FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2017894107> ?p ?o ?g. }

• W2017894107 endingPage "531" @default.
• W2017894107 startingPage "525" @default.
• W2017894107 abstract "Objectives. The aim of the present study was to explore the frequency of clinical and serological manifestations of gastrointestinal immune reactivity in a large group of Swedish patients with sarcoidosis. Design. In patients with documented sarcoidosis, the presence of pernicious anaemia and coeliac disease was examined. Antibodies to H+/K+ ATPase, gliadin (AGA-IgA/IgG) and endomysium (IgA-EMA) were analysed. In H+/K+ ATPase antibody-positive patients, serum gastrin levels were measured and, when elevated, gastrointestinal biopsy was offered (biopsy performed in 6/9 patients); biopsy was also offered to those with positive EMA or AGA of either class (biopsy performed in 8/12 patients). Subjects from national and local studies were used as controls. Setting. The patients were recruited at the Department of Pulmonary Medicine, and the study was conducted at the Department of Endocrinology, University of Lund, Malmö University Hospital, Malmö, Sweden. Subjects. Of all patients (n = 89) with documented sarcoidosis attending the Department of Pulmonary Medicine between January 1980 and December 1991, 78 [34 females and 44 males; median age at the time of the study, 48 (range 22–81) years; median observation time since the diagnosis of sarcoidosis, 120 (range 1–468) months] were examined. Results. Twenty-nine patients (37.2%) had signs of gastrointestinal immune reactivity. H+/K+ ATPase antibodies were detected in 19 patients (24.4 vs. 4% in controls, P = 0.00015). Serum gastrin levels (median 45, range 22–720 pmol L–1) in those patients correlated with antibody titre (r2 = 0.882). Gliadin antibodies were detected in 12 patients (15.4 vs. 8.1% in controls, P = 0.042), of whom 11 (14.1 vs. 4.5% in controls, P = 0.00114) had AGA-IgA alone. One patient had pernicious anaemia and another coeliac disease (EMA-positive). Conclusion. We have demonstrated a high frequency of gastric autoimmunity and gluten-associated immune reactivity in patients with sarcoidosis, occurring in almost 40% of the cases, the former being the most frequent gastrointestinal immune manifestation. Despite a high frequency of humoral autoimmunity, the frequencies of clinical disease, pernicious anaemia and coeliac disease were not increased as compared with the control population. Sarcoidosis, a disease of unknown aetiology, is characterized by the presence of non-caseating granulomas predominantly in lymph nodes, lungs, eyes and skin, but any organ may be involved [1]. Patients with pulmonary sarcoidosis appear to have a heightened local cellular immune response, mediated by excess helper T-lymphocyte activity, and a heightened humoral immune response manifested by increased amounts of circulating immunoglobulins with reactivity towards multiple antigens, including self-antigens [2]. The initiating event for the above aberrant immune response is not known, but genetic influences and antigenic insults by viruses, bacteria, mycobacteria and/or autoantigens have been implicated [2]. Autoimmune diseases and sarcoidosis may be related [3] and, in particular, the association between sarcoidosis and autoimmune thyroid disease (ATD) has long been recognized [4]. Polyglandular autoimmune (PGA) syndromes occurring together with sarcoidosis have been described in a few cases [5–7]. A high frequency of endocrine autoimmunity in patients with sarcoidosis has recently been reported [8, 9]. Furthermore, an association between gastrointestinal diseases, particularly coeliac disease, and sarcoidosis has been suspected [10, 11] and we have previously shown a link between PGA syndrome type III (ATD and type 1 diabetes), coeliac disease and sarcoidosis [12, 13]. The aim of the present study was to explore the frequency of clinical and serological manifestations of gastrointestinal immune reactivity in a large group of Swedish patients with sarcoidosis. Between January 1980 and December 1991, 89 patients (also including patients diagnosed before 1980, n = 36) with documented sarcoidosis attended the Department of Pulmonary Medicine, Malmö University Hospital. Six patients could not be located, one was deceased and four refused to participate in the study. Accordingly, the final cohort consisted of 78 patients (34 females, 