Biomedical subjects
Publications and source records attributed to P Collin.
The role of the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) in T-cell activation makes them good candidates for coeliac disease susceptibility genes. We conducted a genetic linkage study of the CD80/86 gene region in the general Finnish population and in a local subisolate. No linkage was found in either population.
BACKGROUND: Coeliac disease and dermatitis herpetiformis are phenotypically distinct gluten-sensitive diseases. Coeliac disease is known to cluster in families, whereas there is little evidence for dermatitis herpetiformis and for the occurrence of both diseases in the same families. METHODS: The study group comprised 380 patients with coeliac disease and 281 patients with dermatitis herpetiformis, with a total of 3158 first-degree relatives, followed up for a mean of 14 years. The patients were questioned about affected first-degree relatives. The prevalence and incidence of biopsy-proven coeliac disease and dermatitis herpetiformis in relatives were determined. RESULTS: Seventy-three (19.2%) patients with coeliac disease and 51 (18.1%) with dermatitis herpetiformis had affected first-degree relatives. The prevalence among relatives was similar for both diseases; 4.7% and 3.9% of the relatives had coeliac disease and 0.8% and 1.5% had dermatitis herpetiformis, respectively. The disease prevalence was 7% among siblings, 4.5% among parents and 3.5% among children. The annual incidence was 3/1,000 relatives, which is 15 times higher than among the general population. Coeliac disease and dermatitis herpetiformis were mixed in several multiple-case families. CONCLUSIONS: The present long-term follow-up study of coeliac disease and dermatitis herpetiformis shows that every fifth patient can have affected first-degree relatives, and that the prevalence among relatives is 5.5%. Dermatitis herpetiformis segregates also in the families of patients with coeliac disease, and vice versa, indicating the same genetic background.
BACKGROUND: HLA-DQ is the only established susceptibility factor for coeliac disease. We tested whether all HLA haplotypes with the known risk marker, HLA-DQ2, confer equal susceptibility to coeliac disease, i.e. whether haplotype transmission from DQ2 homozygous parents to patients is random. The random transmission would strengthen the importance of DQ2 as the only risk factor within the HLA region. METHODS: Inheritance of DQ2-positive haplotypes from parent to patients was investigated in 14 of 127 Finnish coeliac families who had an HLA-DQ2 homozygous parent. HLA alleles and 18 HLA-linked microsatellite markers were used to determine the haplotypes, which were divided into those transmitted and those non-transmitted from DQ2-homozygous parents to patients: RESULTS: Transmitted haplotypes differed clearly from those not transmitted. The alleles in the transmitted haplotypes were strongly conserved and predominantly consisted of the well-known HLA-A*01, B*08, DRB1*03, DQ2, DPB1*0101 haplotype. The non-transmitted haplotypes, on the other hand, were significantly more heterogeneous; in particular, markers near HLA-A and -B genes differed from the transmitted haplotypes. CONCLUSIONS: The results suggest that DQ2 is not the only HLA-linked genetic risk factor for coeliac disease but the conserved haplotype harbours at least one other risk gene.
BACKGROUND: The main objective of the study was to assess the frequency of undetected coeliac disease among the first-degree relatives of families with two or more previously diagnosed coeliac disease patients. The value of the serum endomysial antibody test as a single means of detecting clinically silent coeliac disease was evaluated. The correlation of endomysial and tissue transglutaminase antibodies and the correlation of endomysial antibodies to the HLA typical for coeliac disease was determined. METHODS: A total of 137 multiple-case coeliac disease families with 872 family members were recruited; 466 healthy family members were simultaneously screened for gliadin and endomysial antibodies and thereafter for tissue tranglutaminase antibodies. Antibody-positive persons were typed for HLA-DQ2 and DQ8. The diagnosis of coeliac disease was based on the typical mucosal lesion on small-bowel biopsies. RESULTS: Forty-four (9.4%) of the healthy family members were positive for endomysial and 48 (10.3%) for gliadin antibodies; 42 biopsies revealed 29 new coeliac disease patients (6.2% of healthy individuals). Endomysial antibodies detected 97% and gliadin antibodies 52% of the new cases. All 44 endomysial-antibody-positive and 35 of 48 gliadin-antibody-positive individuals were positive for DQ2. Tissue transglutaminase antibodies corresponded well with endomysial antibodies. CONCLUSIONS: Undetected coeliac disease is common even among healthy first-degree relatives of multiple case families. The findings emphasize the value of serum endomysial antibodies in the detection of clinically silent coeliac disease. Endomysial-antibody-positive individuals, unlike gliadin-antibody-positive ones, share the coeliac disease-type HLA-DQ.
