Diverse phenotypic manifestations of small intestinal mucosa in non-infectious common variable immunodeficiency bowel disease: A case report

Abstract

BACKGROUND

Common variable immunodeficiency (CVID) is a primary antibody immunodeficiency disorder characterized by diminished IgG levels. Despite ongoing research, the precise pathogenesis of CVID remains unclear. Genetic factors account for only 10%-20% of cases, with an estimated incidence of 1 in 10000 to 1 in 100000, affecting individuals across all age groups.

CASE SUMMARY

We report the case of a 32-year-old man with CVID who presented with a chief complaint of “recurrent diarrhea and significant weight loss over the past 2 years”. Laboratory tests on admission showed fat droplets in stool, while other parameters were within normal ranges. Gastroscopy revealed a smooth gastric mucosa without bile retention or signs of Helicobacter pylori infection; however, the mucosa of the descending segment of the duodenum appeared rough. Further evaluation of the small intestine using computed tomography indicated no abnormalities. Finally, the whole-small bowel double-balloon enteroscopy (DBE) was performed, which revealed various phenotypic changes in the small intestinal mucosa. The patient was diagnosed with CVID, which improved after immunoglobulin therapy, with favorable follow-up outcomes.

CONCLUSION

Non-infectious enteropathy in CVID is rare. Therefore, DBE is essential for diagnosing small intestinal involvement in such cases.

Key Words: Diverse phenotypic manifestations; Common variant immunodeficiency disease; Double balloon-assisted enteroscopy; Inflammatory bowel disease; IgG; Case report

Core Tip: We report a case of non-infectious common variable immunodeficiency (CVID) patient associated bowel disease with non-specific clinical manifestations, which is characterized by B-cell dysfunction and reduced levels of serum IgG. The disease is rare and the etiology and pathogenesis remain unknown, making it difficult to diagnose, thus resulting in high mortality. Whole small intestinal double balloon enteroscopy is helpful for early diagnosis and reveals the involvement of the whole small intestinal mucosa. This case emphasizes that timely diagnosis, effective intervention and follow-up management are essential to improve the outcome of CVID patients.

INTRODUCTION

Common variable immunodeficiency (CVID) is a primary antibody immunodeficiency disorder characterized by low IgG levels. Its clinical presentation is multifaceted, with prominent gastrointestinal symptoms particularly affecting the duodenum and distal ileum. Microscopic examination often reveals mucosal thinning, villous atrophy, congestion, and edema. However, few comprehensive reports have detailed the extent of small intestinal mucosal involvement and associated microscopic changes. In this study, we report a case of a patient with CVID primarily presenting with diarrhea. During diagnosis and treatment, a thorough evaluation of multiple systems was conducted, focusing specifically on double-balloon enteroscopy (DBE) to assess the entire small intestinal mucosa. Notably, a spectrum of mucosal lesions was identified, underscoring the phenotypic presentations of CVID heterogeneity. The following narrative offers a detailed explanation of this intriguing case.

CASE PRESENTATION

Chief complaints

A 32-year-old man was admitted to our department on May 14, 2023, with a chief complaint of “recurrent diarrhea and significant weight loss over the past 2 years”.

History of present illness

The patient reported recurrent diarrhea and significant weight loss over the past 2 years.

History of past illness

The patient’s medical history is unremarkable.

Personal and family history

The patient had no history of substance abuse, consanguineous marriage with parental relatives, or familial genetic disorders.

Physical examination

Upon admission, the patient had a body mass index (BMI) of 18 kg/m², indicating emaciation, with no other discernible positive clinical signs noted during the initial examination.

Laboratory examinations

On the day of admission, laboratory tests revealed several abnormalities: Stool tests showed the presence of fat droplets; blood biochemistry indicated decreased levels of total protein (53.3 g/L; normal: 60-80 g/L), albumin (39.4 g/L; normal: 40-55 g/L), globulin (13.9 g/L; normal: 20-29 g/L), and immune proteins, including IgG (0.85 g/L; normal: 7.0-16.6 g/L), IgA (0.07 g/L; normal: 0.7-3.5 g/L), IgM (0.13 g/L; normal: 0.5-2.6 g/L), and complement C3 (0.67 g/L; normal: 0.8-1.5 g/L). Other parameters, including blood routine, liver and kidney function, pancreatic enzymes, blood glucose, electrolytes, and thyroid function, were within normal ranges.

