Gastrointestinal Amyloidosis

Gastrointestinal amyloidosis is deposition of misfolded protein fibrils in the wall of the oesophagus, stomach, small intestine, colon or liver, as part of a systemic or, rarely, localised amyloidosis. It causes dysmotility, malabsorption, bleeding, obstruction and protein loss.

Gastrointestinal involvement is found at autopsy or biopsy in over 70% of patients with systemic amyloidosis, but symptoms are present in 8% to 20%. The main types are light chain (AL), serum amyloid A (AA), transthyretin (ATTR) and hereditary forms. AL amyloidosis has the highest rate of symptomatic gut involvement, and median survival ranges from months in advanced cardiac disease to over 10 years with effective treatment.

Pathophysiology.

Fibrils infiltrate the muscle layers, nerves and vessels of the gut, causing smooth muscle dysfunction, autonomic neuropathy, mucosal fragility, ischaemia and impaired absorption.

Macroglossia, dysphagia, early satiety, gastroparesis, chronic diarrhoea or constipation, intestinal pseudo obstruction, steatorrhoea, weight loss, gastrointestinal bleeding, protein losing enteropathy, hepatomegaly and cholestasis. Cardiac, renal and neurological features are frequent.

Red flags.

• Gastrointestinal haemorrhage.
• Perforation or ischaemia.
• Acute pseudo obstruction.
• Heart failure or nephrotic syndrome.

Tissue diagnosis with Congo red staining (apple green birefringence under polarised light) from rectal, gastric, duodenal or fat pad biopsy. Identify the fibril type by mass spectrometry or immunohistochemistry, since treatment depends on type. Send serum free light chains, serum and urine immunofixation, troponin, natriuretic peptide, albumin, urine protein and liver function. Imaging includes echocardiography and scintigraphy for transthyretin disease. Gut motility studies and CT enterography assess dysfunction.

Differential diagnosis.

• Coeliac disease and other causes of malabsorption.
• Diabetic autonomic neuropathy.
• Scleroderma.
• Crohn disease.
• Chronic intestinal pseudo obstruction.
• Lymphoma.

Treat the type of amyloid. AL amyloidosis needs chemotherapy to suppress the clone; AA amyloidosis needs control of the inflammatory disease; transthyretin amyloidosis needs a stabiliser or silencer. Give nutritional support and symptomatic treatment.

• Daratumumab with bortezomib, cyclophosphamide and dexamethasone (AL, for 6 cycles of 28 days): daratumumab 1,800 mg subcutaneously weekly in cycles 1 and 2, every 2 weeks in cycles 3 to 6, then every 4 weeks for up to 2 years; bortezomib 1.3 mg/m2 subcutaneously weekly; cyclophosphamide 300 mg/m2 (maximum 500 mg) orally or IV weekly; dexamethasone 20 mg weekly (reduce to 10 mg with heart failure or in frail patients); maximum bortezomib 1.3 mg/m2 each dose; monitor blood counts, neuropathy, cardiac function and infusion reactions; reduce doses in cardiac, renal or hepatic impairment and with neuropathy.
• Tafamidis (transthyretin cardiac disease): 61 mg orally once daily long term; maximum 61 mg daily; monitor liver tests and heart failure symptoms; no dose change for renal impairment, and use caution in severe hepatic impairment.
• Loperamide (diarrhoea): 4 mg orally initially, then 2 mg after each loose stool; maximum 16 mg daily; monitor for ileus, and avoid in obstruction or infection; reduce in hepatic impairment.
• Octreotide (refractory diarrhoea): 50 to 100 micrograms subcutaneously two to three times daily; maximum 600 micrograms daily; monitor glucose and heart rate.

Avoid prokinetics that prolong the QT interval in heart disease. Total parenteral nutrition is used for severe malabsorption, and surgery for bleeding, obstruction or perforation, with a high operative risk.

Monitoring. Light chains every cycle in AL disease, with organ response assessment every 3 months; weight, albumin and nutrition status.

Referral and escalation. Haematology or amyloid centre, cardiology, nephrology and gastroenterology.