The gastrointestinal tract is most commonly involved in all types of systemic amyloidosis, manifesting uncontrollable diarrhea, constipation, malabsorption syndrome and pseudointestinal obstruction, but fatal hemorrhagic accidents appear to be rare (1–5).

In this report we describe a patient with primary AL systemic amyloidosis who had suffered recurrent gastric hemorrages from ulceration for the preceding two years, and finally developed life-threatening submucosal hematomas with bleeding in the stomach.

A 62-year-old woman was admitted to our hospital in January 1997 because of epigastralgia and hematemesis. She had been diagnosed as having benign M proteinemia at the age of 58, but had had no gastrointestinal symptoms up to that time. On endoscopic examination she was found to have four gastric ulcers on the greater curvature and one on the gastric angle (Fig. 1A). A proton pump inhibitor (PPI: rabeprazole sodium 20 mg/day) was administered and the ulcerative lesions improved considerably. In August of the same year, she noticed tarry stools and epigastric discomfort; endoscopy disclosed a large gastric ulcer which extended from the antrum to middle body of the stomach on the greater curvature (Fig. 1B). The PPI was restarted, but she experienced epigastral discomfort again two months later. Endoscopy revealed white submucosal hematomas on the upper body and a red submucosal hematoma on the antrum to middle body of the stomach. In April 2000, at the age of 64, she was readmitted to our hospital because of massive hematemesis, even though she had been taking an H₂ blocker (famotidine 40 mg/day). Endoscopically a huge submucosal hematoma was seen on the upper body of the stomach, which was the source of the bleeding (Fig. 1C, D).

On examination, blood pressure was 178/101 mmHg and pulse rate was 72 beats/min. She had macroglossia but other physical findings were normal. Although routine laboratory studies were normal (Table 1), she had slight coagulatory dysfunction (Table 2): factor X activity was decreased to 54% (normal range: 70–130%) and other factors were within the normal range. The result of the thrombotest was 37% (≥80) and the Hepaplastin test 41% (70–130), both of which were causally related to the decreased activity of factor X.

Serum immunoelectrophoresis revealed IgG λ type M proteinemia and Bence-Jones protein was positive in her urine. Although the electrocardiogram showed low voltage in limb leads and a negative T wave in the _aV_L, V₅ and V₆ leads, cardiac function was normal on echocardiogram. Amyloid deposition was observed in the gastric mucosal and skin biopsies. Aspiration biopsy showed hypocellular bone marrow with a normal percentage of plasma cells (nuclear cell count: 575,200/mm³, plasma cells: 2.2%). Three weeks after admission endoscopic examinations disclosed new submucosal hematomas and ulcers (Fig. 1E, F). Gastric hemorrhages readily recurred from the huge hematomas, but abdominal angiography was normal. Since the hematomas were easily enlarged by air-pumping from endoscope, the patient could not undergo further examinations or treatment under endoscopic control. Total gastrectomy was, therefore, carried out to stop the recurrent hemorrhages: the patient continued to take PPI for three months preceding the operation, and after hospitalization she was not allowed to eat or drink to avoid inducing gastric hemorrhage. Her pre-operative condition was almost stable except for slight anemia (hemoglobin was 9.8 g/dl). The operation was successfully completed, but the patient fell into shock on the 2nd post-operative day and subsequently died of multiple organ failure on the 23rd post-operative day.

On gross examination of the removed stomach, large hematomas and ulcerative lesions with hemorrages were seen (Fig. 2). Hematoma was easily ruptured during operation, leading to the formation of ulcers. Histological examination revealed submucosal hemorrhage (Fig. 3A) and amyloid deposition on the muscularis mucosa, submucosal vessels and muscularis propria in almost all areas of the gastric wall, involvement of the submucosal vessels being most prominent (Fig. 3B). Autopsy revealed systemic amyloid deposition on many visceral organs: among them esophageal and bladder walls were heavily affected, and multiple ulcer formations in the jejunum and ileum were also noted. Myocardial interstitium was severely involved by amyloid deposition, showing atrophy of myocardial cells. This amyloid was specifically immunolabeled by an anti-Aλ antibody (Fig. 3C).

Primary AL systemic amyloidosis is caused by deposition of amyloid fibrils, the precursor of which is the N-terminal portion of immunoglobulin light chain (1, 2). This abnormal protein (M-protein) is produced by plasma cells with a monoclonal proliferative process, but the treatment for causally related plasma cell dyscrasia has not been established, resulting in a poor prognosis for patients with this disorder (1, 2).

In primary AL systemic amyloidosis the heart, kidneys, and gastrointestinal tract are commonly affected by amyloid deposition, with the occasional appearance of gastrointestinal bleeding (1, 2). Levy et al described that this symptom occurred in 25% of patients (6), usually with other bowel dysfunctions, but in a rare case gastrointestinal bleeding was reported to be the sole presenting symptom of the disease (6). This form of bleeding is considered to be caused by oozing without an identifiable lesion or erosive lesions in a severely involved gastrointestinal tract, and its pathogenic mechanism is surmised to be vascular fragility (6). Amyloid-related gastric symptoms were reported to occur in about 1% of a large series of primary AL-amyloidosis patients (2): they consisted of tumor formation, erosive lesions with hemorrhages, outlet obstruction or gastroparesis with autonomic failure (5, 7–14).

The present patient suffered recurrent formation of huge gastric submucosal hematoma with bleeding, which was the predominant clinical manifestation of the primary AL systemic amylodosis. Submucosal or intramural hematoma of the stomach is a well-recognized complication of patients with clotting disorders, particularly hemophilia, and is also known as a result of direct trauma during endoscopic examination (15). Some patients with primary AL systemic amyloidosis were reported to develop an acquired coagulation disorder characterized by factor X deficiency, which was considered to be due to rapid immobilization of circulating factor X (16). Massive deposits of amyloid on the submucosal vessels, which was the main pathology of the stomach in the present patient, seem to cause large submucosal hematomas with bleeding: amyoid deposition weakens the vascular walls by destroying their normal structures, usually associated with microaneurysmal formation or double barreling (17). In our patient, amyloid-related coagulation disorder may have played an additional role in the recurrence of gastric hemorrhages. To improve the patient's condition operative intervention was employed, but the outcome was unfavorable. It has been emphasized that surgical treatment is not helpful and is in fact dangerous for patients with systemic amyloidosis: gastrointestinal tract amyloidosis involves extensive areas and thus, the involved segment is not amenable to surgical extirpation. Additionally, post-operative serious complications that include cardiac and/or renal failure frequently occur, since the patients' condition is typically bad (1, 2, 18).

In conclusion, we described a rare manifestation of primary AL systemic amylodosis, showing recurrent formation of huge submucosal hematoma in the stomach with bleeding. Its unique endoscopic and histopathological findings are noteworthy.