Miklós Szathmári

Has there been a change in the natural history of Crohn's disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009

OBJECTIVES:Medical therapy for Crohns disease (CD) has changed significantly over the past 20 years with increasing use of immunosuppressives. In contrast, surgery rates are still high and there is little evidence that disease outcomes for CD have changed over the past decades. The objective of this study was to analyze the evolution of the surgical rates and medical therapy in the population-based Veszprem province database.METHODS:Data of 506 incident CD patients were analyzed (age at diagnosis: 31.5 years, s.d. 13.8 years). Both hospital and outpatient records were collected and comprehensively reviewed. The study population was divided into three groups by the year of diagnosis (cohort A: 1977–1989, cohort B: 1990–1998 and cohort C: 1999–2008).RESULTS:Overall, azathioprine (AZA), systemic steroid, and biological (only available after 1998) exposure was 45.8, 68.6, and 9.5%, respectively. The 1- and 5-year probability of AZA use were 3.2 and 6.2% in cohort A, 11.4 and 29.9% in cohort B, and 34.8 and 46.2% in cohort C. In a multivariate Cox-regression analysis, decade of diagnosis (P<0.001, hazard ratio (HR)cohorts B−C: 2.88–6.53), age at onset (P=0.008, HR: 1.76), disease behavior at diagnosis (P<0.001, HRcomplicated: 1.76–2.07), and need for systemic steroids (P<0.001, HR: 2.71) were significantly associated with the time to initiation of AZA therapy. Early AZA use was significantly associated with the time to intestinal surgery in CD patients; in a multivariate Cox analysis (HR: 0.43, 95% confidence interval (CI): 0.28–0.65) and after matching on propensity scores for AZA use (HR: 0.42, 95% CI: 0.26–0.67).CONCLUSIONS:This population-based inception cohort has shown that the recent reduction in surgical rates was independently associated with increased and earlier AZA use.

Bone mineral density in patients with endogenous subclinical hyperthyroidism: Is this thyroid status a risk factor for osteoporosis?

OBJECTIVE The aim of the present study was to elucidate whether endogenous subclinical hyperthyroidism due to a solitary autonomously functioning thyroid nodule affects bone metabolism and is a risk factor for osteoporosis. DESIGN In a cross‐sectional study measurements of bone mineral density were performed in premenopausal and post‐menopausal women. Patients were categorized into non‐toxic nodular goitre (n= 32), subclinical hyperthyroid (n= 37) and toxic solitary autonomous thyroid nodule (n= 22) subgroups and the results were compared with those of sex and age‐matched control reference population (n= 68).

Altered Bone Metabolism in Inflammatory Bowel Disease

UNLABELLED A reduced bone mineral density has been reported in inflammatory bowel disease (IBD). OBJECTIVE To assess the mechanisms of bone disease in IBD. METHODS We studied in 90 patients (61 with Crohns disease, 22 with ulcerative colitis, 7 with indeterminate colitis) biochemical markers of bone metabolism in serum and bone mineral density by peripheral quantitative computed tomography at the forearm. RESULTS Forty-five percent of the patients had a reduced bone density (Z score 5 microg/L; mean, 12.9 +/- 4.7 microg/L). Data derived from a retrospective survey of 245 patients with IBD suggest that the prevalence of bone fractures in IBD is unexpectedly high, particularly in patients with a long duration of disease, frequent active phases, and high cumulative doses of corticosteroid intake. CONCLUSIONS Several mechanisms may be involved in IBD-associated bone disease: (1) a high inflammatory activity directly induces bone degradation via yet unknown pathways, (2) treatment with corticosteroids may exert catabolic effects on the bone, or (3) malabsorption and vitamin D deficiency may activate bone turnover.

Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn's disease

Aliment Pharmacol Ther 2011; 34: 911–922

Genetic Variants of TNF-α, IL-1β, IL-4 Receptor α-Chain, IL-6 and IL-10 Genes Are Not Risk Factors for Sepsis in Low-Birth-Weight Infants

The amount of inflammatory cytokines is a major determinant for the development of sepsis in very-low-birth-weight (VLBW) neonates. We investigated whether variants of tumor necrosis factor-α, interleukin (IL)-1β, IL-4 receptor α-chain, IL-6 and IL-10 genes, associated with altered cytokine production, might influence the risk and complications of sepsis in VLBW infants. We determined the presence of these genetic variants in dried blood samples of 33 septic, 35 infected and 35 healthy VLBW neonates by PCR and RFLP methods and analyzed their association with the risk and complications of sepsis. The frequencies of genetic variants did not differ in uninfected and in infected infants with or without sepsis. Moreover, none of the studied complications was associated with carrier state of any of genetic variants. Four of the 5 septic neonates with disseminated intravascular coagulation, however, carried simultaneously the variants of IL-1β and IL-10 genes. We concluded that these genetic polymorphisms do not influence the risk and course of sepsis in VLBW neonates.

