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Is it worth investigating splenic function in patients with celiac disease?
Antonio Di Sabatino, Laura Brunetti, Gabriella Carnevale Maffè, Paolo Giuffrida, Gino Roberto Corazza
Antonio Di Sabatino, Laura Brunetti, Gabriella Carnevale Maffè, Paolo Giuffrida, Gino Roberto Corazza, Department of Internal Medicine, Celiac Centre, S. Matteo Hospital Foundation, University of Pavia, 27100 Pavia, Italy
ORCID number: $[AuthorORCIDs]
Author contributions: All authors synthesized ideas and wrote the paper.
Correspondence to: Dr. Antonio Di Sabatino, Department of Internal Medicine, Celiac Centre, S. Matteo Hospital Foundation, University of Pavia, Piazzale Golgi 5, 27100 Pavia, Italy. firstname.lastname@example.org
Telephone: +39-382-501596 Fax: +39-382-502618
Received: October 5, 2012 Revised: January 8, 2013 Accepted: January 18, 2013 Published online: April 21, 2013
Celiac disease, an immune-mediated enteropathy induced in genetically susceptible individuals by the ingestion of gluten, is the most frequent disorder associated with splenic hypofunction or atrophy. Defective splenic function affects more than one-third of adult patients with celiac disease, and it may predispose to a higher risk of infections by encapsulated bacteria and thromboembolic and autoimmune complications, particularly when celiac patients have concomitant pre-malignant and malignant complications (refractory celiac disease, ulcerative jejunoileitis and enteropathy-associated T-cell lymphoma). However, the clinical management of patients with celiac disease does not take into account the evaluation of splenic function, and in patients with high degree of hyposplenism or splenic atrophy the prophylactic immunization with specific vaccines against the polysaccharide antigens of encapsulated bacteria is not currently recommended. We critically re-evaluate clinical and diagnostic aspects of spleen dysfunction in celiac disease, and highlight new perspectives in the prophylactic management of infections in this condition.
Citation: Di Sabatino A, Brunetti L, Carnevale Maffè G, Giuffrida P, Corazza GR. Is it worth investigating splenic function in patients with celiac disease? World J Gastroenterol 2013; 19(15): 2313-2318
Functional hyposplenism has been regarded as an acquired disorder, potentially associated with several diseases, sometimes accompanied by a reduction in spleen size, and burdened by the same complications occurring in surgical asplenia[1,2]. The spleen, apart from acting as a phagocytic filter, thus removing ageing and damaged cells, is crucial in regulating immune homeostasis by linking innate and adaptive immunity, and in protecting against infections by encapsulated bacteria[3-5].
Removal of encapsulated bacteria in the course of initial infection requires natural antibodies produced by immunoglobulin M (IgM)-memory B cells, a unique B cell population resident in the marginal zone of the spleen, which, unlike switched-memory, are responsible for a T-independent response against bacteria[6-9]. The key role of the spleen in mounting an immune response against encapsulated bacteria is supported by the dramatic reduction of the IgM-memory B cell pool following removal of the spleen[10,11]. An impairment of the immune function of the spleen results in (1) reduced number of IgM-memory B cells and defective activity of opsonizing molecules, i.e., properdin and tuftsin, thus predisposing to infections caused by encapsulated bacteria (mainly Streptococcus pneumoniae, Neisseria meningitidis and Haemophylus influenzae); and (2) decreased number of marginal zone B cells which predisposes to the emergence of autoreactive T-cell clones as a consequence of T-regulatory cells depletion, with subsequent development of autoimmunity[8,9,12]. On the other hand, an impairment of the filtering function results in (1) reduced platelet sequestration, which predisposes to thromboembolism; and (2) defective removal of pits from erythrocytes with consequent increase of circulating Howell-Jolly bodies and pitted red cells (Figure 1)[1-3].
Figure 1 Schematic representation of immune and filtering function of the spleen.
IgM: Immunoglobulin M; Treg: T-regulatory cells.