BACKGROUND: Serological screening suggests that most coeliac disease goes undetected. AIM: To determine how often coeliac disease is found in patients referred for gastroscopy by general practitioners. DESIGN: Testing of 9971 consecutive patients referred to a single health centre for their first open-access gastroscopy over a 10-year period, without previously-diagnosed coeliac disease or dermatitis herpetiformis. METHODS: Endoscopy and routine duodenal biopsy were in use throughout the study period. The occurrence of coeliac disease was evaluated in patients with dyspepsia, in those with regurgitation, and in those with symptoms suggestive of coeliac disease. RESULTS: Altogether, 147 (1.47%) patients had coeliac disease: 18/2974 (0.61%) with regurgitation, 41/5347 (0.77%) with dyspepsia, and 88/1650 (5.33%) with suspected coeliac disease. Increasing age reduced the risk very slightly (OR 0.98; 95%CI 0.97-0.99). Risk was significantly increased when there was a suspicion of coeliac disease (OR 9.085; 95%CI 5.371-15.369), while no difference was found between patients with dyspepsia and those with reflux disease (OR 1.33; 95%CI 0.75-2.34). The risk in women was not increased (OR 0.97; 95%CI 0.69-1.38). DISCUSSION: In this primary-care setting, <1% of patients with upper abdominal symptoms suffered from coeliac disease; population-based serological screening is expected to yield a corresponding prevalence. When physicians had suspected coeliac disease, the condition was nine times more common.
BACKGROUND AND AIMS: Coeliac disease is characterised by atrophy of the villi and hyperplasia of the crypts in the mucosa of the small intestine. It is caused by an environmental trigger, cereal gluten, which induces infiltration of the mucosa by inflammatory cells. We hypothesised that these inflammatory cells express cyclooxygenase 2 (COX-2), an enzyme that contributes to the synthesis of pro and anti-inflammatory prostaglandins and is known to be expressed at sites of inflammation in the stomach and colon. We have investigated expression of COX-2 in the coeliac disease affected small intestinal mucosa where it may be an indicator of either disease induction or mucosal restoration processes. PATIENTS AND METHODS: Small intestinal biopsy samples from 15 coeliac patients and 15 non-coeliac individuals were stained immunohistochemically for COX-2. Samples from 10 of the patients were also stained after these patients had been on a gluten free diet for 6-24 months. Various cell type marker antigens were used for immunohistochemical identification of the type of cell that expressed COX-2. To further verify colocalisation of the cell type marker and COX-2, double immunoperoxidase and immunofluorescence methods were employed. Immunoelectron microscopy was used to investigate the subcellular location of COX-2. RESULTS: In all samples taken from coeliac patients, clusters of cells with strong immunoreactivity for COX-2 were found in those areas of the lamina propria where the epithelium seemed to blister or was totally detached from the basement membrane. These clusters were reduced in number or totally absent in samples taken after a gluten free diet. No such clusters were seen in any control samples. The density of COX-2 positive cells lining the differentiated epithelium decreased significantly from 13.5 (5.1) cells/10(5) microm(2) (mean (SD)) in the untreated patient samples to 6.5 (2.0) cells/10(5) microm(2) after a gluten free diet (p<0.001), and was 3.3 (1.9) cells/10(5) microm(2) in control samples (p<0.001 compared with untreated or diet treated coeliac samples). Staining for COX-2 was localised to CD3+ T cells and CD68+ macrophages in the mucosal lesions but not all of these cells were positive for COX-2. Immunoelectron microscopy revealed that the ultrastructure of the COX-2 positive cells resembled that of lymphocytes, and the immunoreaction was localised to the rough endoplasmic reticulum and the nuclear envelope. CONCLUSIONS: Our results show that in coeliac disease, blistering of small intestinal epithelial cells is associated with accumulation of COX-2 positive T cells, and the number of these cells decreases after a gluten free diet. These observations suggest that COX-2 mediated prostanoid synthesis contributes to healing of the coeliac mucosa and may be involved in maintenance of intestinal integrity.