44 males, Table 1). All patients were Caucasian except one of Afro-Caribbean origin. The diagnosis of sarcoidosis was based on histological or clinical, biochemical and radiological evidence [14]. Histological diagnosis of sarcoidosis was present in 51/78 patients (66%). Twenty-eight of 78 patients (35.9%) had been treated with corticosteroids (median 42, range 2–240 months). After informed consent was obtained, all patient records and all patients (n = 78) were examined at the Department of Endocrinology by one of us (K.I.P.) and blood samples were obtained. The prevalence of clinical pernicious anaemia in Sweden was found to be 0.198% [15] and the prevalence of H+/K+ ATPase antibodies in healthy Swedish control subjects, using the same elisa method as in the present study, was found to be 4.0% [16]. The prevalence of coeliac disease, gliadin IgA and/or IgG antibodies, and gliadin IgA antibodies only, in healthy blood donors in Malmö, using the same detection method as in the present study, was found to be 0.065, 8.1 and 4.5%, respectively [17]. The following blood samples were taken in all patients and analysed with in-hospital methods: full blood count; serum electrolytes; serum creatinine; serum iron and total iron binding capacity; serum cobalamin (reference range 110–450 pmol L–1); blood folate; serum aspartate aminotransferase; serum alanine aminotransferase; serum calcium; serum magnesium; serum zinc; and a quantitative plasma protein analysis, including serum albumin, serum orosomucoid and serum immunoglobulins G, A and M [18]. Gastric autoimmunity. H+/K+ ATPase antibodies were measured in all patients (n = 78) by an ELISA method (reference value ≤ 0.8 U) [19]. In H+/K+ ATPase antibody-positive patients, serum gastrin (reference value ≤ 50 pmol L–1) was measured from blood samples obtained during their first visit. H+/K+ ATPase antibody-positive patients with elevated serum gastrin were offered oesophageal–gastric–duodenal endoscopy, including multiple biopsies from gastric antrum and fundus mucosa, and from the proximal duodenum. Gluten-associated immune reactivity. Gliadin IgA/IgG antibodies (AGA-IgA/AGA-IgG) were measured in all patients (n = 78) using an ELISA method (reference values: IgA ≤ 8.5 U; IgG ≤ 330 U) [17]. In patients with untreated coeliac disease, compared with inflammatory bowel disease or irritable bowel syndrome, AGA-IgA/AGA-IgG analysis has a sensitivity of 92% and a specificity of 86%, if the occurrence of either AGA-IgA or AGA-IgG is regarded as a positive test result [17]. Patients with normal AGA-IgA and AGA-IgG were categorized as not having coeliac disease, whilst those with either or both classes of AGA higher than the cut-off value were considered as positive and were offered a small bowel biopsy with a Watson capsule. In unsuccessful capsule biopsy cases, an upper gastrointestinal endoscopy with biopsy of the duodenal mucosa was performed. The small bowel specimens were examined at the Department of Pathology, Malmö University Hospital using Marsh’s criteria [20]. All patients (n = 78) were tested for IgA-endomysium antibodies (EMA) with an indirect immunofluorescence analysis [21], using commercially available fixed sections of the distal third part of monkey oesophagus as the antigen substrate [22]. The data were analysed using Fischer’s exact test and Yates correction. StatView 4.0 (Abacus Concepts, Berkeley, CA, USA) was used for regression analysis. A P-value < 0.05 was considered significant. Median and range are given. The study was approved by the Ethics Committee of the Medical Faculty, University of Lund. Twenty-nine out of 78 patients (37.2%, 12 females, 17 males) and 23 out of 54 patients aged 40 years and over (42.6%, nine females, 14 males) had signs of gastrointestinal immune reactivity ( Table 2). The characteristics of the patients with gastric autoimmunity and gluten-associated immune reactivity were compared with those of the patients (n = 41; 18 females, 23 males) with no autoimmune manifestations at all, i.e. no gastrointestinal immune reactivity or endocrine autoimmunity (information about endocrine autoimmunity was collected from our previous work [8]). There were no significant differences with respect to disease duration, disease activity (pulmonary X-ray stage, serum ACE) and corticosteroid treatment. With regard to the age at the time of diagnosis of sarcoidosis, we observed that males