Bjarni Thjodleifsson

A simple method for assessing intestinal inflammation in Crohn's disease

BACKGROUND AND AIMS Assessing the presence and degree of intestinal inflammation objectively, simply, and reliably is a significant problem in gastroenterology. We assessed faecal excretion of calprotectin, a stable neutrophil specific marker, as an index of intestinal inflammation and its potential use as a screening test to discriminate between patients with Crohns disease and those with irritable bowel syndrome. METHODS The validity of faecal calprotectin as a marker of intestinal inflammation was assessed in 22 patients with Crohns disease (35 studies) by comparing faecal excretions and concentrations using four day faecal excretion of111indium white cells. A cross sectional study assessed the sensitivity of faecal calprotectin concentration for the detection of established Crohns disease (n=116). A prospective study assessed the value of faecal calprotectin in discriminating between patients with Crohns disease and irritable bowel syndrome in 220 patients referred to a gastroenterology clinic. RESULTS Four day faecal excretion of 111indium (median 8.7%; 95% confidence interval (CI) 7–17%; normal <1.0%) correlated significantly (p<0.0001) with daily (median ranged from 39 to 47 mg; normal <3 mg; r=0.76–0.82) and four day faecal calprotectin excretion (median 101 mg; 95% CI 45–168 mg; normal <11 mg; r=0.80) and single stool calprotectin concentrations (median 118 mg/l; 95% CI 36–175 mg/l; normal <10 mg/l; r=0.70) in patients with Crohns disease. The cross sectional study showed a sensitivity of 96% for calprotectin in discriminating between normal subjects (2 mg/l; 95% CI 2–3 mg/l) and those with Crohns disease (91 mg/l; 95% CI 59–105 mg/l). With a cut off point of 30 mg/l faecal calprotectin has 100% sensitivity and 97% specificity in discriminating between active Crohns disease and irritable bowel syndrome. CONCLUSION The calprotectin method may be a useful adjuvant for discriminating between patients with Crohns disease and irritable bowel syndrome.

Large-scale whole-genome sequencing of the Icelandic population

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

Prevalence and Mechanism of Nonsteroidal Anti-Inflammatory Drug–Induced Clinical Relapse in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMS It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS First, patients with quiescent Crohns disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.

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 Crohns 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 Crohns disease. METHODS A total of 49 patients with Crohns 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 Crohns 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 Crohns disease that conforms best to an additive inheritance pattern. The genetic basis for this abnormality may represent a risk factor for Crohns disease.

C reactive protein levels are increased in non-allergic but not allergic asthma: a multicentre epidemiological study

Background: High sensitivity C reactive protein (HsCRP) is an inflammatory marker known to be related to smoking, obesity, and cardiovascular disease. A study was undertaken to determine whether HsCRP is related to respiratory symptoms, asthma, atopy, and bronchial hyperresponsiveness in population samples from three countries. Methods: HsCRP was measured in 1289 subjects from three centres in ECRHS II: Reykjavik, Uppsala and Tartu. The HsCRP values ranged from <0.01 mg/l to 70.0 mg/l and were divided into four equal groups (⩽0.45, 0.46–0.96, 0.97–2.21, and >2.21 mg/l). Results: HsCRP increased with increasing body mass index (r = 0.41; p<0.0001) and was higher in smokers than in never smokers (p = 0.02). A significant relationship was found between increased HsCRP levels and respiratory symptoms such as wheeze, attacks of breathlessness after effort, and nocturnal cough (p<0.0001). The crude odds ratio (95% CI) for the probability of non-allergic asthma was 3.57 (1.83 to 6.96) for subjects in the 4th quartile compared with the 1st quartile of HsCRP. This association remained significant after adjusting for study centre, age, sex, body weight, and smoking history (OR 2.19 (95% CI 1.04 to 4.63)). No significant relationship was observed between HsCRP and allergic asthma or bronchial responsiveness. Conclusions: Raised levels of HsCRP are significantly associated with respiratory symptoms and non-allergic asthma but not with allergic asthma.

Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen

BACKGROUND Selective inhibitors of cyclooxygenase (COX)-2 may provoke less gastric damage and platelet inhibition than conventional non-steroidal anti-inflammatory drugs. AIMS We compared the biochemical and gastrointestinal effects of nimesulide, a potent and selective COX-2 inhibitor, with naproxen which exhibits no selectivity. SUBJECTS Thirty six healthy volunteers were randomised to nimesulide 100 mg or naproxen 500 mg twice daily for two weeks in a double blind, crossover study with a washout between treatments. METHODS Gastrointestinal side effects were assessed by endoscopy, and by estimation of small intestinal absorption-permeability and inflammation. Comparisons were made between variables at the end of each treatment phase. RESULTS Nimesulide caused significantly less gastric injury using the modified Lanza score (p<0.001) as well as reduced duodenum injury (p=0.039). Nimesulide had lower visual analogue scores (VAS) for haemorrhage and erosive lesions in the stomach (p<0.001) and for mucosal injection in the duodenum (p=0.039). Naproxen increased excretion of calprotectin, a marker of intestinal inflammation (5.5 (1.2) to 12.1 (2.1) mg/l) while nimesulide had no effect (treatment difference p=0.03). Naproxen abolished platelet aggregation to arachidonic acid and suppressed serum thromboxane B2 (TXB2) by 98%, indices of COX-1 activity. In contrast, nimesulide had no significant effect on platelet aggregation, although it reduced serum TXB2 by 29%. Production of prostaglandin E2 and prostacyclin by gastric biopsies, also COX-1 dependent, was inhibited by naproxen, but not by nimesulide. COX-2 activity, determined as endotoxin induced prostaglandin E2 formation in plasma, was markedly suppressed by both treatments. INTERPRETATION Nimesulide has preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses and induces less gastrointestinal damage than that seen with naproxen in the short term.

A randomized, double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years

Background : Gastro‐oesophageal reflux disease has a chronic course, and often requires long‐term treatment. Proton pump inhibitors are the treatment of choice for both acute and maintenance treatment, but little is known from randomized controlled trials of their effects beyond 1 year.

Seroprevalence of Toxoplasma gondii in Sweden, Estonia and Iceland.

Toxoplasmosis is a disease caused by the intracellular protozoan parasite, Toxoplasma gondii which infects up to one-third of the world human population. Toxoplasmosis in neonates and immunocompromized patients can lead to severe disease and death. We investigated the prevalence and risk factors for T. gondii infection in Iceland, Sweden and Estonia, and tested the hypothesis that T. gondii infection causes systemic inflammation and protects against atopy. Blood samples were collected from 1277 randomly selected subjects. The presence of T. gondii IgG antibodies was determined by an ELISA method and levels of Hs-CRP by immunoturbidimetric assay. The prevalence of T. gondii antibodies was 54.9% in Tartu, 23% in Uppsala and 9.8% in Reykjavik (p<0.0001). The risk of positive T. gondii antibodies increased with the number of siblings and with age in Sweden. T. gondii infection was associated with asthma related symptoms and increased Hs-CRP (p = 0.02). No association was found with IgE-sensitization and lung function. We concluded that risk factors for T. gondii infection suggested that soil exposure was 1 of the mechanisms in all 3 countries and a meat-associated infection route is a risk in Sweden.

Seroprevalence of Helicobacter pylori and cagA antibodies in Iceland, Estonia and Sweden

The public health implications from H. pylori infection are considerable but the transmission routes are largely unknown. In this study, the prevalence, patient characteristics and risk factors for Helicobacter pylori infection were comparatively investigated in Iceland, Sweden and Estonia. Blood samples were collected from 1046 subjects aged≈25–50 y (447 in Reykjavik, 359 in Uppsala and 240 in Tartu) for determination of antibodies to H. pylori and its cagA protein. The prevalence of H. pylori antibodies was 69% in Tartu, 36% in Reykjavik and 11% in Uppsala (p<0.0001). There was an increase in prevalence with age in Iceland and Sweden but not in Estonia. The prevalence of antibodies to the cagA protein in subjects seroreactive to H. pylori was lower in Reykjavik (36%) than in Uppsala (69%) and Tartu (62%) (p<0.0001). H. pylori infection, as determined by seroreactivity, was positively associated with smoking and BMI. Overall, socioeconomic development during the childhood period seems to be the most important factor for the prevalence of H. pylori infection. In adults, smoking may be a contributory factor

Prevalence of iron deficiency and iron overload in the adult icelandic population

The aim of this cross-sectional study was to estimate the prevalence of iron deficiency and overload in the adult population in Iceland, a developed Scandinavian country. The study population consisted of 4240 individuals aged 25-74 years randomly selected from the national roster. Basic hematological, S-iron, S-total iron binding capacity (TIBC), and S-ferritin measurements were obtained on 2588 individuals (61.0%). The results indicated unusually large iron stores in the adult Icelandic population and significantly larger iron stores in the rural compared to the urban population. Iron deficiency was rare except in urban premenopausal women, where 1 in 4 showed evidence of iron deficiency and 3.2% had iron deficiency anemia. Seven patients with hereditary hemochromatosis were identified from a subgroup of 1887 subjects, resulting in a prevalence of 0.37%. Two of the hereditary hemochromatosis patients had been gastrectomized. Measures to improve the iron balance in urban premenopausal women cannot therefore include increased iron fortification of food but must be more directed towards the target group.