Gastrointestinal Manifestation of Light Chain Deposition Disease: Beware of the Snakeskin Duodenum

Abstract

Gastrointestinal manifestations of light chain deposition disease are exceedingly rare and are characterized by gastrointestinal bleeding, nutritional deficiencies and protein-losing enteropathy. Diagnosis is challenging due to nonspecific symptomatology and indolent disease progression. We describe the case of a 69-year-old woman presenting with melena, chronic diarrhea, and recurrent sepsis. Gastroscopy revealed a highly unusual snakeskin appearance of the duodenum, with histopathology and immunofluorescence confirming light chain deposition disease. This case highlights the importance of prompt biopsy acquisition, hematological evaluation and assessment of extragastrointestinal involvement in facilitating a timely diagnosis, particularly when an underlying lymphoplasmacytic lymphoma is a possible driver of disease.

INTRODUCTION

Light chain deposition disease (LCDD) is characterized by the overproduction of monoclonal light chains from an abnormal clone of plasma cells, with subsequent nonfibrillar deposition within tissues leading to organ dysfunction.^1,2 It is typically associated with plasma cell dyscrasias such as multiple myeloma or monoclonal gammopathy of undetermined significance, and less commonly with macroglobulinemia or other lymphoproliferative disorders.² The true prevalence of LCDD is unknown and thought to be underrepresented in contemporary literature due to its heterogenous, but often asymptomatic clinical course. The kidneys are invariably affected, but other end organ manifestations involving the heart, liver, nerves, and gastrointestinal tract have been occasionally reported.² Specifically, gastrointestinal (GI) manifestations of LCDD may include GI bleeding, nutritional deficiencies, and protein-losing enteropathy.^3,4

CASE REPORT

We present the case of a 69-year-old woman with a history of rheumatoid arthritis, hypertension, and sleeve gastrectomy. She was admitted to hospital with septic shock secondary to recurrent skin and soft tissue infection of the leg. Before this, she had a tumultuous 2-month hospitalization with necrotizing soft tissue infection of the same leg requiring debridement and a split skin graft, pulmonary embolism, and a new diagnosis of the Waldenström macroglobulinemia (WM). There had also been a 6-month history of nonbloody diarrhea (up to 8 times per day) and unintentional weight loss of 10 kg leading up to her presentation.

Relevant medications included apixaban 5 mg twice daily, hydroxychloroquine 400 mg daily, atorvastatin 40 mg daily, omeprazole 20 mg daily, and loperamide 2 mg as required. Blood tests showed hemoglobin 99 g/L, mean corpuscular volume 95 fL, lymphocytes 1.4 × 10⁹/L, white cell count 4.9 × 10⁹/L, platelets 182 × 10⁹/L, total protein 37 g/L, globulin 24 g/L, albumin 13 g/L, creatinine 66 μmol/L, urea 5.3 mmol/L, and C-reactive protein 140 mg/L. Urine, stool, and blood cultures were negative for infection.

Her recent diagnosis of WM was established based on a low-level serum IgM paraprotein, a mildly elevated kappa/lambda free light chain ratio of 1.98 (reference range 0.26–1.65) and a bone marrow aspirate and trephine demonstrating a normocellular marrow with 15%–20% lymphoplasmacytic infiltrate. Serum immunoglobulins showed markedly elevated IgM 9.62 g/L (reference range 0.33–2.93) but normal IgG and IgA levels. Several micronutrient deficiencies were noted, including selenium, zinc, and vitamin C.

An inpatient gastroscopy was performed to investigate causes of upper GI bleed following an episode of melena with hemoglobin drop to 68 g/L without urea rise. While no altered blood or source of bleeding was identified, a striking snakeskin/cobblestone-appearing mucosa was noted throughout the duodenum (Figure 1). Esophagus and stomach appeared macroscopically normal. Biopsies were taken from the duodenum for histopathology (Figure 2). Histopathological examination of the duodenal biopsies demonstrated amorphous eosinophilic deposits within the lamina propria, causing expansion of villous tips with associated increase in foamy macrophages (Figure 2). Brunner glands were not seen. Further testing showed negative Congo red staining and an absence of apple-green birefringence under polarized light, swaying the diagnosis away from amyloidosis. Kappa light chain restriction on immunohistochemistry and immunofluorescence confirmed LCDD (Figure 3).