Is Current smoking still an important environmental factor in inflammatory bowel diseases? Results from a population-based incident cohort

Background:Previous studies suggest that smoking is an important environmental factor in inflammatory bowel diseases (IBDs), with dichotomous effects in ulcerative colitis (UC) and Crohns disease (CD). The aim of this study was to analyze the relationship between smoking and IBD risk in a population-based database from Veszprem Province, which included incident cases diagnosed between January 1, 1977, and December 31, 2008. Methods:Data from 1420 incident patients were analyzed (UC: 914, age at diagnosis: 38.9 years; CD: 506, age at diagnosis: 31.5 years). Both inpatient and outpatient records were collected and comprehensively reviewed. Overall, smoking frequency in the adult general population was 36.1%. Results:Of patients with CD, 47.2% were current smokers at diagnosis. Smoking was more frequent in male patients (P = 0.002) and was associated with an increased risk of CD (odds ratio, 1.96; 95% confidence interval, 1.63–2.37; P < 0.001). In contrast, current smoking was protective against UC (odds ratio, 0.33; 95% confidence interval, 0.27–0.41). The effect of smoking was linked to gender (in CD, more deleterious in male patients) and age at diagnosis and was most prominent in young adults, with a difference already being seen in 18- to 19-year-olds. In CD, a change in disease behavior (P = 0.02), location from ileal or colonic to ileocolonic (P = 0.003), arthritis/arthropathy (P = 0.002), need for steroids (P = 0.06), or AZA (P = 0.038) was more common in current smokers. Smoking in UC was associated with more extensive disease (P = 0.01) and a tendency for decreased need for colectomy (P = 0.06). Conclusions:Current smoking was associated with the risk of IBD. This effect was linked to gender and age at diagnosis and was most prominent in young adults. No association was observed in pediatric or elderly patients. The deleterious and protective effects of smoking on the course in CD and UC were partially confirmed.

Serum osteoprotegerin level, carotid-femoral pulse wave velocity and cardiovascular survival in haemodialysis patients

BACKGROUND Osteoprotegerin (OPG) is a marker and regulator of arterial calcification, and it is related to cardiovascular survival in haemodialysis patients. The link between OPG and aortic stiffening--a consequence of arterial calcification--has not been previously evaluated in this population, and it is not known whether OPG-related mortality risk is mediated by arterial stiffening. METHODS At baseline, OPG and aortic pulse wave velocity (PWV) were measured in 98 chronic haemodialysis patients who were followed for a median of 24 months. The relationship between OPG and PWV was assessed by multivariate linear regression. The role of PWV in mediating OPG related cardiovascular mortality was evaluated by including both OPG and PWV in the same survival model. RESULTS At baseline mean (standard deviation) PWV was 11.2 (3.3) m/s and median OPG (interquartile range) was 11.1 (7.5-15.9) pmol/L. There was a strong, positive, linear relationship between PWV and lnOPG (P = 0.009, model R(2) = 0.540) independent of covariates. During follow-up 23 patients died of cardiovascular causes. In separate univariate survival models both PWV and lnOPG were related to cardiovascular mortality [hazard ratios 1.31 (1.14-1.50) and 8.96 (3.07-26.16), respectively]. When both PWV and lnOPG were entered into the same model, only lnOPG remained significantly associated with cardiovascular mortality [hazard ratio 1.11 (0.93-1.33) and 7.18 (1.89-27.25), respectively). CONCLUSION In haemodialysis patients OPG is strongly related to PWV and OPG related cardiovascular mortality risk is, in part, mediated by increased PWV.

Bone mineral density and bone acquisition in children and young adults with cystic fibrosis: a follow-up study.

