FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2-7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10-24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10-4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10-4) and coeliac disease (OR = 1.62, P = 1.20 × 10-4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10-3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.

Natural history of functional dyspepsia: a 10-year population-based study.

BACKGROUND: Functional dyspepsia (FD) is a common disorder, but information on its natural history is limited. AIM: To study the natural history of FD as assessed by 2 criteria over a 10-year period. METHOD: A population-based study conducted by mailing a questionnaire to the same age- and gender-stratified random sample of the Icelandic population aged 18-75 in 1996 and again in 2006. FD was estimated by the Functional Dyspepsia Score List and by dyspepsia subgroups categorized into 4 groups: (1) frequent upper pain, (2) meal-related, (3) nausea or vomiting, and (4) combinations of these groups. RESULTS: FD was diagnosed in 13.9% of the subjects in the 1996 sample (11.3% male, 15.8% female) and 16.7% in 2006 (12.3% male, 20.2% female) with a significant difference between males and females in 2006. Dyspepsia subgroup criteria showed a higher prevalence than conventional FD criteria. The proportion of FD subjects in one of the dyspepsia subgroups was low. There was a significant relationship between FD and heartburn and irritable bowel syndrome. A high proportion of subjects who seek medical care have FD. CONCLUSION: FD was stable over the 10-year period, but there was turnover in symptoms and increased intensity and frequency of gastrointestinal pain. Dyspepsia subgroup criteria showed a higher prevalence than FD, which was more common in young subjects and females. FD poses a heavy burden on the health care system.

Antibiotic susceptibility of Helicobacter pylori in Iceland.

BACKGROUND: Increasing resistance of Helicobacter pylori (H. pylori) to antibiotics calls for constant re-evaluation of multidrug regimens that have been used to eradicate the infection. The aim of this study was to evaluate the current antibiotic susceptibility of H. pylori in an Icelandic cohort. METHODS: Patients referred for gastroscopy were recruited prospectively. Those found to have a positive rapid urease test were included in the study. Susceptibility testing was conducted by the Epsilometer test (E-test) method for ampicillin, clarithromycin, levofloxacin, metronidazole and tetracycline. Results were obtained after three days of incubation in microaerophilic conditions at 37 °C, except for the metronidazole were the first 24 hours were anaerobic. RESULTS: Of the 613 patients who underwent gastroscopy, 138 (23%) had a positive rapid urease test. H. pylori was successfully cultured from 105 (76%) of the urease test positive patients and the isolates were tested for antibiotic susceptibility. Five patients had prior H. pylori eradication. Antibiotic resistance for ampicillin, clarithromycin, levofloxacin, metronidazole and tetracycline was 0%, 9%, 4%, 1% and 0%, respectively. If those who had previously undergone eradication treatment were excluded, the resistance was 0%, 6%, 3%, 1% and 0%, respectively. Clarithromycin resistance was higher amongst women than men, 13% vs. 5%, however, not significantly. Clarithromycin resistance was 60% amongst those who had previously received eradication treatment compared to 6% of those who had not (p < .0001). CONCLUSIONS: Clarithromycin resistance amongst the H. pylori isolates can be considered relatively low. Therefore, in the current cohort, standard triple-drug clarithromycin-containing regimen should remain the first-line treatment against H. pylori.

[Mediastinal parathyroid cyst - a case report]. / Kalkkirtlablaðra í midmæti - sjúkratilfelli.

The most common causes of mediastinal masses are thymomas, lymphomas and neuromas. Mediastinal cysts, such as bronchogenic cysts, which are usually benign, are less common. We report the case of a 59-year-old woman with a history of progressive dysphagia. A computed tomography scan revealed a cystic lesion in the anterior mediastinum. The cyst was surgically resected and turned out to be a benign parathyroid cyst. The patient's symptoms disappeared after surgical removal. Both the serum calcium and parathyroid hormone levels were normal before, and after surgery. Parathyroid cysts are rare lesions of the mediastinum and only around 100 cases have been reported in literature. Here we report the first case of a mediastinal parathyroid cyst in Iceland.

Natural history of functional gastrointestinal disorders: comparison of two longitudinal population-based studies.

BACKGROUND: Functional gastrointestinal disorders are common but information on their natural history is limited. AIMS: To document the natural history of functional gastrointestinal disorders in a population based study and to compare with the Olmsted County study. METHOD: A questionnaire was mailed to the same age- and gender-stratified random sample of the Icelandic population aged 18-75 in 1996 and 2006. Results were compared to the Olmsted County study. RESULTS: Prevalence of functional gastrointestinal disorder symptoms was stable between these periods in time: 16.9% and 17.2% for irritable bowel syndrome, and 4.8% and 6.1% for functional dyspepsia. Onset of each disorder was more often higher in the Olmsted County study than in Iceland. Disappearance rates were similar for both studies. Transition probabilities varied across the different subgroups and were different between studies. The same proportion had the same symptoms in the initial and final studies. More subjects had no symptoms in Iceland (52% vs. 40%) and different symptoms at follow up (38% vs. 23%). CONCLUSION: Prevalence of functional gastrointestinal disorder symptoms was stable over time but the turnover in symptoms was high. A higher number of subjects had no symptoms in Iceland than in Olmsted County and there was a greater variation in subjects having different symptoms at follow up.