NAD(P)H:quinone oxidoreductase (NMO1; EC 1.6.99.2), also called DT-diaphorase, is involved in the reduction of coenzyme Q, an important cellular lipophilic antioxidant that can function as an intermediate electron carrier in plasma membrane-associated electron transport regulating cell growth. We examined the ability of normal human trabecular osteoblastic cells to express NAD(P)H:quinone oxidoreductase (NMO1) and studied its modulation during cell proliferation and growth arrest. We found that confluent primary human trabecular osteoblastic cells derived from healthy individuals constitutively express NMO1 activity, measured using 2-6 dichlorophenol indophenol (DCI) or menadione (vitamin K3) as substrate, and NADPH or NADH as electron donor. We also found that NMO1 activity was related to osteoblastic cell growth. NMO1 activity increased with osteoblastic cell density. Confluent growth-arrested cells expressed an eightfold higher NMO1 specific activity than proliferative human osteoblastic cells. Reverse-transcription polymerase chain reaction analysis showed that NMO1 mRNA levels did not differ in growth-arrested confluent cell and growing cells, suggesting that the increased NMO1 activity with cell density was due to posttranslational events. Harvesting and replating the cells at low density resulted in a 93.4% loss of NMO1 enzymatic activity. Removal of serum from high-density growth-arrested cells resulted in a 48.5% decrease in NMO1 activity. NMO1 activity does not appear to be related to induction of osteoblast differentiation because treatment with the differentiating agent 1,25(OH)(2) vitamin D(3) had no effect on NMO1 activity. The finding that human osteoblastic cells express NMO1 constitutively and that NMO1 activity increases with density-dependent growth inhibition suggest a role for NAD(P)H:quinone oxidoreductase in the control of growth arrest in normal human osteoblastic cells.
Current diagnostic criteria of celiac disease require small bowel villous atrophy, although the damage develops gradually. We therefore searched for evidence of disease in 10 adults suspected to have celiac disease, but evincing only minor mucosal inflammation and increase in gammadelta+ cells without villous atrophy. Twenty untreated celiac and 27 nonceliac patients served as biopsy controls. CD3+, alphabeta+, and gammadelta+ cells were increased in patients with only minor mucosal lesions, but less than in celiac patients. The inflammation resolved on gluten-free diet, and abdominal symptoms were alleviated. Eight of 10 had positive endomysial, seven gliadin, and nine tissue transglutaminase antibodies; all normalized on diet. Eight patients had osteopenia; HLA DQ2 was found in all. Minor mucosal lesions with an increase in gammadelta+ intraepithelial lymphocytes were suggestive of celiac disease. Our patients showed a clinical, histological, and serological recovery on diet; risk of osteopenia speaks in favor of dietary treatment.
Our aim was to investigate the occurrence of clinical and subclinical autoimmune thyroid disease in 79 patients with celiac disease as reflected in thyroid function, antibodies, and ultrasound. Since subclinical thyroid diseases are common in the population, 184 nonceliac controls were also studied. Normal thyroid function combined with positive antibodies and marked hypoechogenicity was considered subclinical disease. Autoimmune thyroid disease was observed in 13.9% of celiac patients and in 2.1% of controls (P = 0.0005); and subclinical disease in 10.1% and 3.3%, respectively (P = 0.048). The mean thyroid gland volume was 8.3 ml in celiac patients and 10.4 ml in controls (P = 0.007). Hypoechogenicity was found in 73% of celiac patients and in 42% of controls (P < 0.0001). Positive thyroid antibodies were associated with hypoechogenicity in celiac patients but not in controls. In conclusion, the occurrence of both clinical and subclinical autoimmune thyroid disease was increased in celiac disease; subclinical thyroid disease indicates regular surveillance.
Coeliac disease does not always respond properly to a gluten-free diet, and treatment may be complicated by an underlying autoimmune endocrine disorder. We report three cases of hypopituitarism in patients with coeliac disease who seemed to have incomplete dietary response. The first patient had diabetes and suffered from hypoglygaemic events; the second had muscular atrophy of unknown origin while the third had growth failure. None had a pituitary mass, suggesting that hypopituitarism was of autoimmune origin. Overall condition improved only after replacement therapy for the underlying hormone deficiency; this association should thus be recognized.