Imaging examinations

On May 16, gastroscopy revealed a smooth gastric mucosa without bile retention or signs of Helicobacter pylori infection. However, the descending segment of the duodenum had a rough mucosa. Colonoscopy revealed a smooth mucosa in the colon and rectum, without inflammation or masses; however, scattered lymphoid follicular hyperplasia was observed in the distal ileum (Figure 1). Further evaluation of the small intestine using computed tomography showed no abnormalities. Capsule endoscopy revealed polypoid protrusions in the ileum, with increasing density from the oral to anal side. Whole-small bowel DBE revealed rough and swollen mucosa with shrunken villi in the horizontal and descending segments of the duodenum and jejunum, along with segmental longitudinal mucosal swelling with nodular protrusions in the ileum (Figures 2, 3 and 4). Multiple scattered lymphoid follicular hyperplasia were observed on the ileal mucosa. Pathological examination of multiple tissue samples revealed a blunted villous structure, an elongated crypt structure, increased number of intraepithelial lymphocytes, and decreased or absent plasma cells in the lamina propria. Additionally, lymphoid follicular hyperplasia with increased intraepithelial and lamina propria lymphocytes, and focal lymphocyte proliferation were noted in the ileum (Figures 5 and 6). Additional tests for infectious causes, including tuberculosis and viral, parasitic, and fungal infections, were negative. Non-infectious investigations, such as antinuclear antibody profile, anti-neutrophil cytoplasmic antibodies, celiac disease (CeD) antibodies, tumor antigen markers, and bone puncture results, were all within normal limits.

Figure 1 Gastroscopy and colonoscopy. A: There was no bile retention in the gastric cavity, the gastric mucosa was smooth; B: The mucosa of the descending part of the duodenum was rough; C: Colonoscopy showed smooth colorectal mucosa; D: Lymphoid follicular hyperplasia was seen at the end of the ileum, which was scattered and multifocal and relatively homogeneous in morphology.

Figure 2 Whole-small bowel double-balloon enteroscopy. A: Roughness of the mucosa of the descending duodenum; B: Cracking changes of the villi after indigo carmine staining of the descending duodenum; C: Roughness and swelling of the mucosa of the horizontal segment of the duodenum, with cracking and mosaic changes of the villi atrophy; D: Mosaic-like changes in the jejunal mucosa.

Figure 3 Whole-small bowel double-balloon enteroscopy. A: Multiple segmental longitudinal mucosal lesions in the ileal segment; B-D: Mucosal lesions after indigo carmine staining at a distance and close up: Some of the villi on the surface were detached, there was no white moss or exudation at the base, and the mucosal swelling at the edge of the base was obvious as a nodule-like bulge, and the ileal villi around the lesion were flattened and atrophied.

Figure 4 Whole-small bowel double-balloon enteroscopy. A-D: Scattered multiple lymphoid follicular hyperplasia is seen in the ileum, with lymphoid follicles becoming progressively larger and denser from the proximal to the distal part.

Figure 5 HE staining of small intestinal mucosa. A and B: The villous structure becomes blunt, the crypt structure extends, and the number of lymphocytes in the surface epithelium increases, but the number of plasma cells in the lamina propria decreases or is missing; C and D: Increased intraepithelial and intrinsic membrane lymphocytes, with some showing focal lymphocyte proliferation.

Figure 6 Immunohistochemistry. A and B: CD138 staining was negative in lamina propria mucosa.

MULTIDISCIPLINARY EXPERT CONSULTATION

After thorough multidisciplinary discussions involving gastroenterology, rheumatology, hematology, pathology, imaging, nutrition, and infection control specialists, the patient was diagnosed with adult CVID-associated enteropathy with hypogammaglobulinemia and hypoalbuminemia. A systematic and comprehensive evaluation revealed low levels of vitamin B12 (< 60 pmol/L) and folic acid (< 5 nmol/L). Genetic tests for the associated genes yielded negative results. Furthermore, investigations indicated the absence of bronchiectasis in the lungs, normal mediastinal lymph node size, and absence of hepatosplenomegaly. Bone marrow aspiration and serum lymphocyte counts were within the normal ranges.

FINAL DIAGNOSIS

Taking into account the patient’s medical history, the final diagnosis was adult CVID-associated enteropathy, characterized by hypogammaglobulinemia and hypoalbuminemia.

TREATMENT

The treatment consisted of intravenous immunoglobulin (IVIg) replacement therapy at a dose of 0.5 g/kg, combined with partial enteral nutrition, folate, mecobalamin, probiotics, and personalized glutamine therapy for mucosal repair. After 5 days of treatment, a follow-up assessment revealed serum globulin level of 20 g/L and a reduction in stool frequency to twice daily with yellow, watery stools. The patient recovered well and was discharged on the fifth day post-operation.