Detection of pitted red cells by phase-interference microscopy is considered an accurate method to assess splenic function, quite easy to perform, less expensive and invasive than radioisotopic methods, and more accurate than Howell-Jolly bodies detection, particularly in the quantitation of mild degrees of hyposplenism. The inverse correlation observed in asplenic and hyposplenic patients between pitted red cells and IgM-memory B cells suggests the possible use in clinical practice of flow cytometric B cell analysis as a quantitative alternative test. The little we know about the natural history of hyposplenism leads us to believe that it evolves from a reversible mild impairment of splenic function - as occurs in responder Crohn’s disease patients after anti-tumor necrosis factor treatment with infliximab - to an irreversible impairment of splenic function, up to severe splenic atrophy.
Among all the various diseases associated with hyposplenism, celiac disease is the most frequent[2,17]. Hyposplenism, assessed by pitted red cell counting, affects more than one-third of celiac patients. Defective filtering function, measured by pitted red cell counting, is paralleled by a defect in the frequency of circulating IgM memory B cells and serum tuftsin activity, and both these parameters significantly correlate with the degree of splenic function in untreated celiac disease[18,19]. Hyposplenism does not complicate celiac disease in infancy; in adults its incidence correlates with the duration of pre-exposure to gluten as shown by the correlation with age at diagnosis, and a gluten-free diet is effective in restoring splenic function. When the data are split according to clinical severity, the prevalence of hyposplenism increases from 19% to 80% in celiacs with premalignant or malignant complications. Both splenic atrophy and mesenteric lymph node cavitation are recognised as poor prognostic factors in celiac disease[19,22,23].
Major infections have been reported in a number of hyposplenic celiac patients in the last 25 years, variably associated with spleen atrophy and mesenteric lymph node cavitation (Table 1)[23-29]. However, it was only in 2008 that two ad hoc studies highlighted the importance of this predisposition by showing a significantly higher relative risk of pneumococcal sepsis in adult celiacs, which is still significant when hospitalised patients are considered as reference individuals[30,31]. The absolute risk of sepsis turned out to be even higher than that of hip fracture and lymphoma in the celiac cohort. These findings fit with the demonstration of an increased mortality due to infections (in particular septicemia) and respiratory diseases (mainly pneumonia) in the Swedish celiac cohort.
Table 1 Case reports of hyposplenism-related infections in patients with celiac disease.
Although anti-pneumococcal vaccination has been shown to reduce the prevalence of major infections in asplenic patients[34-38], it is dramatically underused as shown by these data collected in England and Wales by examining 3584 patients with celiac disease or sickle cell anemia. Vaccines currently used in patients at risk of pneumococcal infections are the 23-valent pneumococcal polysaccharide vaccine, whose protective action is based on the production of opsonising anti-capsular antibodies by means of a T-independent mechanism (it is actually recommended in asplenic/hyposplenic adults and children older than 5 years), and the 13-valent protein-conjugate pneumococcal vaccine (PCV-13, Prevnar), in which the CRM197 diphtheria protein changes the nature of the response from T-independent to T-dependent, making this vaccine particularly suitable in infants, especially below the age of 2 years, when the splenic IgM-memory B cell pool is still immature (Table 2)[42-45]. Similarly, adult hyposplenic patients, in whom IgM-memory B cell are depleted, would benefit from PCV-13, as its T-dependent mechanism is supposed to bypass the immunological impairment due to the lack of IgM-memory B cells. Nevertheless, Prevnar is recommended by current guidelines only in infancy (Table 2).
Table 2 Traditional polysaccharide and new conjugate anti-pneumococcal vaccines used in the prophylactic management of asplenic/hyposplenic patients.
Celiac disease is frequently associated with a number of autoimmune disorders, including Hashimoto’s thyroiditis, insulin-dependent diabetes mellitus, Sjögren’s syndrome, Addison disease, systemic lupus erythematosus, rheumatoid arthritis[47,48]. The evidence that autoantibodies may develop within months of splenectomy, together with the demonstration that celiac patients with blood film features of hyposplenism have a higher prevalence of autoantibodies, have led to the hypothesis that defective splenic function might predispose the development of autoimmunity in celiac disease[51,52].