with gluten-associated immune reactivity were significantly older than males with no autoimmune manifestations [median 43.5 (range 23–61) vs. median 27 (range 18–67) years, P < 0.0239], and that females with gastric autoimmunity were significantly younger [median 25 (range 19–44) vs. median 41 (range 21–59) years, P < 0.0260] than females with no autoimmune manifestations. Serological findings. H+/K+ ATPase antibodies were detected in 19 patients [24.4%; 7/34 females (20.6%) and 12/44 males (27.3%); median age at diagnosis of sarcoidosis, 30 (range 16–70) years; median age at study, 47 (range 25–75) years] with a median titre of 1.5 (range 0.8–≥13.0 U ). The observed H+/K+ ATPase antibody frequency was higher (P = 0.00015) than in controls ( Table 2). When the positivity of the antibody was studied in the patients aged 40 and over, the overall frequency was 27.8% [5/26 females (19.2%) and 10/28 males (35.7%); median age at diagnosis of sarcoidosis, 33 (range 19–70) years; median age at study, 54 (range 41–75) years; median titre, 1.9 (range 0.8–≥13.0 ) U]. Serum cobalamin levels measured in all antibody-positive patients (n = 19) were normal (median 300, range 180–930 pmol L–1). Serum gastrin levels in antibody-positive patients (median 45, range 22–720 pmol L–1) were correlated with antibody titre (r2 = 0.882). Eight of the 19 patients were treated with corticosteroids (median 24.5, range 2–156 months), but only one of the patients selected for gastric biopsy was receiving steroids at the time of the biopsy and had been continuously treated for 156 months. None of the 19 patients with gastric autoimmunity was receiving H2-receptor blockers or proton pump inhibitors. Gastric biopsies. In nine patients, serum gastrin values were above 48 pmol L–1 (reference range ≤ 50 pmol L–1), and these were selected for gastric biopsy. Six patients accepted, of which three had normal gastric biopsies. No atrophic changes, signs of inflammation, intestinal metaplasia or Helicobacter pylori inflammation were seen. Two males showed isolated sarcoid granulomas and one female had atrophic gastritis. Clinical disease. Pernicious anaemia was seen, previously diagnosed at the age of 40 years, in one of the 19 H+/K+ ATPase antibodies-positive patients, 9 years after the diagnosis of sarcoidosis. The observed frequency of pernicious anaemia in the present study was not significantly increased (P = 0.146) as compared with controls ( Table 2). Serological findings. Gliadin antibodies were detected in 12 patients [15.4%; 6/34 females (17.6%) and 6/44 males (13.6%); median age at diagnosis of sarcoidosis, 40.5 (range 20–61) years; median age at study, 56 (range 23–72) years], none with IgA deficiency. Amongst the 12 patients, 11 had AGA-IgA antibodies (median titre 10.8, range 8.5–25.0 U) and two AGA-IgG antibodies (450.5 and ≥ 750.0 U). One patient had both AGA-IgA ≥ 25 U and AGA-IgG ≥ 750 U and this was the only patient with positive EMA. The observed AGA frequency was significantly higher (AGA-IgA and/or AGA-IgG, P = 0.042; AGA-IgA only, P = 0.00114) than controls ( Table 2). When the positivity of the antibodies was studied amongst the patients aged 40 and over, the overall frequency was 18.5% [5/26 females (19.2%) and 5/28 males (17.9%); median age at diagnosis of sarcoidosis, 43.5 (range 20–61) years; median age at study, 56.5 (range 45–72) years]. Of the 10 positive patients aged 40 years and over, nine had positive AGA-IgA (median titre 10.8, range 8.5–≥25 U) and two had AGA-IgG. Two of the 12 patients with positive AGA were treated with corticosteroids (range 48–54 months) but none of those who accepted small bowel biopsy. Small-bowel biopsies. Of the 12 patients with elevated AGA titres, 11 were offered a small bowel biopsy, excluding the one patient with previously diagnosed coeliac disease, and eight accepted. All eight biopsies were normal (evaluated with Marsh’s criteria) without any villous atrophy or increased intraepithelial leucocyte numbers. Clinical disease. Coeliac disease was seen in one female patient and was histologically diagnosed before the study, at the age of 43, 20 years after the diagnosis of sarcoidosis. The observed frequency of overt coeliac disease was not increased (P = 0.09) as compared with controls ( Table 2). Information about the present group’s endocrine autoimmune diseases was collected from our previous work [8]. Seven patients (four