Figure 1.

Endoscopic appearance of duodenum D1 (A) and D2 (B) with light chain deposition secondary to the Waldenström macroglobulinemia.

Figure 2.

Hematoxylin and eosin stain of duodenal biopsy, demonstrating eosinophilic deposition within the lamina propria (100×).

Figure 3.

Immunohistochemistry (A) and immunofluorescence (B) of duodenal biopsy showing positive signals for Kappa light chains (100×).

Following a histologic diagnosis of LCDD, the patient was screened for extragastrointestinal manifestations. She had a normal estimated glomerular filtration rate and creatinine level with an elevated protein/creatinine ratio of 70 mg/mmol (N < 30), suggestive of possible renal involvement. A transthoracic echocardiogram did not show features of cardiac amyloidosis. Her diarrhea was managed symptomatically with loperamide once an infective cause was excluded.

The driver of LCDD in this case was WM with low paraprotein level and mildly elevated free light chain ratio, which represented an indolent disease course. As such, urgent WM-directed therapy was not felt to be beneficial, particularly when the clinical priority was managing recurrent sepsis. Unfortunately, the patient died within 2 months following another episode of complex polymicrobial sepsis before any hematological treatment could be considered.

DISCUSSION

As seen in our case, the discovery of a snakeskin-appearing duodenum should prompt consideration of several differential diagnoses. These include coeliac disease, Brunner gland hyperplasia, and Crohn's disease, as well as less common entities of primary intestinal lymphangiectasia or Whipple disease. Each of these conditions has unique endoscopic patterns and could be further differentiated on histology.

The diagnosis of GI LCDD is challenging owing to its indolent clinical course and the possibility of paradoxically normal serum electrophoresis stemming from light chain aggregation.² Nevertheless, establishing a diagnosis is crucial in unravelling a potential underlying lymphoproliferative disorder. GI manifestations are exceedingly rare, and biopsy-proven GI LCDD had only been reported in 4 cases.^1,3,4 However, patients typically present with highly nonspecific symptoms, ranging from micronutrient deficiencies, GI bleeding, to subacute or chronic diarrhea.^3,4

Interestingly, the patient's micronutrient deficiencies and a profoundly low nadir albumin of 13 g/L (albeit confounded by sepsis) raised the suspicion for concomitant protein-losing enteropathy. The underlying pathophysiology is thought to resemble that of amyloidosis, whereby light chain deposition within the villous interstitium and lacteals causes lymphatic obstruction and impaired absorptive function.^5–7 Confirmatory testing with fecal α1-antitrypsin and complete disease assessment of the small bowel with capsule endoscopy would have been helpful but could not be pursued as the patient died shortly after diagnosis. Her initial episode of gastrointestinal bleeding may be due to LCDD-related mucosal fragility and impaired microcirculation secondary to vascular depositions.⁶

Conventional treatment strategies for LCDD consist of bortezomib-based therapies, monoclonal antibodies such as daratumumab and autologous hemopoietic stem cell transplant.² Clinical outcomes of GI LCDD vary from resolution of disease following local resection of an asymptomatic isolated polypoid lesion,¹ to recurrent sepsis as observed in our case, highlighting that systemic LCDD involvement may confer a poorer overall prognosis.

Endoscopic finding of a snakeskin-appearing duodenum should prompt biopsy acquisition, hematological workup, and screening for extragastrointestinal involvement of a lymphoproliferative disorder to support timely diagnosis and initiation of systemic therapy where appropriate. Albeit rare, gastrointestinal LCDD is an important differential for patients presenting with nonspecific GI symptoms and profound hypoalbuminemia, particularly in the context of a known lymphoproliferative disorder.

DISCLOSURES

Author contributions: All listed authors contributed to the writing, reviewing and editing of this case report. A. Zhu prepared the original draft. A. Brett provided supervision and is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

ABBREVIATIONS:

GI

gastrointestinal

LCDD

light chain deposition disease

LPL

lymphoplasmacytic lymphoma

WM

Waldenström macroglobulinemia