Elevated tissue transglutaminase immunoglobulin A: Celiac disease or polytypic plasmacytosis?

Abstract

We report a case of an adolescent girl post cardiac transplant with hypergammaglobulinemia and presumed celiac disease (CD), who had a persistently elevated anti‐tissue transglutaminase immunoglobulin A despite a gluten free diet. Refractory CD and Crohn's disease were excluded. Concomitant dairy elimination led to normalization of celiac titers but no histological improvement. Ultimately, she was diagnosed with polytypic plasmacytosis from suspected immune dysregulation.

1. INTRODUCTION

Celiac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten‐containing foods and requires treatment with a strict gluten‐free diet (GFD). Diagnosis of CD is confirmed through elevated blood tests, such as antitissue transglutaminase (tTG) immunoglobulin A (IgA) and anti‐endomysial antibody (EMA), and endoscopy that shows villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. ¹ In rare cases, children with CD maintain elevated serum tTG levels despite years of adherence to a strict GFD. In case reports, some of these patients improved after the additional elimination of cow's milk protein from the diet. ²

2. CASE REPORT

A 2‐year‐old female postheart transplant for hypoplastic left heart syndrome presented to gastroenterology clinic for vomiting and poor weight gain. With presumptive cow's milk protein allergy, she was switched to pediasure peptide 1.5 kcal/oz and pureed foods containing only small amounts of gluten and dairy. This diet change resulted in no symptom improvement, so an esophagogastroduodenoscopy (EGD) was performed showing distal esophagus biopsy with intraepithelial eosinophils up to 30 eosinophils/high powered field and the duodenal biopsies showing mildly increased intra‐epithelial lymphocytes (IELs) and mild villous blunting (Table 1). Lansoprazole was increased to 9 mg twice a day. Celiac titers were normal at this time.

Table 1.

Summary of bloodwork, growth, and biopsy findings over time.

Age (years)	2	3	7	12	13
Height (cm)	80	91.1	100	123.5	125.8
Weight (kg)	9.0	12.8	13.8	23.5	25.4
tTG immunoglobulin A	4.8 (n < 20 EIA/U)	24.6 (n < 20 EIA/U)	124.5 (n < 20 EIA/U)	1.94 (n < 4 U/mL)	3.0 (n < 7 U/mL)
Biopsy results:
Esophagus	− Mid esophagus: normal − Distal esophagus: intraepithelial eosinophils (up to 30/hpf). mild basal zone expansion. c/w focal mild to moderate reflux esophagitis	− Mid esophagus: Active esophagitis with prominent eosinophils (up to 15–20 per hpf) − Distal esophagus: Active esophagitis with prominent eosinophils (up to 15 per hpf)	− Normal	− Normal	− No biopsies taken
Stomach	− Inactive chronic gastritis	− Antral mucosa without diagnostic abnormality	− Inactive chronic gastritis − Negative for Helicobacter pylori	− Chronic gastritis with focal mild interstitial fibrosis	− Chronic gastritis and reactive epithelial changes
Duodenum	− Mild increased intraepithelial lymphocytes − Mild villous blunting increased intraepithelial lymphocytes in few villi without associated epithelial damage or crypt elongation	− Duodenal mucosa with villous blunting, mild intraepithelial lymphocytes and lamina propria plasma cells	− Marked villus blunting, associated epithelial damage and crypt elongation − Cellular debris in multiple areas in the superficial epithelium − Increased intraepithelial lymphocytes in occasional villi	− Duodenal and duodenal bulb: variable partial blunting of villi and a prominent increase in large plasma cells (marked by CD138 immunostaining within the lamina propria − Admixed with the plasma cells are a polymorphous population of CD3‐positive T cells and CD19 positive B cells ‐ There is no significant intraepithelial lymphocytosis − EBER staining negative − No evidence of posttransplant lymphoproliferative disorder	− Duodenal bulb: variably shortened villi. Intraepithelial lymphocytosis not seen. Reactive features are noted including crypt hyperplasia, glandular tortuosity, and mild mucin depletion. − Duodenal mucosa: subtle reactive features including mucin depletion and glandular tortuosity. No intraepithelial lymphocytes − Duodenal polyp: Most consistent with adenomatous polyp. No evidence of high‐grade dysplasia or malignancy.

Abbreviations: CD, celiac disease; EBER, Epstein‐Barr virus encoded RNA; EIA, enzyme immunoassy; tTG, tissue transglutaminase.

With diarrhea, abdominal pain, and weight loss continuing, a second opinion was sought at age 3. Parents had stopped lansoprazole since the diet had improved. EGD biopsies showed persistent esophagitis, villous blunting in the duodenum, though intra‐epithelial lymphocytosis remained mild (Table 1). With tTG IgA now slightly positive (24.6, ref < 20), CD was diagnosed and the patient was started on strict GFD. EMA was negative at this time.

At age 7, symptoms continued and the tTG IgA was now significantly elevated at 124.5 (n < 20) despite a strict GFD. EGD biopsies now showed marked villous blunting with associated epithelial damage and crypt elongation in the duodenum, with increased intraepithelial lymphocytes in occasional villi (Table 1). Esophageal biopsies were normal.

Due to concern for immunosuppressant related enteropathy, sirolimus and tacrolimus were changed to azathioprine and cyclosporine. The frequent emesis, abdominal distention, and diarrhea subsequently improved.

