyloidosis (TTR gene) if typing is inconclusive or family history is positive.
  • •Diagnostic criteria: positive tissue biopsy with amyloid or at least one involved organ with biopsy-proven amyloid plus a monoclonal protein (for AL) or elevated SAA (for AA). Also consider the Mayo Clinic staging system for AL amyloidosis (based on NT-proBNP, troponin, and free light chain difference).

Management

  • •Initiate disease-specific therapy as soon as the amyloid type is confirmed. For AL amyloidosis, first-line therapy is bortezomib‑based chemotherapy: CyBorD regimen (cyclophosphamide 300 mg/m² PO weekly, bortezomib 1.3 mg/m² SC weekly, dexamethasone 40 mg PO weekly in 28‑day cycles) for 4-6 cycles until best response.
  • •For AL patients with advanced cardiac involvement (Mayo stage III or IV), consider a reduced-intensity approach: lower-dose bortezomib (1.0 mg/m²) and dexamethasone 20 mg weekly, with close monitoring for fluid overload and arrhythmias.
  • •Alternative AL regimens: daratumumab (16 mg/kg IV weekly for 8 weeks, then every 2 weeks) combined with bortezomib, cyclophosphamide, and dexamethasone (Dara‑CyBorD) for newly diagnosed patients; or lenalidomide‑based regimens for relapsed/refractory disease.
  • •For AA amyloidosis, the cornerstone is aggressive treatment of the underlying inflammatory condition: colchicine 0.6 mg BID for familial Mediterranean fever; anti‑TNF agents (e.g., adalimumab 40 mg SC every 2 weeks) or IL‑6 inhibitors (tocilizumab 8 mg/kg IV every 4 weeks) for rheumatoid arthritis and other chronic inflammatory diseases.
  • •For ATTR amyloidosis with GI involvement, prescribe tafamidis 61 mg PO daily. For patients with advanced ATTR and polyneuropathy, consider patisiran (diflunisal is no longer recommended due to GI side effects).
  • •Supportive care for GI symptoms: prokinetic agents (metoclopramide 5-10 mg PO TID before meals) for gastroparesis; antiemetics (ondansetron 4-8 mg PO TID) for nausea; and loperamide 2-4 mg PO PRN for diarrhea, up to 16 mg/day.
  • •For malabsorption and weight loss, consider pancreatic enzyme replacement (lipase 10,000-20,000 units per meal) and medium‑chain triglyceride (MCT) oil supplementation. Consult a dietitian for high‑calorie, low‑residue diet.
  • •For GI bleeding due to amyloid vasculopathy, manage conservatively with proton pump inhibitors (e.g., pantoprazole 40 mg IV daily) and avoid non‑selective beta‑blockers (which may worsen bleeding). Endoscopic therapy (e.g., epinephrine injection, clip placement) is often ineffective due to diffuse mucosal friability; consider octreotide 100 mcg SC TID as a vasoconstrictive alternative.
  • •Avoid NSAIDs, anticoagulants, and antiplatelet agents (except for mandatory indications) because of the high risk of spontaneous GI bleeding.
  • •Monitor for cardiac complications: obtain echocardiography and NT-proBNP every 3 months during active therapy. In AL amyloidosis, a > reduction in NT-proBNP after 3 cycles indicates a cardiac response.
  • •Refer to a specialized amyloidosis center or hematology (for AL), rheumatology (for AA), or neurology (for ATTR) for coordinated, multidisciplinary care. Consider referral for autologous stem cell transplantation (ASCT) in eligible AL patients (age < 65, no cardiac involvement, adequate organ function).
  • •Discharge criteria for hospitalized patients: initiation of disease‑specific therapy, stabilization of GI symptoms (e.g., resolution of bleeding, ability to tolerate oral intake), and no evidence of decompensated heart failure or renal failure. Arrange outpatient follow‑up within 2 weeks.

Board Review — High Yield

  • •Congo red stain, apple-green birefringence under polarized light is the gold standard for identifying amyloid deposits.
  • •Macroglossia, pathognomonic for AL amyloidosis; seen in ~20% of cases.
  • •AL vs. AA, AL is associated with plasma cell dyscrasia (monoclonal light chains); AA with chronic inflammation (elevated SAA).
  • •Duodenal biopsy, highest yield among endoscopic biopsies for GI amyloidosis (sensitivity > 80%).
  • •CyBorD regimen, cyclophosphamide, bortezomib, dexamethasone; first-line for AL amyloidosis.
  • •Tafamidis, first-line therapy for ATTR amyloidosis; stabilizes transthyretin tetramers.
  • •Autonomic neuropathy, manifests as orthostatic hypotension, gastroparesis, and diarrhea; common in AL amyloidosis.
  • •Mayo stage III, NT-proBNP > 332 pg/mL and troponin T > 0.035 ng/mL; associated with median survival < without treatment.
  • •Avoid colchicine in AL amyloidosis, it has no role and can cause toxicity.
  • •Fat pad aspiration, less invasive alternative to endoscopic biopsy; sensitivity ~60-70%.

Deep Dive — Evidence Details

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