Intestinal Amyloidosis

Intestinal amyloidosis is deposition of misfolded protein fibrils in the small bowel and colon wall, causing dysmotility, malabsorption, protein loss, bleeding, obstruction or ischaemia. It may be systemic or local.

Gastrointestinal involvement occurs in about 8% of systemic AL amyloidosis and in a larger proportion of AA amyloidosis on biopsy; clinical features are less common. Intestinal disease is mostly found in adults over 50 years.

Types are AL (light chain, from plasma cell clones), AA (reactive, with chronic inflammation such as inflammatory bowel disease, familial Mediterranean fever, rheumatoid arthritis and tuberculosis), ATTR (hereditary or wild type transthyretin) and, in long term dialysis, beta-2 microglobulin amyloid.

Pathophysiology.

Deposits infiltrate the mucosa, submucosa, muscularis and vessels, impairing absorption, smooth muscle and autonomic nerve function, and cause ischaemia through vascular infiltration. Protein loss is via leaky mucosa.

Diarrhoea (often with steatorrhoea), constipation, pseudo obstruction, early satiety, weight loss, gastrointestinal bleeding, protein losing enteropathy with oedema and, in AL, macroglossia, periorbital bruising, hepatomegaly, nephrotic syndrome, cardiomyopathy and neuropathy.

Red flags.

• Ischaemia, perforation or obstruction.
• Heart failure or arrhythmia.
• Massive bleeding.
• Orthostatic hypotension.

Tissue diagnosis: Congo red staining with apple green birefringence under polarised light, from endoscopic biopsy (rectal, duodenal), abdominal fat aspirate, or involved organ. Type the amyloid by mass spectrometry or immunohistochemistry.

Test serum free light chains, serum and urine protein electrophoresis with immunofixation, and bone marrow examination for AL. Serum amyloid A and C-reactive protein for AA; transthyretin gene sequencing and bone scintigraphy for ATTR. Assess organs with NT-proBNP, troponin, echocardiography, urinary protein, creatinine and liver enzymes. Endoscopy shows granular, friable, thickened mucosa with erosions, or normal mucosa.

Differential diagnosis.

• Coeliac disease.
• Inflammatory bowel disease.
• Chronic intestinal pseudo obstruction.
• Diabetic autonomic neuropathy.
• Lymphoma.
• Small intestinal bacterial overgrowth.

Treat the cause and support the gut.

• AL amyloidosis: daratumumab 1,800 mg subcutaneously weekly in weeks 1 to 8, every 2 weeks in weeks 9 to 24, then every 4 weeks, with cyclophosphamide 300 mg/m2 (maximum 500 mg) orally or IV weekly, bortezomib 1.3 mg/m2 subcutaneously weekly and dexamethasone 40 mg weekly (20 mg in frail or older patients) for 6 cycles of 28 days, then daratumumab alone to 24 months in total; maximum bortezomib 1.3 mg/m2 and cyclophosphamide 500 mg for each dose; monitor blood counts, free light chains every cycle, NT-proBNP, infusion reactions, neuropathy, hepatitis B reactivation and fluid retention; reduce dexamethasone and bortezomib in cardiac involvement and hepatic impairment; adjust cyclophosphamide in severe renal impairment.
• AA amyloidosis: suppress the inflammation (colchicine 1 to 2 mg orally once daily in familial Mediterranean fever, with biologic agents in inflammatory disease); monitor serum amyloid A, aiming under 10 mg/L; reduce colchicine in renal impairment.
• ATTR: tafamidis 61 mg orally once daily for cardiomyopathy (20 mg of the meglumine salt for polyneuropathy); long term; maximum 61 mg daily; monitor NT-proBNP and neurological status; no dose change in renal or mild to moderate hepatic impairment. Vutrisiran 25 mg subcutaneously every 3 months is used for hereditary polyneuropathy.

Symptom control:

• Loperamide: 4 mg orally initially, then 2 mg after each loose stool; long term as needed; maximum 16 mg daily; monitor QTc at high doses and for ileus; avoid in infective colitis and obstruction; reduce in hepatic impairment.
• Octreotide: 50 to 100 microgram subcutaneously every 8 hours for refractory diarrhoea; maximum 600 microgram daily; monitor glucose and gallstones; reduce in renal failure.

Add nutritional support, with enteral or parenteral feeding for severe malabsorption, and surgery for ischaemia, perforation or obstruction.

Monitoring. Haematological response every cycle, organ function every 3 months, nutritional status, and echocardiography.

Referral and escalation. Haematology or amyloidosis centre urgently, cardiology, nephrology and nutrition support. Genetic counselling for hereditary forms.