Objective: To investigate bone mineral density and bone homeostasis in cystic fibrosis (CF) and to assess changes in a 2-year period. Methods: Thirty-eight patients with clinically stable CF (11 children, 16 adolescents, 11 young adults) were enrolled. No patient was treated with corticosteroids before or during the study. Weight and height Z scores and bone mineral density (BMD) Z-score at the femoral neck and the lumbar spine were recorded at the beginning of the study and after 2 years. Osteocalcin and cross-link excretion, both measurements of bone turnover were also measured. Correlations between BMD, bone turnover parameters, disease severity, pubertal stage, and nutritional state were calculated. The maternal BMD was also determined and related to that of the child. Results: Height and weight Z scores were normal in children and below normal in adolescents. Puberty was delayed in most patients. Bone age was lower than chronological age in adolescents. Lumbar spine and femoral neck BMD Z scores were below normal in each age group. Disease severity determined by Schwachman score correlated with lumbar BMD (r = 0.45, P < 0.02). BMD Z scores did not change during 2 year follow-up. Maternal and patient lumbar and femoral BMD correlated significantly (r = 0.51, P < 0.01, and r = 0.54, P < 0.01, respectively). Conclusions: Bone deficit is present in patients with CF who have never received steroid treatment. Delay of puberty, chronic inflammation, or genetic susceptibility might be responsible for this phenomenon which was found in patients who had never received steroids and who were in relatively good clinical state.

Bone mineral content and density in asymptomatic children with coeliac disease on a gluten-free diet

Objectives Osteoporosis is a complication of coeliac disease. A gluten-free diet improves but does not normalize bone mineral density in adult patients. Only limited data are available regarding the influence of the disease and diet on bone mineralization in children. The aim of this study was to evaluate the radial bone mineral content and density in children and adolescents who are asymptomatic on a gluten-free diet. Subjects and methods The bone mineral content (BMC) and density (BMD) values of the non-dominant radius mid-shaft in 91 children (53 girls, 38 boys, mean age 11.7 years, mean duration of disease 8.7 years) were determined by single-photon absorptiometry. At the diagnosis and at least three years after commencement of a gluten-free diet, serum calcium, phosphorus, albumin concentrations and alkaline phosphatase activities were measured in all patients, and intact parathormone concentrations in 16 patients. Results The mean BMC Z-score value in the female adolescent group only was significantly lower than normal (mean Z-score –1.04, P < 0.01). In contrast, the mean BMD Z-score was significantly higher compared to a healthy population both in girls (mean Z-score +1.36, P < 0.001) and in boys (mean Z-score +0.53, P < 0.02), as well as in the total patient group (mean Z-score +1.01, P < 0.001). The radial diameter was significantly smaller than normal in both pre-pubertal and adolescent groups. Serum laboratory parameters of asymptomatic patients were in the normal range. The parathormone mean value was significantly lower after at least three years of gluten-free diet than at diagnosis (mean ± SD 3.77 ± 1.07 versus 7.89 ± 2.54 pmol/l, P < 0.01), but significantly higher compared to controls (2.89 ± 0.90 pmol/l, P < 0.05). Conclusions These data indicate that treated, asymptomatic coeliac children and adolescents have normal or even higher radius mineral density values than controls, but the bone size remains reduced. Although there is no direct evidence of calcium malabsorption in this cohort of coeliac patients, the slightly higher parathormone levels, together with some other factors, particularly delayed puberty, may result in reduced bone size.

Dehydroepiandrosterone sulphate and bone mineral density

Several series of data suggest that alterations in adrenal androgen output might be a contributing factor to changes in bone mass. To study the possible relationship between bone density and serum levels of dehydroepiandrosterone sulphate (DHEAS) we investigated 105 women (aged 45–69 years; 76 postmenopausal, 29 perimenopausal). The patients were divided into two groups according to the bone mineral density (BMD) measurement (normal densityn=50, low densityn=55). BMD was measured by dual-energy X-ray absorptiometry of the lumbar spine and femoral neck. Bone mineral content (BMC) of the radius midshaft was measured by single photon absorptiometry. Serum DHEAS level was significantly lower in the ‘low density’ group than in the ‘normal’ one (1.91±1.04 v 4.77±2.03 µmol/l,p<0.001). The serum DHEAS level decreased significantly with age in both groups (r=0.43,p<0.001 in the ‘normal’ group;r=0.35,p<0.01 in the ‘low density’ group). Unlike the slopes, the positions of the regression lines differed significantly (difference 2.85 µmol/1,p<0.001). Correcting for age by multiple linear regression we established a significant positive relationship between DHEAS and BMD of the lumbar spine and femoral neck, and BMC of radius midshaft as well. Since there was no significant difference between the two groups regarding oestrogens, we suggest that DHEAS may have a non-oestrogenic effect on bone. The odds ratio of a subject with a low (<3.3 µmol/l) serum DHEAS level having low BMD was 40 (confidence interval 13–126). We conclude that serum DHEAS may be a useful indicator of low BMD in peri- and postmenopausal women.