Natural history of irritable bowel syndrome in women and dysmenorrhea: a 10-year follow-up study.

Background. Studies have shown that women are more likely to have irritable bowel syndrome (IBS) and more women seek healthcare because of IBS than men. Aim. We wanted to examine the natural history of IBS and dysmenorrhea in women over a 10-year period and to assess the change in IBS after menopause. Method. A population-based postal study. A questionnaire was mailed to the same age- and gender-stratified random sample of the Icelandic population aged 18-75 in 1996 and again in 2006. Results. 77% premenopausal women had dysmenorrhea in the year 1996 and 74% in 2006. 42% of women with dysmenorrhea had IBS according to Manning criteria in the year 2006 and 49% in 1996. 26% of women with dysmenorrhea had IBS according to Rome III 2006 and 11% in the year 1996. In 2006 30% women had severe or very severe dysmenorrhea pain severity. More women (27%) reported severe abdominal pain after menopause than before menopause 11%. Women without dysmenorrhea were twice more likely to remain asymptomatic than the women with dysmenorrhea. Women with dysmenorrhea were more likely to have stable symptoms and were twice more likely to have increased symptoms. Conclusion. Women with IBS are more likely to experience dysmenorrhea than women without IBS which seems to be a part of the symptomatology in most women with IBS. IBS symptom severity seems to increase after menopause.

Irritable bowel syndrome: physicians' awareness and patients' experience.

AIM: To study if and how physicians use the irritable bowel syndrome (IBS) diagnostic criteria and to assess treatment strategies in IBS patients. METHODS: A questionnaire was sent to 191 physicians regarding IBS criteria, diagnostic methods and treatment. Furthermore, 94 patients who were diagnosed with IBS underwent telephone interview. RESULTS: A total of 80/191 (41.9%) physicians responded to the survey. Overall, 13 patients were diagnosed monthly with IBS by specialists in gastroenterology (SGs) and 2.5 patients by general practitioners (GPs). All the SGs knew of the criteria to diagnose IBS, as did 46/70 (65.7%) GPs. Seventy-nine percent used the patient's history, 38% used a physical examination, and 38% exclusion of other diseases to diagnose IBS. Only 18/80 (22.5%) physicians used specific IBS criteria. Of the patients interviewed, 59/94 (62.8%) knew they had experienced IBS. Two out of five patients knew IBS and had seen a physician because of IBS symptoms. Half of those received a diagnosis of IBS. A total of 13% were satisfied with treatment. IBS affected daily activities in 43% of cases. CONCLUSION: Half of the patients with IBS who consulted a physician received a diagnosis. Awareness and knowledge of diagnostic criteria for IBS differ between SGs and GPs.

Natural history of heartburn: a 10-year population-based study.

AIM: To study the natural history and prevalence of heartburn at a 10-year interval, and to study the effect of heartburn on various symptoms and activities. METHODS: A population-based postal study was carried out. Questionnaires were mailed to the same age- and gender-stratified random sample of the Icelandic population (aged 18-75 years) in 1996 and again in 2006. Subjects were classified with heartburn if they reported heartburn in the preceding year and/or week, based on the definition of heartburn. RESULTS: Heartburn in the preceding year was reported in 42.8% (1996) and 44.2% (2006) of subjects, with a strong relationship between those who experienced heartburn in both years. Heartburn in the preceding week was diagnosed in 20.8%. There was a significant relationship between heartburn, dyspepsia and irritable bowel syndrome. Individuals with a body mass index (BMI) below or higher than normal weight were more likely to have heartburn. Heartburn caused by food or beverages was reported very often by 20.0% of subjects. CONCLUSION: Heartburn is a common and chronic condition. Subjects with a BMI below or higher than normal weight are more likely to experience heartburn. Heartburn has a great impact on daily activities, sleep and quality of life.

[Epidemiological study of functional bowel disorders in Iceland]. / Faraldsfraedileg rannsókn á starfraenum einkennum frá meltingarvegi hjá Islendingum.

OBJECTIVE: The aim of the present study was to evaluate the prevalence of functional bowel disorders (FBD) in a population-based sample and to assess FBD-related health care seeking and medication in Iceland. MATERIAL AND METHODS: A self-report questionnaire was sent to a random sample of 2000 inhabitants, 18-75 years of age. The questionnaire addressed 46 gastrointestinal symptoms and 42 other health related, sociodemographic and psychosomatic symptom items. The questionnaire classified subjects into two symptom categories, dyspepsia and irritable bowel syndrome. RESULTS: The response rate was 67% which represents 1% of the 18-75 year old population of Iceland. Dyspepsia in the year prior to the study was reported by 17.8% who had symptoms that were defined as moderate or severe (15.3% male, 20% female). Based on the Manning Criteria, which define IBS as having two or more abdominal symptoms out of six at least six times in the previous year in addition to abdominal pain, the crude prevalence of IBS was 30.9% (25.3% men, 35.8% women) (Chi2=15.77, p<0.05). Both symptom categories were more common in women and the prevalence decreased with age. No correlation with socioeconomic status was found. There was more than 90% overlap between the two diagnostic categories. Irritable bowel syndrome was found to be associated with depression, appendectomy and dysmenorrhea. CONCLUSIONS: This population-based study shows a high prevalence of functional bowel disorders in Iceland and higher than reported in other studies that use similar criteria. It can be speculated that the reasons for this high prevalence are associated with special features of the socio-psychological profile of the Icelandic society.