females, three males) with positive H+/K+ ATPase antibodies had evidence of a polyglandular involvement. The patient with overt pernicious anaemia had a PGA syndrome type II including Addison’s disease and autoimmune thyroiditis. One male and one female patient had positive AGA-IgA. Four had a thyroid engagement: one female with Graves’ disease, one female with autoimmune thyroiditis and two (one male and one female) with isolated thyroid antibodies. Four patients (two females and two males) with gluten-associated immune reactivity had evidence of polyglandular involvement. The female patient with overt coeliac disease had a PGA syndrome type III including autoimmune thyroiditis and type 1 diabetes. One patient (male) had thyroid antibodies and two (one male and one female) had H+/K+ ATPase antibodies. In a recent study, we demonstrated a high frequency of endocrine autoimmunity with subsequent clinical endocrine autoimmune disease in patients with sarcoidosis [8], and similar results have been reported by independent researchers [9]. In the present study, we found evidence of gastrointestinal immune reactivity in almost 40% of patients with sarcoidosis. Furthermore, as the prevalence of H+/K+ ATPase and gliadin antibodies may increase with age, we considered the patients aged over 40 years , but did not find any significant additional increase. In a previous study of patients with sarcoidosis [11], AGA-IgG, but not AGA-IgA, were investigated and a frequency of 41% was reported, whereas, to the best of our knowledge, no studies have been performed on gastric autoimmunity in patients with sarcoidosis. Sarcoidosis has been reported in association with multiple autoimmune diseases, but in none of these was the association indisputably the result of a space-occupying sarcoid lesion [1, 3–7, 10, 12, 13, 23]. Macroscopic sarcoid invasion may occur in any organ [1] including the gastrointestinal tract. Asymptomatic gastric sarcoid infiltration has been reported in 0–10% [24–26], with symptomatic gastric involvement in less than 1%. In the latter cases, achlorhydria or marked hypochlorhydria of the gastric aspirate were an almost constant finding [26], suggesting that extensive granulomatous involvement of the stomach may lead to intrinsic factor deficiency and resultant malabsorption of vitamin B12[27, 28]. However, the possibility of gastric autoimmunity was not discussed and H+/K+ ATPase antibodies were not measured [27, 28]. We found H+/K+ ATPase antibodies in 24% of our sarcoid patients, a significantly higher frequency than in controls [16], but only one patient with pernicious anaemia. In this context it is of interest that, of our six sarcoid patients with positive H+/K+ ATPase antibodies and elevated serum gastrin, selected for gastric biopsies, two had sarcoid granulomas in the gastric mucosa and one had atrophic gastritis. Although serum cobalamin levels in our H+/K+ ATPase antibody-positive patients were normal, elevated serum gastrin levels indicated deranged parietal cell function and correlated well with antibody titre. The reason that we found only one biopsied patient with atrophic gastritis might be a patchy involvement of the gastric mucosa. The association between pernicious anaemia/autoimmune gastritis, ATD and other autoimmune diseases is well known [29] and this association was demonstrated in almost 40% of our sarcoid patients with gastric autoimmunity. An association between coeliac disease and sarcoidosis has been proposed [10–13, 30], and altered gastrointestinal immune response has been reported in sarcoidosis, including raised serum AGA-IgG in 41% and increased intraepithelial lymphocyte counts in the small bowel mucosa regardless of AGA positivity [11]. In the present study, gluten-associated immune reactivity was noted in 15% of all patients with sarcoidosis, with overt coeliac disease in one. The frequencies of AGA-IgA alone, AGA-IgA and AGA-IgG were significantly increased compared with local blood donors [17]. The reason for the discrepancy in frequency between AGA-IgG in the present and the previous study [11] is not known, but the high frequency of AGA-IgA in the present study is notable, possibly reflecting the gastrointestinal location of the proposed immunological reaction in sarcoidosis. Despite the high frequency of AGA-IgA, the small bowel biopsies were normal in the eight biopsied patients, in accordance with