At age 12, the patient sought care at our institution for elevated celiac titers and ongoing growth concerns. Although the Celiac Dietary Adherence Test was not utilized, the parents reported strict adherence to a GFD, multiple gluten intestinal peptide stool tests were negative, and a celiac dietitian did not find any concerns of accidental gluten ingestion. Thus, the work‐up was expanded to evaluate for other etiologies such as Crohn's, auto‐immune enteritis, refractory CD, and protein losing enteropathy. Fecal calprotectin was 73 mcg/g (normal < 50), stool alpha‐1 antitrypsin was 55 mg/dL (normal < 55), and serum anti‐enterocyte antibody levels were normal. Staining of previous biopsies showed no concern for monoclonality or refractory CD.

With case reports ² , ³ showing that some patients with CD require dairy elimination for serological and histological improvement, a milk protein‐free diet was initiated. Three weeks later, she reported reduced bloating and an EGD and flexible sigmoidoscopy revealed significant pan‐duodenitis (Figure 1), with biopsies showing polytypic plasmacytosis of unclear cause in the duodenum (Figure 1), with no evidence of CD or posttransplant lymphoproliferative disorder, and Epstein‐Barr encoding region testing was negative. Ten weeks after starting the milk protein‐free diet, tTG IgA normalized to 1.94 U/mL (reference: <4).

Figure 1.

Left: Diffuse duodenal swelling noted on esophagogastroduodenoscopy, age 12. Right: Hematoxylin and eosin‐stained sections of duodenal mucosa show variable partial blunting of villi and a prominent increase in large reactive‐appearing plasma cells within the lamina propria. The plasma cells are admixed with a polymorphous population of lymphocytes in the lamina propria without significant intraepithelial lymphocytosis. Kappa and Lambda in situ hybridization showed no evidence of kappa or lambda light chain restriction and EBER in situ hybridization was negative (not shown). Original magnification ×400. EBER, Epstein‐Barr virus encoded RNA.

Given the polytypic plasmacytosis and hypergammaglobulinemia, immunology was consulted. Lab evaluation was notable for T‐ and B‐cell lymphopenia. Cell counts and cluster of differentiation markers were consistent with azathioprine and cyclosporine use. She also had an elevated interleukin (IL)‐2 receptor count. An inborn error of genetic immunity was considered less likely, and the immunophenotype was thought to be consistent with chronic immunosuppression (Table 2). Oncology also saw the patient and confirmed the condition was currently benign, after testing beta‐2 microglobulin, serum protein electrophoresis, and serum immunofixation electrophoresis.

Table 2.

Summary of key immunology labs.

Test	Result	Reference
IgG	2170	613–1295 mg/dL
Soluble IL‐2 receptor	2951	175.3–858.2 pg/mL
Immunoglobulin A	650	69–309 mg/dL
CD8 central memory cells	18.64	0.33%–3.44% of CD8 cells
CD4 effector memory cells	31.21	2.12%–27.5% of CD4 T cells
CD4 Naïve T cells	0.9	16.88%–79.40% of CD4 T cells
CD3 absolute count	985	1051–3031/mm3
CD19 absolute count	34	203–1139/mm3
Naïve B cell	25.92	54.85%–96.02%

Abbreviations: CD, cluster of differentiation, IgG, immunoglobulin G; IL, interleukin.

A follow‐up EGD was performed 1 year after a gluten and dairy free diet and showed no histological improvement. A 6‐week trial of prednisone with follow‐up EGD and biopsies noted improvement in plasma cell number but little improvement in reactive changes or endoscopic duodenitis. An incidental adenomatous polyp was also found (Table 1).

3. DISCUSSION

After years of being diagnosed with CD, our patient's duodenal biopsies progressed to polytypic plasmacytosis. In the bone marrow, plasmacytosis has been found with neoplasms, autoimmune disease, liver diseases, and infections. ⁴ There has been one reported case of gastric plasmacytosis in an adult, ⁵ but to our knowledge, there are no reports of this finding in the duodenum. The finding of duodenal plasmacytosis, with the additional elevation in tTG levels, has not been reported.

Regarding the esophagitis noted in the early biopsies, the patient met criteria for eosinophilic esophagitis (EoE). By age 7, when the patient was off lansoprazole, eating dairy, and off gluten, esophagitis resolved. EoE has a known association with CD, ⁶ so it is possible that the gluten elimination treated EoE.

Ultimately, we suspect that our patient does not have CD, but instead has immune dysregulation. Increased levels of sIL2R have been observed across various pathological states, such as infections, autoimmune disorders, inflammatory diseases, rejection of allografts, graft‐versus‐host disease post‐allogeneic hematopoietic stem cell transplantation, and hemophagocytic lymphohistiocytosis. ⁷ A referral has been placed for genetic testing such as whole exome sequencing, with consideration of the risk versus benefit of additional immunosuppression with biologics. A gluten containing diet is planned in the future to see if the celiac titers worsen. Surveillance of the duodenum, with disaccharidase levels, capsule endoscopy, and colonoscopy will follow.

4. CONCLUSION

This case serves as a reminder that when treating those with persistently elevated tTG IgA on a strict GFD, etiologies outside of CD need to be considered. In this case, the mild increase in IELs and persistent titer elevation suggested an alternate diagnosis, which ultimately progressed to polytypic plasmacytosis from an immune‐mediated phenomenon.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

The mother provided written consent for case details to be published.

Turunen A, Ahmed A, Thrush P, North P, Chugh A. Elevated tissue transglutaminase immunoglobulin A: celiac disease or polytypic plasmacytosis? JPGN Rep. 2025;6:312‐315. 10.1002/jpr3.70037