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BACKGROUND: Gluten sensitivity is a common multifactorial disorder, manifested in the small intestine or on the skin as typical coeliac disease or dermatitis herpetiformis, respectively. The only established genetic risk factor is HLA DQ2. AIMS: We tested genetic linkage of previously reported chromosomal loci 5q and 11q in Finnish families with gluten sensitivity. We also tested if genetic linkage to candidate loci on 5q, 11q, 2q33, and HLA DQ differed with respect to clinical manifestations or sex. SUBJECTS: We studied 102 Finnish families with affected sibpairs. For heterogeneity analysis, families were divided into subgroups according to sex and the presence of dermatitis herpetiformis, the skin manifestation of gluten sensitivity. METHODS: Non-parametric linkage between microsatellite markers and disease was tested. Linkage heterogeneity between subgroups was tested using the M test. The transmission/disequilibrium test and association analysis were performed. RESULTS: Evidence of linkage to 11q (MLS 1.37), but not to 5q, was found in the entire dataset of 102 families. Heterogeneity between subgroups was suggested: families with only the intestinal disease showed linkage mainly to 2q33 whereas families with dermatitis herpetiformis showed linkage to 11q and 5q, but not to 2q33. Linkage in all three non-HLA loci was strongest in families with predominantly male patients. HLA DQ2 conferred much stronger susceptibility to females than males. CONCLUSIONS: Independent evidence for the suggested genetic linkage between 11q and gluten sensitivity was obtained. The possible linkage heterogeneity suggests genetic differences between intestinal and skin manifestations, and the gender dependent effect of HLA DQ2.
Patients with epilepsy and posterior cerebral calcifications have an increased risk of coeliac disease (CD). The occurrence of this syndrome and the overall risk of CD and epilepsy remain still poorly understood. This study presents the prevalence of CD, brain atrophy, and cerebral calcifications in patients with epilepsy of unknown aetiology. The medical records of 900 consecutive adult patients with epilepsy diagnosis were reviewed. The occurrence of CD in living patients with epilepsy of unknown aetiology (n = 199) was investigated; all patients without previously known CD were asked for serological screening for the disease and the diagnosis was verified with small bowel biopsy. The presence of occipital calcifications and brain atrophy in all available CT scans (n = 130) was evaluated. Five of 199 cases had prior history of CD. The prevalence of definite CD in the patients was 2.5% (5/199), which is significantly higher that the current prevalence of CD in our area (0.27%). Antibody testing and small bowel biopsy in positive cases failed to increase prevalence of CD. Eleven (8.5%) patients had intracerebral calcifications and 3 of them posterior calcifications; all 11 had negative screening results for CD. Four (80%) patients with definite CD had supratentorial brain atrophy compared with 33 (26%) of 125 patients without CD. Prevalence of CD was increased among patients with epilepsy of unknown aetiology, but the combination of CD, epilepsy and intracranial posterior calcifications was rare in Finnish adult epilepsy population.
Celiac disease can be defined as the classical manifestation of gluten sensitivity, which primarily affects the small intestine. Gluten sensitivity has also a skin manifestation, i.e., dermatitis herpetiformis. Both diseases have a strong genetic association with HLA DQ on chromosome 6. In this study we tried to estimate how much different clinical expressions of gluten sensitivity are determined by genetic factors, and hence how feasible they are for genetic mapping; therefore, we studied all six monozygous twin pairs found among 1292 prospectively collected patients of dermatitis herpetiformis in Finland. Three of the six twin pairs were concordant for dermatitis herpetiformis and for simultaneous enteropathy, celiac disease. Two other twin pairs were partially discordant, one of each pair had dermatitis herpetiformis and celiac disease, whereas the other had solely the gut manifestation of gluten sensitivity, i.e., celiac disease. Only one pair was found to be discordant for gluten sensitivity. All the pairs had typical risk alleles for gluten sensitivity, i.e., either HLA DQ2 or DQ8. These results demonstrate that the genetic component in gluten sensitivity as broadly defined is very strong (5/6 concordant). Genetically identical individuals can have clearly distinguished phenotypes, either dermatitis herpetiformis or celiac disease, suggesting that environmental factors determine the exact phenotype of this multifactorial disease. These findings are of importance in genetic linkage analyses, which focus to only certain phenotypic properties of a complex trait.