negative EMA in all but the patient with overt coeliac disease. In the present study, the patient with coeliac disease had a constellation of PGA syndrome type III (including ATD and type 1 diabetes) and sarcoidosis previously described by the authors [12]. This patient has been described in detail [13] and we have discussed whether this disease constellation might constitute a new syndrome [13]. In addition, polyglandular involvement in the form of thyrogastric autoimmunity was seen in one-third of the patients with gluten autoimmunity, possibly formes frustes of the above-described association [12, 13]. Cell-mediated [2] and humoral immunity [31] appear deranged in sarcoidosis and in autoimmune diseases [32, 33]. Activated T-helper lymphocytes in the lungs or other sites of active disease in patients with sarcoidosis might stimulate B-lymphocytes to produce antibodies [2, 31], with affinities for gastrointestinal antigens. Whether gastrointestinal antibodies produced by such a mechanism in sarcoidosis are due to the deranged immune function in sarcoidosis and are cytotoxic, leading to the associated diseases, is not known [34]. Circulating autoantibodies do not appear to damage the target cells severely [35]. This contention is exemplified by the long latency that precedes the clinical onset of autoimmune diseases in genetically predisposed individuals, who maintain the function of the organ almost intact for a variable length of time, despite the presence of a variety of circulating autoantibodies directed against that organ, as for example in pre-type 1 diabetes [35]. However, autoantibodies do remain important serological markers to identify individuals at risk [35], as seen in our previous study on endocrine autoimmunity in sarcoidosis, where a significantly high prevalence of clinical endocrine autoimmune disease was found [8]. The reason for this discrepancy in the predictive value of circulating antibodies in gastrointestinal immune reactivity in sarcoidosis is not known, but special HLA haplotypes may be involved, either conferring protection (HLA-DQ1) [36] or predisposing to the development of autoimmune diseases (HLA-A1/B8/DR3) [37–40]. In conclusion, in the present study we have demonstrated a high frequency of gastric autoimmunity and gluten-associated immunity in patients with sarcoidosis, occurring in almost 40% of cases, the former being the most frequent gastrointestinal immune manifestation. Despite a high frequency of humoral autoimmunity, the frequencies of clinical disease, pernicious anaemia and coeliac disease were not increased as compared with the control population. Complex immunological and genetic mechanisms might explain the role of sarcoidosis in gastrointestinal immune reactivity. Immunogenetic studies are in progress in order to define the significance of these observations. We thank Professor F. A. Karlsson, Uppsala, Sweden, for performing the H+/K+ ATPase antibody analyses and Associate Professors P. Mikulowski, P. O. Sandberg and H. Yokoyama, Malmö, Sweden, for evaluating the gastrointestinal biopsies. We thank Birgitta Tenngart for skilful technical assistance. We also wish to thank Dr Anders Bredberg and Birgitta Lindholm at the Department of Microbiology for the analysis of the endomysial antibodies. The present work was supported by grants from the Nordisk Insulin Foundation Committee, the Albert Påhlsson Foundation, the Ernhold Lundström Foundation, Malmö Sjukvårdsförvaltning, University of Lund, and the Alfred Österlund Foundation. Received 15 April 1998; accepted 21 August 1998." @default.
• W2017894107 created "2016-06-24" @default.
• W2017894107 creator A5057370560 @default.
• W2017894107 creator A5058285254 @default.
• W2017894107 creator A5065824777 @default.
• W2017894107 creator A5070935502 @default.
• W2017894107 date "1999-05-01" @default.
• W2017894107 modified "2023-10-11" @default.
• W2017894107 title "Evidence of gastrointestinal immune reactivity in patients with sarcoidosis" @default.
• W2017894107 cites W1447648519 @default.
• W2017894107 cites W1554120713 @default.
• W2017894107 cites W1963032265 @default.
• W2017894107 cites W1968234573 @default.
• W2017894107 cites W1979728530 @default.
• W2017894107 cites W1980877557 @default.
• W2017894107 cites W1985432688 @default.
• W2017894107 cites W1992593885 @default.
• W2017894107 cites W1993972592 @default.
• W2017894107 cites W2009381279 @default.
