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Volume: 19 Issue: 6 June 2021


Immunoproliferative Small Intestinal Disease in a Liver Transplant Recipient: A Case Report and Literature Review

Key words : Case report, Diarrhea, Immunosuppression


Immunoproliferative small intestinal disease (IPSID) belongs to the primary lymphomas that affect the gastrointestinal (GI) tract and is also known as α heavy chain disease or Mediterranean lymphoma because it is characterized by the production of monoclonal defective α heavy chains and is mostly prevalent in the Mediterranean basin. This disease particularly affects patients with low socioeconomic status and poor sanitation conditions.1,2

Immunoproliferative small intestinal disease is a subtype of extranodal marginal zone B-cell lymphomas that arises from mucosa-associated lymphoid tissue.1 It strongly resembles gastric mucosa-associated lymphoid tissue lymphoma in etiology, since these are both infection-associated lymphoid malignancies. Pathogenetically, a chronic antigenic stimulation of the immune system in genetically susceptible people by pathogens is implicated in lymphoid transformation. Chronic infection with Campylobacter jejuni has been etiologically associated with IPSID.1

Immunoproliferative small intestinal disease usually develops on a background of impaired immunity, either cellular or humoral.1,2 Interestingly, the incidence of IPSID in transplant recipients, who have impaired function of B and T lymphocytes due to immunosuppression, is low. There are reports of IPSID in renal transplant recipients who present with diarrhea or other GI complications with an estimated incidence of around 3.4%.3 Herein, we report a rare case of IPSID lymphoma in a liver transplant recipient who was successfully treated with antibiotics and modifications in immunosuppression.

Informed consent was obtained from the patient for publication of this manuscript and the accompanying images.

Case Report

An 18-year-old white male patient presented to our department for evaluation of chronic diarrhea and weight loss of 8 kg. He had a history of liver transplant (age of 19 months, deceased donor) to treat biliary atresia after a previously failed hepatoportoen­terostomy. His immunosuppressive regimen on presentation was tacrolimus at 6 mg daily in divided doses and tapering doses of methylprednisolone (4 mg/day). The latter com­menced 1 year before admission to treat recurrent episodes of throm­bocytopenic purpura. The patient did not have any follow-up from a transplant physician.

The patient presented with mild anemia (hemoglobin, 11.5 g/dL) and elevated serum amylase (875 U/L; reference range, 20-80 U/L) with absence of elevated inflammatory markers. Further laboratory examinations showed elevated serum immunog­lobulin A (IgA, 828 mg/dL; reference range, 48-368 mg/dL), whereas the other immunog­lobulin fractions were normal, with absence of free α-chains in both serum protein electrophoresis and urine immunofixation, and no bone marrow involvement in the aspiration biopsy. Initial evaluation and cultures excluded various infectious causes, and subsequently the patient underwent GI endoscopy. Small erosions and a nodular pattern of the mucosa were evident in the terminal ileum, whereas submucosal hemorrhages and aphthoid ulcers were detected at the cecum and sigmoid colon, respectively. Abdominal computed tomography scan showed symmetrical mucosal thickening of the terminal ileum along with mesenteric lymphadenopathy at the right peritoneal cavity.

The terminal ileum histology specimens revealed broadened villi with dense inflammatory infiltrate predominantly composed of plasma cells in the lamina propria. Immunochemistry depicted IgA/κ monoclonal cell populations to be positive for CD38, CD138, and multiple myeloma oncogene 1 (MUM1) (Figure 1 and Figure 2). An infiltration of the small bowel by an indolent non-Hodgkin lymphoma was suggested by the histology. The diagnosis of mucosa associated marginal zone lymphoma was made. Similar but less intense infiltration was also detected in the colonic biopsy specimens, as well as in biopsy specimens obtained from macroscopically normal duodenal mucosa.

The combination of the patient’s medical history of immunosuppression, symptoms, laboratory findings, endoscopic and radiographic features as well as histopathology assessment (site of involvement, plasmacytic infiltration, IgA/κ monoclonal chains) were suggestive of possible early-stage IPSID or IPSID-like disease.

Our therapeutic approach included treatment with antibiotics in combination with modification of the immunosuppression, a practice often followed in cases of lymphoproliferative diseases after transplant. Tacrolimus dose was initially reduced and thereafter changed to the mammalian target of rapamycin inhibitor everolimus. This agent has a favorable profile because, apart from the immunosuppressive effects, it also demonstrates antineoplastic properties.4 The patient was commenced on doxycycline (100 mg once daily) for 6 months. He had gradual improve­ment in clinical symptoms with no documented relapse thereafter. Presently, at the time of this writing, 7 years after the initial episode, he is asymptomatic under regular follow-up. A persistent elevation of serum IgA is still noted, although at much lower values (ie, 579 mg/dL). The latest endoscopies did not reveal any abnormal findings, and histology showed no evidence of lymphoma.