OBJECTIVE: We investigated oral disorders and compared the findings with the occurrence of neuropathy in type 2 diabetes mellitus. STUDY DESIGN: Mucosal diseases, tooth loss, and temporomandibular joint dysfunction were examined in 45 patients with long-term type 2 diabetes mellitus and in 77 control subjects. The occurrence of neuropathy was evaluated by neurophysiologic tests. RESULTS: Of patients with diabetes, 56% suffered from dry mouth and 18% from glossodynia; of controls, correspondingly, 36% and 7% (P <.05); 2 or more mucosal lesions were detected in 42% and 20%, respectively (P =. 008). Temporomandibular joint dysfunction was found in 27% of subjects with diabetes and in 16% of control subjects. Peripheral neuropathy was present in 42% of patients with diabetes and in none of the controls (P <.01), and autonomic parasympathetic neuropathy in 54% and 31%, respectively (P =.02). Peripheral and autonomic parasympathetic neuropathies were independent risk factors for tooth loss and temporomandibular dysfunction. CONCLUSIONS: Diabetic neuropathy was found to be associated with tooth loss and temporomandibular joint dysfunction.
BACKGROUND: Abdominal complaints after ingestion of cereals are not uncommon. We assessed how reliable such a history is as a marker for the presence of overt coeliac disease, and whether we should also take into account latent coeliac disease and cereal allergy. METHODS: The study group comprised 93 consecutive adults from health centres spontaneously reporting abdominal symptoms after consumption of cereals. Small bowel mucosal morphology, CD3+, alphabeta+ and gammadelta+ intraepithelial lymphocytes (IELs), HLA DQ alleles and serum IgA-class endomysial (EmA), tissue transglutaminase (tTg) and gliadin (AGA) antibodies were determined. Skin prick and patch tests and serum radioallergosorbent tests for cereals were carried out. Thirty non-coeliac adults served as biopsy controls. RESULTS: Eight (9%) patients had coeliac disease and one mild partial villous atrophy. Altogether 17 had an increased density of gamma delta+ IELs without atrophy. However, only seven (8%) showed evidence of latent coeliac disease, i.e. both an increase in gammadelta+ IELs and the presence of coeliac disease-type HLA. One or more of the allergy tests for cereals was positive in 19; 9 adopted a gluten-free diet and abdominal symptoms were alleviated in all. In non-coeliac patients, serum EmA and tTg tests were negative in all, whereas AGA was seen in 40%. CONCLUSIONS: Intolerance to cereals is not a specific sign of overt or latent coeliac disease. All experimental dietary interventions before proper diagnosis of coeliac disease are therefore to be discouraged. Allergy to cereals, on the other hand, should be considered even in adults.
BACKGROUND: A wheat starch-based gluten-free diet is widely adopted in the treatment of coeliac disease, even though the products contain trace amounts of gluten. The aim here was to establish whether such a diet sustains abdominal symptoms. METHODS: The Gastrointestinal Symptom Rating Scale (GSRS) was applied to 58 coeliac disease patients on gluten-free diets and 110 non-coeliac controls. An estimate was made of daily dietary fibre and wheat starch-derived gluten. Psychological well-being was evaluated by a structured interview. Twenty-three coeliac patients consented to small-bowel biopsy. RESULTS: The mean GSRS score in coeliac disease patients did not differ from that in control subjects. Poorer psychological well-being was associated with abdominal symptoms in coeliac patients, whereas the daily amount of wheat starch had no effect on GSRS score. Overall dietary compliance was good, and villous atrophy was found in only 2 out of 23 patients. The average fibre consumption, 13 g per day, was lower than recommended. CONCLUSIONS: Wheat starch-based gluten-free products are well-tolerated in coeliac disease patients, provided that their diets are otherwise strict.
Bone-mineral density was measured in 19 clinically silent coeliac patients. The density was low, comparable with that in coeliac cases, and improved by gluten-free diet.