• W2017894107 cites W2016470327 @default.
• W2017894107 cites W2016797123 @default.
• W2017894107 cites W2017410837 @default.
• W2017894107 cites W2017481094 @default.
• W2017894107 cites W2024587681 @default.
• W2017894107 cites W2037038083 @default.
• W2017894107 cites W2062938886 @default.
• W2017894107 cites W2075680649 @default.
• W2017894107 cites W2082435312 @default.
• W2017894107 cites W2093587241 @default.
• W2017894107 cites W2099563758 @default.
• W2017894107 cites W2121066558 @default.
• W2017894107 cites W2121494869 @default.
• W2017894107 cites W2128353487 @default.
• W2017894107 cites W2139757224 @default.
• W2017894107 cites W2153751304 @default.
• W2017894107 cites W2184298082 @default.
• W2017894107 cites W2289063408 @default.
• W2017894107 cites W2326904657 @default.
• W2017894107 cites W4212902860 @default.
• W2017894107 cites W4251824554 @default.
• W2017894107 cites W4294305087 @default.
• W2017894107 cites W90855620 @default.
• W2017894107 cites W95586623 @default.
• W2017894107 doi "https://doi.org/10.1046/j.1365-2796.1999.00451.x" @default.
• W2017894107 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/10363754" @default.
• W2017894107 hasPublicationYear "1999" @default.
• W2017894107 type Work @default.
• W2017894107 sameAs 2017894107 @default.
• W2017894107 citedByCount "34" @default.
• W2017894107 countsByYear W20178941072013 @default.
• W2017894107 countsByYear W20178941072015 @default.
• W2017894107 countsByYear W20178941072016 @default.
• W2017894107 countsByYear W20178941072019 @default.
• W2017894107 countsByYear W20178941072020 @default.
• W2017894107 countsByYear W20178941072021 @default.
• W2017894107 countsByYear W20178941072022 @default.
• W2017894107 crossrefType "journal-article" @default.
• W2017894107 hasAuthorship W2017894107A5057370560 @default.
• W2017894107 hasAuthorship W2017894107A5058285254 @default.
• W2017894107 hasAuthorship W2017894107A5065824777 @default.
• W2017894107 hasAuthorship W2017894107A5070935502 @default.
• W2017894107 hasBestOaLocation W20178941071 @default.
• W2017894107 hasConcept C16005928 @default.
• W2017894107 hasConcept C177713679 @default.
• W2017894107 hasConcept C203014093 @default.
• W2017894107 hasConcept C2781301800 @default.
• W2017894107 hasConcept C71924100 @default.
• W2017894107 hasConcept C8891405 @default.
• W2017894107 hasConceptScore W2017894107C16005928 @default.
• W2017894107 hasConceptScore W2017894107C177713679 @default.
• W2017894107 hasConceptScore W2017894107C203014093 @default.
• W2017894107 hasConceptScore W2017894107C2781301800 @default.
• W2017894107 hasConceptScore W2017894107C71924100 @default.
• W2017894107 hasConceptScore W2017894107C8891405 @default.
• W2017894107 hasIssue "5" @default.
• W2017894107 hasLocation W20178941071 @default.
• W2017894107 hasLocation W20178941072 @default.
• W2017894107 hasOpenAccess W2017894107 @default.
• W2017894107 hasPrimaryLocation W20178941071 @default.
• W2017894107 hasRelatedWork W1566569358 @default.
• W2017894107 hasRelatedWork W1991069481 @default.
• W2017894107 hasRelatedWork W2008678957 @default.
• W2017894107 hasRelatedWork W2433437944 @default.
• W2017894107 hasRelatedWork W2462877351 @default.
• W2017894107 hasRelatedWork W2990887036 @default.
• W2017894107 hasRelatedWork W3045884788 @default.
• W2017894107 hasRelatedWork W3081483692 @default.
• W2017894107 hasRelatedWork W4292012078 @default.
• W2017894107 hasRelatedWork W1906033448 @default.
• W2017894107 hasVolume "245" @default.
• W2017894107 isParatext "false" @default.
• W2017894107 isRetracted "false" @default.
• W2017894107 magId "2017894107" @default.
• W2017894107 workType "article" @default.