Gastroduodenal Involvement in AL Amyloidosis: Case Report and Literature Review

Introduction

Amyloidosis is a condition characterized by abnormal protein folding leading to the extracellular deposition of insoluble protein fibrils. This deposition causes disruption of tissue structure and function leading to a myriad of clinical consequences. The most common form of amyloidosis is systemic AL amyloidosis, also known as primary amyloidosis, which is caused by the deposition of immunoglobulin light chains produced by clonal plasma cells into organ systems throughout the body. The incidence rate of AL amyloidosis is estimated to range from 10.8 to 15.2 cases per million person-years. ¹ It commonly affects the heart, kidneys, and musculoskeletal system, but also affects the gastrointestinal tract. One retrospective chart review found that in 2334 patients with amyloidosis, 3.2% had biopsy-proven amyloid involvement of the gastrointestinal tract. ² Although, the prevalence of gastrointestinal amyloidosis may be higher given that patients often present subclinically. ³ Amyloid can deposit throughout the gastrointestinal (GI) tract and the resulting symptoms vary depending on the site of deposition. GI manifestations can range from dyspepsia or abdominal pain, to more serious complications such as gastrointestinal bleeding, malabsorption, dysmotility, and obstruction. We are reporting a patient with known history of IgG lambda AL amyloidosis, presenting with epigastric pain and unintentional weight loss. The patient underwent esophagogastroduodenoscopy (EGD) and was diagnosed with gastroduodenal amyloidosis.

Case Description

Our patient is a 66-year-old female with AL amyloidosis, chronic kidney disease, hypertension, and hyperlipidemia. Patient was diagnosed with AL amyloidosis based on serum protein electrophoresis (IgG lambda spike), renal (scattered foci of randomly arranged fibrillary material in the glomerular mesangium and glomerular capillary walls and positive Congo red stain compatible with amyloid), and bone marrow biopsies (lambda-restricted CD138-positive cells).

She presented for evaluation of epigastric discomfort, bloating, and unintentional weight loss of 10 pounds. She denied dysphagia, odynophagia, change in bowel habits, nausea, vomiting, melena, or hematochezia. She underwent colonoscopy 1 year prior to presentation and was normal with the exception of small hemorrhoids. Given the history of epigastric discomfort and unintentional weight loss, EGD was performed. During EGD, the entire esophagus and duodenal bulb were normal, and the patient had mild gastropathy with 6 mm subepithelial nodular lesion in the gastric body (Figure 1) and fine granular appearance in the second portion of the duodenum (Figure 2). Biopsies of the stomach (Figure 3) and duodenum (Figure 4) demonstrated positive Congo red stain consistent with amyloid deposition. The biopsy findings are consistent with gastroduodenal amyloidosis and are the most likely explanation of her symptoms. Patient is being treated with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and has been started on hemodialysis due to progression of renal disease. She has been advised ongoing follow-up at the outpatient clinic for monitoring of symptoms.

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Figure 1.

Endoscopic finding—nodular lesion in the gastric body (yellow arrowhead).

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Figure 2.

Endoscopic finding—fine granular appearance in the second portion of the duodenum (yellow arrowhead).

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Figure 3.

Gastric biopsies—positive Congo red stain (red arrow).

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Figure 4.

Duodenal biopsies—positive Congo red stain (red arrow).

Discussion

Clinical manifestations of GI amyloidosis depend on the location and degree of amyloid deposition. These symptoms are not specific and frequently mimic other gastrointestinal disorders, which makes diagnosis difficult. One retrospective study found that patients with AL amyloidosis with GI involvement had a median delay in diagnosis of 7 months. ⁴ This delay in diagnosis is significant as the prognosis of patients with AL amyloidosis with GI involvement was found to be worse than those without GI involvement. ⁵ Due to its association with underlying malignancy, AL amyloidosis is often associated with poor prognosis. Thus, familiarity with this rare condition is important to appropriately diagnose and initiate timely management.

The most common presenting symptoms of GI amyloidosis are weight loss and gastrointestinal bleeding. ² Other typical symptoms include nausea, vomiting, early satiety, abdominal pain, diarrhea, steatorrhea, and obstruction. ⁶ Our patient presented with epigastric pain and unintentional weight loss, and endoscopic biopsies were consistent with gastroduodenal amyloidosis. Amyloid deposition in the stomach and small intestine causes diffuse inflammation and vascular friability and can manifest as gastrointestinal bleeding. ⁷ Malabsorption presents with diarrhea and weight loss. It is thought to occur due to small bowel mucosal infiltration but may additionally be associated with autonomic neuropathy of the enteric nervous system, bacterial overgrowth due to dysmotility and ischemia due to vascular infiltration. ⁸ Dysmotility may occur as a result of destruction of neuroendocrine cells or from deposition of amyloid in the smooth muscle layer of the intestine and into the myenteric plexus. This can present as constipation, nausea, and abdominal pain or as intestinal pseudo-obstruction. ⁹

The definitive diagnosis of GI amyloidosis based on biopsy with Congo red staining and visualization under polarized light microscopy. On a routine hematoxylin-eosin stain, amyloid fibrils appear as amorphous, eosinophilic deposits which can be easily confused with hyaline changes or sclerosis. ¹⁰ Green birefringence under polarized light after Congo red stain will aid in the diagnosis of amyloidosis. In AL amyloidosis these findings should be correlated with immunoelectrophoresis and immunofixation to test for the presence of monoclonal light chains as well as fat pad or bone marrow biopsy. In GI amyloidosis the duodenum has the highest frequency of amyloid deposition, followed by the stomach. ¹¹ In a review of patients with amyloidosis of the small intestine, gross endoscopic features included a fine granular appearance, erosions, mucosal friability, thickening of the valvulae conniventes, and multiple polypoid protrusions. ¹² Other endoscopic modalities have proved to be useful in the diagnosis of GI amyloidosis as well. Double-balloon enteroscopy has been useful in diagnosing amyloidosis involving the jejunum after noted previous negative biopsies in the duodenum. ¹³ Capsule endoscopy may show certain features such as mucosal hematomas, intraluminal stenosis, irregular shaped ulcerations, and polypoid protrusions. ¹⁴ Endoscopic ultrasound identifies wide-spread thickening of the stomach, with loss of the normal layer structure of the mucosa and submucosa in the setting GI amyloidosis. ¹⁵

Currently, there are no specific guidelines for the management of GI amyloidosis. Generally patients receive treatment of the underlying cause of the amyloidosis along with symptom management. In patients with upper GI symptoms such as dyspepsia, it is recommended to trial proton pump inhibitors. Associated nausea and dysmotility symptoms have benefited from antiemetic and prokinetic agents. ⁶ Eligible patients with primary amyloidosis secondary to plasma cell dyscrasias, undergo autologous stem cell transplantation (ASCT). Complete resolution of GI amyloidosis after ASCT has been reported. ¹⁶ For those who are not eligible for ASCT, a combination of dexamethasone, bortezomib, and melphalan has shown improved survival. ¹⁷ Surgery is typically only considered in patients with localized amyloidosis with severe or refractory symptoms.

Conclusion

Gastrointestinal amyloidosis can present with a wide spectrum of clinical manifestations based on the location and degree of infiltration. Diagnosis is often delayed in these cases and thus it is important to consider GI amyloidosis as a possible explanation for unexplained gastrointestinal symptoms in the setting of known AL amyloidosis. Management should be tailored to treating the symptoms and the underlying cause of amyloidosis.