Background:

Gastrointestinal (GI) symptoms are frequent in patients (pts) with systemic light chain amyloidosis (AL), yet their clinical significance remains poorly defined. We investigated the role of symptomatic GI involvement in disease burden, survival, and organ-specific outcomes in a large single-center cohort.

Methods

From 2010–2025, 4,396 AL pts were evaluated at our center; 560 pts (13%) had provider-attributed symptomatic GI AL. Pts with localized AL or positive biopsy without GI symptoms were excluded (n=38). We analyzed relationships between GI symptoms, anatomic/histologic involvement, laboratory parameters, survival, and need for nutritional support using Wilcoxon rank-sum, Chi-square, Kaplan-Meier, and logistic regression tests.

Results

GI symptoms included early satiety (n=320/57%), diarrhea (n=189/34%), nausea (n=184/33%), abdominal pain (n=148/26%), dysphagia (n=119/21%), vomiting (n=75/13%), GI bleeding (n=74/13%), and heartburn (n=71/13%). Only nausea and GI bleeding were not associated with cardiac (n=366/65%) renal (n=274/49%) or hepatic (n=84/15%) AL, whereas dysphagia, early satiety and heartburn were more frequent with cardiac (all OR=1.7), abdominal pain and diarrhea with hepatic (OR=2 and 1.6, respectively), and vomiting with renal involvement (OR=2; all p<0.04).

Autonomic involvement impacted GI symptoms, often without proof of parenchymal GI amyloid. Of the 124 pts with formal autonomic testing, only 44 (35%) had positive GI biopsies as compared to AL GI pts without proven autonomic involvement (240/436, 55%). Pts with autonomic involvement were more symptomatic than pts with positive GI biopsies, suffering more often from dysphagia (29% vs 19%), diarrhea (41% vs 32%), and gastroparesis (34% vs 9%, all p<0.001).

We screened changes in body weight, calcium, VitB12, Hb, PO4, and albumin at diagnosis. Of the 175 pts with documented weight loss in this cohort, pts with GI AL lost more weight compared to those with other organ involvement (21% vs 14% of weight, p=0.002), and had lower phosphate (3.7 vs 4.0 mg/dL, p=0.06).

In our cohort of pts with GI symptoms, 298 (53%) had a positive GI biopsy. Biopsy-proven anatomic involvement dictated symptoms (all p<0.05): Of the 20 pts with positive esophageal biopsy, dysphagia was present in 45%; only 33% of the pts without an esophageal biopsy had dysphagia. Similar patterns were seen for the 170 pts with a positive gastric biopsy (n=170) in terms of heartburn (21% vs 11%), for the 165 pts with positive small bowel biopsies in terms of abdominal pain (68% vs 32%), and for the 130 pts with positive colon biopsies and diarrhea (46% vs 33%).

Specific histopathological patterns were prognostic. Mucosal involvement (n=161) was an independent risk factor for survival compared to submucosal (n=64) and vascular (n=102) involvement throughout the GI tract (HR 1.83; p=0.03). Three-layer GI infiltration was associated with inferior mOS (2.4 vs 5.1 vs 7.8 y for 3 vs 2 vs 1-layer involvement, HR 3.19/1.56/1; p<0.05). Counterintuitively, vascular involvement had the lowest risk of bleeding in all GI anatomic sites (p=0.02). In the colon, only mucosal involvement was associated with a higher risk of bleeding (OR=5; p=0.04).

GI involvement in AL pts did not worsen prognosis (mOS 10.0/6.3y, p=0.02), and pts with isolated GI AL (n=74/13%) had an even better survival (55% surviving at 10 y). Cachexia (n=120; mOS 3.5 vs 7.8 y, p<0.001), need for nutritional support (n=36; mOS 0.9 vs 7.0 y, p<0.001), and diarrhea (mOS 5.8 vs 6.9 y, p=0.06) were risk factors for death.

In pts with hematologic response (≥PR), bleeding did not recur within 3 y (n=27), but even with response, diarrhea (n=160) persisted in 39%. Resolution was less frequent without hematologic response (persistence in 69%, OR=3.5). Improvement was most often due to treatment of bacterial overgrowth (11/35 pts; 68%) and loperamide (54/59 pts; 91%).

Conclusion

In AL, meaningful GI involvement is defined by nausea, diarrhea, occurrence of bleeding, and malnutrition. These are primarily associated with mucosal infiltration. GI symptoms can occur in the face of autonomic involvement. While long-term persistence of GI bleeding is rare after serologic response, cachexia and persistent diarrhea drive morbidity, need for nutritional support, and poor survival.

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2025
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