OUTCOME AND FOLLOW-UP

The patient was discharged with a comprehensive follow-up plan aimed at monitoring for non-infectious complications. Follow-up evaluations via telephone consultation at the local hospital in July showed that the patient regularly received IVIg therapy. At present, the patient reports improved abdominal symptoms, with stable stool frequency and weight.

DISCUSSION

CVID represents a heterogeneous spectrum of primary antibody immunodeficiency disorders characterized by B-cell dysfunction and reduced serum IgG levels. Despite extensive research, the exact pathogenesis of CVID remains unclear. Genetic factors account for only 10%-20% of cases[1,2], and the estimated incidence ranges from 1 in 10000 to 1 in 100000 individuals, affecting all age groups. Clinical presentations are varied, often complicated by recurrent infections, autoimmune phenomena, lymphoproliferative disorders, malignancies, and non-infectious respiratory and gastrointestinal symptoms. Gastrointestinal involvement is reported in approximately 10%-20% of CVID cases, with a subset presenting with non-infectious gastrointestinal symptoms, such as chronic diarrhea. This condition often lacks distinctive signs, leading to a diagnostic delay of 6-8 years after symptom onset. Moreover, only 25%-45% of cases are diagnosed in adulthood[3,4], contributing to a challenging prognosis with high mortality rates. Therefore, timely diagnosis and intervention are imperative for optimal management and improved outcomes.

Non-infectious enteropathy associated with CVID may manifest with duodenal and terminal ileal involvement, presenting endoscopically with mucosal thinning, villous atrophy, congestion, and edema. A hallmark characteristic that aids in diagnosis is the absence of plasma cells in the lamina propria[5]. Recent advancements in understanding immune-mediated gastrointestinal disorders have highlighted the resemblance between non-infectious CVID-associated enteropathy and other autoimmune conditions, such as CeD and inflammatory bowel disease (IBD)[6]. Genetic factors also significantly contribute to the development of CeD-like or IBD-like phenotypes in CVID[7,8]. However, the simultaneous occurrence of CeD and IBD throughout the entire small intestinal mucosa has not been previously reported. Here, we present a case of noninfectious CVID-associated enteropathy with nonspecific clinical manifestations. Diagnostic evaluation, including double-balloon enteroscopy (DBE), facilitated early definitive diagnosis, revealing involvement of the entire small bowel mucosa. Microscopic examination revealed villous atrophy and mucosal swelling reminiscent of CeD, along with segmental mucosal lesions resembling those observed in patients with IBD. Whether these changes represent true CeD and IBD or merely CeD-like and IBD-like alterations remains uncertain. Notably, a previously unreported finding indicated follicular lymphoid tissue proliferation, previously termed nodular lymphoid hyperplasia (NLH)[9], extending throughout the ileum. NLH morphology, akin to certain lymphomas, raises concerns about lymphoma transformation, as evidenced by previous reports associating NLH with lymphoma in immunodeficient populations[10]. These findings underscore the importance of vigilant monitoring and further research to elucidate the clinical significance of early diagnosis and specific treatment of CVID.

Therefore, careful monitoring and management of the lymph nodes are imperative to promptly identify any signs of lymphoma. Given the diverse morphological presentations observed throughout the patient’s small intestinal mucosa, our diagnostic approach emphasized thoroughness. During the DBE, multiple tissue samples were obtained from various sites. Histopathological examination revealed the hallmark absence of plasma cells in the lamina propria, a distinguishing feature that aids in differentiating CVID from other conditions, such as CeD, IBD, and lymphoma.

The primary treatment for CVID typically involves IgG replacement therapy. In this particular case, beyond the fundamental regimen, a comprehensive and personalized approach was adopted. The patient received additional supplements, including vitamin B12, folic acid, enteral nutrition, probiotics, and glutamine to repair the mucous membranes. After discharge, a detailed follow-up plan was implemented. Over the past 7 months, the patient had exhibited improved symptom management and weight stabilization, indicating that timely diagnosis of CVID, coupled with effective follow-up management, can significantly enhance prognosis.

CONCLUSION

The patient with CVID presented with unexplained diarrhea and protein loss of unknown cause. The atypical clinical symptoms made diagnosis difficult, highlighting the importance of a comprehensive DBE examination covering the entire small intestine. Accordingly, comprehensive DBE in patients with CVID is particularly suitable for patients with small bowel diseases that cannot be diagnosed through routine examinations. Non-infectious enteropathy associated with CVID can affect the entire small intestine, exhibiting phenotypic similarities to CeD and IBD, along with NLH characterized by diverse morphologies. DBE not only facilitates early diagnosis, disease evaluation, and complication monitoring, but also provides a solid theoretical basis for such clinical interventions. Timely diagnosis, targeted treatment, and effective follow-up management strategies can significantly improve the prognosis of patients with CVID.