The nature of the link between hyposplenism and autoimmune manifestations of celiac disease is not known, and it is not clear whether autoimmune disorders precede and cause splenic hypofunction or atrophy, or vice versa, or whether additional factors influence both conditions. The finding that hyposplenism in nonceliac patients with autoimmune disorders did not differ significantly from that of healthy controls supports the hypothesis that the higher risk for splenic hypofuncion in celiac patients with autoimmune disorders might be related to celiac disease, rather than to autoimmunity per se. Of note, both hyposplenism and autoimmune disorders increase their prevalence with the length of pre-exposure to gluten in celiac disease[18,53]. When we looked at the prevalence of celiac disease-associated hyposplenism, we found that it increases from 19% in uncomplicated patients to 59% in those with associated autoimmune diseases. Moreover, patients with celiac disease-associated autoimmune disorders have a significantly lower percentage of IgM memory B cells in comparison to uncomplicated celiac patients. This finding is quite interesting when considering that memory B cells resident in the marginal zone of the spleen play a role in the tolerance of autoantigens through the B cell receptor. A similar role is exerted by marginal zone dendritic cells which internalise apoptotic leucocytes thus preventing autoantigens exposed on the surface of apoptotic bodies from causing autoantibody formation. Moreover, both marginal zone B cells and dendritic cells may favour the expansion of regulatory T cells which maintain tolerance through the up-regulation of anti-inflammatory cytokines, such as transforming growth factor-β and interleukin-10. The perturbation of these regulatory mechanisms have been shown to predispose to the development of autoimmunity in splenectomised or hyposplenic subjects[19,49,57].
Impaired spleen sequestration of circulating platelets and increased blood viscosity are supposed to be implicated in the development of thromboembolic events in splenectomised patients or in other hyposplenism-associated disorders. In the latter, the risk of thrombosis is difficult to assess as many of these disorders are associated with increased incidence of thrombosis per se. The hyperviscosity secondary to defective splenic function may be the result in part of the persistence of aged and damaged red cells in the circulation as well as intracellular inclusions, such as Howell-Jolly bodies, siderotic granules, and Heinz bodies, all of which promote decreased erythrocyte deformability. An increased risk of thromboembolism has been recently demonstrated in celiac disease, where it correlates with the duration of pre-exposure to gluten. However, in that study no data is available concerning the weight of the thromboembolic risk in the hyposplenic celiac patients, nor hyposplenism is mentioned among the possible factors predisposing to thromboembolism.
There is a number of critical issues that remain to be elucidated to define the optimal management of hyposplenic celiac patients and to clarify the pathogenic mechanisms underlying spleen hypofunction[61,62]. We propose that splenic function is determined in patients with pre-malignant and malignant complications, concomitant autoimmune disorders, old age at diagnosis, previous history of major infections/sepsis or thromboembolism, mesenteric lymph node cavitation and/or spleen atrophy (Table 3). As a diagnostic tool, pitted red cell counting remains an accurate, quantitative and inexpensive method, albeit observer-dependent. Flow cytometric analysis of memory B cells could be an alternative quantitative test, although studies assessing its sensitivity and specificity are lacking. We believe that protein-conjugate vaccines[65-68] should be recommended in patients with major hyposplenism, defined -on the basis of data derived from asplenic patients- by a pitted red cells value higher than 10% and/or an IgM memory B cell frequency lower than 10%. Of note, most of the patients identified by these parameters are refractory or have concomitant autoimmune disorders (Figure 2). Understanding the pathogenic mechanisms underlying spleen dysfunction in celiac disease requires a greater knowledge of the connections between gut and spleen. The demonstration that spleen function is crucial for the presence of IgA-producing plasma cells in the gut of both asplenic mice and patients, and that oral tolerance to gluten is predominantly mounted in the spleen represent preliminary attempts in this direction.
Figure 2 Correlation between circulating pitted red cells and immunoglobulin M memory B cells in splenectomised patients (A) and hyposplenic celiac patients (B).
Among the latter, those affected by pre-malignant or malignant complications of celiac disease are indicated with a square, those affected by concomitant autoimmune disorders are indicated with a triangle. IgM: Immunoglobulin M.
Table 3 Celiac patients in whom splenic function should be assessed.
Patients with complications (RCD, UJI, EATL, collagenous sprue)
Patients with concomitant autoimmune disorders
Patients with old age at diagnosis
Patients with previous history of major infections/sepsis and/or thromboembolism
Patients with mesenteric lymph node cavitation and/or splenic atroph
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