[Prevalence of Helicobacter pylori and Cag-A strains in patients with duodenal ulcer in Iceland.].

OBJECTIVE: The prevalence of Helicobacter pylori infection and related gastric diseases is rapidly changing in western societies. H. pylori has been associated with gastritis, gastric and duodenal ulcer and gastric cancer. This association applies in particular to H. pylori strains which are Cag-A positive. H. pylori is naturally disappearing from western populations in particular Cag-A positive strains which are selectively eradicated due to their association with peptic ulcer. The aim of the study was to assess the prevalence of H. pylori in duodenal ulcer disease and its Cag-A status before the eradication of H. pylori was routinely applied. MATERIAL AND METHODS: Antibodies for H. pylori and Cag-A were investigated by Western blot method in serum samples from 62 patients with duodenal ulcer. The samples were collected during the period 1993-1996 and should represent the Cag-A prevalence before it was changed by active eradication. No subject had received H. pylori eradication before the study. RESULTS: Of the 62 samples 54 (87.1%) were positive for H. pylori specific antigen and of the 54 positive samples 53 (98.1%) were positive for Cag-A. CONCLUSION: H. pylori strains associated with duodenal ulcer in Iceland were predominantly (98.1%) Cag-A positive.

Antimitochondrial antibodies and reactivity to N. aromaticivorans proteins in Icelandic patients with primary biliary cirrhosis and their relatives.

OBJECTIVES: Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic disease of unknown etiology characterized by serum antimitochondrial antibodies (AMA) directed against a functionally related family of mitochondrial enzymes. We recently suggested that N. aromaticivorans might be the trigger of autoimmunity in PBC. No data are available on the specificity and crossreactivity of AMA in a genetically homogenous group of patients, such as the Icelandic population. METHODS: To address these issues and to confirm previous findings in a unique population, we obtained sera from 14 PBC patients and 85 first-degree relatives, all of Icelandic descent. We analyzed such sera for AMA specificity using recombinant mitochondrial antigens and for reactivity against N. aromaticivorans proteins. RESULTS: Thirteen of the 14 Icelandic patients with PBC (93%) were found AMA positive. We found that 5/13 AMA positive sera (38%) reacted against PDC-E2 only; 5/13 (or 38%) reacted against BCOADC-E2; and 2/13 (15%) reacted against all three antigens. There was no reactivity against OGDC-E2. Reactivities of patients' sera against N. aromaticivorans were consistent with the AMA status. One serum among the 85 first-degree relatives (1.2%) was found to be AMA-positive, as well as reactive against N. aromaticivorans. CONCLUSIONS: Interestingly, despite the homogenous genetic background, the group of Icelandic patients with PBC was heterogeneous in their AMA reactive patterns and also reacted with N. aromaticivorans proteins.

Subclinical intestinal inflammation: an inherited abnormality in Crohn's disease relatives?

BACKGROUND & AIMS: One approach to unraveling the genetics of complex inherited disease, such as Crohn's disease, is to search for subclinical disease markers among unaffected family members. We assessed the possible presence, prevalence, and inheritance pattern of subclinical intestinal inflammation in apparently healthy relatives of patients with Crohn's disease. METHODS: A total of 49 patients with Crohn's disease, 16 spouses, and 151 (58%) of 260 available first-degree relatives underwent a test for intestinal inflammation (fecal calprotectin concentration). The mode of inheritance was assessed from 36 index patients (by variance component analysis) when more than 50% of relatives were studied. RESULTS: Fecal calprotectin concentrations in patients with Crohn's disease (47 mg/L; confidence interval [CI], 27-95 mg/L) and relatives (11 mg/L; CI, 9-14 mg/L) differed significantly (P < 0.0001) from controls (4 mg/L; CI, 3-5 mg/L), whereas that of the spouses did not (4 mg/L; CI, 3-6 mg/L; P > 0.5). Fecal calprotectin concentration was increased in 49% of all relatives studied. The increased fecal calprotectin concentration among the relatives of the 36 index patients had an inheritance pattern that was most consistent with an additive inheritance pattern. CONCLUSIONS: There is a high prevalence of subclinical intestinal inflammation in first-degree relatives of patients with Crohn's disease that conforms best to an additive inheritance pattern. The genetic basis for this abnormality may represent a risk factor for Crohn's disease.