Pathogenesis of IPSID implicates C. jejuni as an antigen, which causes excessive clonal proliferation of α heavy chains in lamina propria cells through chronic stimulation to the immune system.1 Moreover, various environmental, ethnic, geographic, and genetic factors play their role on disease development. An underlying acquired immune deficiency state, of either humoral or cellular immunity, is usually required because cases related to immunocompetent patients are extremely rare.1

A typical patient with IPSID may present with chronic diarrhea, abdominal pain, and weight loss due to malabsorption. Patients with advanced-stage IPSID can also present with bowel obstruction and ascites due to lymphomatous mass growth and invasion of all layers of the bowel wall. Some patients present with atypical symptoms that may cause a delay in diagnosis. Endoscopically, the most common finding in the early stages of the disease is thickening of the intestinal mucosa, which forms a cobblestone appearance with or without the presence of nodules or polypoid masses.1

The gold standard for the diagnosis of IPSID is the immunochemistry detection of plasma cell populations that secrete α heavy chain immunog­lobulins in a tissue sample from the small intestine, typically the proximal one, and the presence of clonal proliferation.1,5 The same heavy chains may be also detected in serum, aspirated jejunum luminal content, or urine immunoelectrophoresis. Treatment requires C. jejuni eradication with antibiotics, mainly doxycycline (alternatively, ampicillin and metronidazole), in mild early stages, which accounts for most cases. Doxycycline response rates vary between 33% and 71%, with a 5-year disease-free survival rate of 45%.6 Chemotherapeutic agents or anti-CD20 are essential for advanced disease, and surgery may be mandatory in the presence of obstructive phenomena.

Although IPSID is considered to be an α heavy chain disease, there are a few cases with the clinical characteristics of IPSID with secretions of either monoclonal immunoglobulins other than free α-chains, free light chains, or even polyclonal IgA (polyclonal nonmalignant IPSID). According to a Greek case series study, 3 of 13 cases with IPSID were associated with secretion of IgA-κ and IgA-λ chains.7 A Spanish comparative study defined the term IPSID-like lymphoma or IPSID equivalents to include patients with clinical characteristics indicative of IPSID who lack the conventional histopathology and immunology features that comprise a lymphoma entity different from the classic Western type.8 On the basis of these reports, the term IPSID is now used to include all cases that share the same pathological lesions as α heavy chain disease, no matter which immunoglobulin the plasma cell may secrete to indicate a wide-spectrum disease.

Our patient was diagnosed with IPSID despite that histology depicted intense plasma cell infiltration, not only of IgA but of κ-chain immunoglobulins as well. The regression of symptoms in our patient after change of immunosuppression and tetracycline treatment, as well as the stability of his condition 7 years after the initial diagnosis, supported our approach. The epidemiological characteristics (young male, resident in the Mediterranean basin) were also consistent with the existing experience.

This case is unique as it is the first case of IPSID diagnosed in a liver transplant recipient; in solid-organ transplant recipients, there is paucity of relevant data in the literature, with all reports so far describing renal transplant recipients. Immuno­proliferative small intestinal disease was reported in 5 of 148 renal transplant recipients (3.5%) who presented with GI symptoms and underwent upper GI endoscopy that included duodenal biopsies.3 In another group of renal transplant recipients with persistent diarrhea, the presence of duodenal villus atrophy implicated IPSID in 6.8% of the cases.9

Solid-organ transplant recipients are prone to malignancies posttransplant, with an overall incidence 2 to 3 times higher than in the general population.10 Posttransplant lymphoproliferative disorders (PTLD) are among the most common malignancies described in these patients (21% of all cancers),11 with the highest incidence (60%) observed within the first year after transplant. Immuno­proliferative small intestinal disease and PTLD are completely different entities. Posttransplant lymphoproliferative disorders are described as a complication after solid-organ and hematopoietic stem cell transplant mostly related to the Epstein-Barr virus and immunosuppression therapy, whereas IPSID is a variant of the B-cell lymphoma of mucosa-associated lymphoid tissue and is classified as non-Hodgkin lymphoma.11 Incidence of PTLD varies between 1% and 30% and is apparently more common than IPSID, based on the organ transplanted and the intensity of the immunosup­pressive therapy.12 Intestinal allograft recipients have the highest incidence, up to 25%, whereas the incidence in renal and liver transplant is below 5%.13 The GI tract is frequently involved (20%-30% of the cases), and up to half of the patients diagnosed with PTLD have evident disease anywhere in the GI tract, whether in the stomach, small or large intestine, or mesenteric lymph nodes. Isolated GI PTLD is extremely rare and usually presents with anemia, bleeding, and abdominal pain.14 There is evidence that PTLD with intestinal involvement is associated with better patient outcomes than other PTLD localizations in renal transplant recipients.15

In conclusion, we have presented a case of IPSID lymphoma diagnosed in a liver transplant recipient that highlights the importance of detailed workup for transplant recipients with chronic diarrhea as well as a high index of suspicion for lymphomas in this patient population, since early diagnosis and management can prevent disease progression and improve outcomes.


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Volume : 19
Issue : 6
Pages : 620 - 623
DOI : 10.6002/ect.2021.0015

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From the 1Department of Gastroenterology and Hepatology, Liver Transplantation and Liver Cancer Clinic, University Hospital of Heraklion, Crete; the 2Department of Pathology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki; the 3Fourth Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki; and the 4Department of Hematology, University Hospital of Heraklion, Crete, Greece
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Dimitrios N. Samonakis, Department of Gastroenterology and Hepatology, University Hospital Heraklion, PO Box 1352, 71110 Heraklion, Crete, Greece
Phone: +30 281 039 2687