Addison´s disease : epidemiological and clinical studies

Addison’s disease (AD) is a potentially life-threatening condition that often presents with vague and nonspecific symptoms. Patients with AD have increased mortality risk. Data on parity and pregnancy outcome in women with AD are limited. Furthermore, there are no data on fracture risk or drug prescription patterns in patients with AD. Continuous subcutaneous hydrocortisone infusion (CSHI) is a novel treatment modality, but it has not yet been established whether the circadian hormone profiles and insulin sensitivity differ in patients on CSHI compared with conventional oral hydrocortisone treatment (OHC). The four studies in this thesis aim to enhance knowledge and clinical management of patients with AD. Parity and pregnancy outcome: In all, 1188 women with AD were retrospectively evaluated. Women with AD had a reduced overall parity compared with controls (P < 0.001). Adjusted odds ratios (ORs) (95% confidence interval, CI) for infants born to mothers with deliveries ≤ 3 years before diagnosis of AD were 2.40 (1.27-4.53) for preterm birth, 3.50 (1.83-6.67) for low birth weight and 1.74 (1.02-2.96) for caesarean section. In comparison with controls, women who gave birth after their AD diagnosis were at increased risk for both caesarean delivery (adjusted OR, 2.35, 95% CI; 1.68-3.27) and preterm delivery (adjusted OR, 2.61, 95% CI; 1.69-4.05). No differences were found in risks of congenital malformations or infant death. Hip fracture risk: Totally, 3219 patients with AD were retrospectively evaluated. Patients with AD had a higher risk of hip fracture (hazard ratio, HR 1.8, 95% CI; 1.6-2.1; p < 0.001) than matched controls. The increased risk was independent of age at diagnosis, sex and calendar period. A positive association between hip fracture and undiagnosed AD was noted with the highest risk estimates during the last year before AD diagnosis (OR 2.8, 95% CI; 1.8-4.2). Drug prescription patterns:We identified 1305 patients with both a diagnosis of AD and on combination treatment with hydrocortisone/cortisone acetate and fludrocortisone. The yearly prevalence of AD increased from 12.2 to 13.1 (Pfor trend = .062); incidence varied between 0.5 and 0.6 (Pfor trend = .131) per 100 000 person-years during the period 2005-2009. Patients with AD received more prescribed drugs than controls. Both before and after AD diagnosis, patients used more gastrointestinal medications, antianemic preparations, lipid-modifying agents, antibiotics for systemic use, hypnotics and sedatives and drugs for obstructive airway disease (pvalues < 0.05). Notably, an increased prescription of several antihypertensive drugs and highceiling diuretics was observed after AD diagnosis. Circadian hormone profiles and insulin sensitivity:CSHI provided a more physiological circadian cortisol curve, including a late night cortisol surge, than OHC treatment. CSHI yielded a normalization of adrenocorticotropic hormone (ACTH) levels and showed a more normal circadian variation than OHC. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. The expected growth hormone (GH) peak during nighttime was more pronounced for CSHI, which, together with the higher insulin-like growth factor type 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels, suggest a more anabolic status. Conclusion: This thesis demonstrates that both undiagnosed and diagnosed AD entail increased risks of unfavorable pregnancy outcome, hip fractures and altered drug prescription patterns compared to controls. In addition, parity is reduced in patients diagnosed with AD. This raises concerns about the conventional replacement therapy. CSHI is a safe and reliable mode of glucocorticoid replacement and might become a treatment option in selected patients

Dental health of patients with X-linked hypophosphatemia: A controlled study

ObjectiveThe present study compared the dental health of patients with X-linked hypophosphatemia (XLH) with healthy age- and gender-matched controls to increase our knowledge of the impact of XLH on oral health.Materials and methodsTwenty-two adult patients with XLH in the Stockholm region of Sweden were referred to the Department of Orofacial Medicine at Karolinska Institutet for an extended clinical and radiological examination. Pre-existing radiologic examinations of 44 healthy age- and gender-matched controls were retrieved from the Department of Oral Radiology, at Karolinska Institutet.ResultsThe 22 patients with XLH (15 females, median age 38 years, range 20–71; 7 males, median age 49 years, range 24–67) had a significantly higher number of root-filled teeth compared to healthy controls (p = .001). In the XLH group, females had significantly better oral health than males, especially concerning endodontic and cariological status (p's = .01 and .02, respectively). Periodontal status differed non-significantly between the XLH and control groups.ConclusionPatients with XLH had a significantly lower oral health status compared to a healthy population especially concerning endodontic conditions. Male patients with XLH had a higher risk of poor oral health compared to female patients with XLH

Women With Chronic Hypoparathyroidism Have Low Risk of Adverse Pregnancy Outcomes

Context: There are scarce data on the management of chronic hypoparathyroidism (hypoPT) in pregnant women. Objective: The aim of this study was to evaluate pregnancy outcome and total number of births in maternal chronic hypoPT. Methods: The Swedish National Patient Register, The Swedish Prescribed Drug Register, Swedish Medical Birth Register, and the Total Population Register were used to identify 97 women with chronic hypoPT and 1030 age-matched controls who delivered 139 and 1577 singleton infants, respectively, following diagnosis between 1997 and 2017. Results: Women in the chronic hypoPT group had more frequent diabetes (DM) and chronic kidney disease (CKD) compared with the control group (P = 0.043 and P < 0.001, respectively). After adjusting for DM, CKD, maternal age at delivery, and calendar year of delivery, chronic hypoPT cases were associated with increased risk of induction of labor (OR, 1.82; 95% CI, 1.13-2.94) and birth of infants with lower birth weight (beta-coefficient -188 g; 95% CI, -312.2 to -63.8) compared with controls. No difference was found in infant length, small for gestational age, or head circumference after adjustments. Mean gestational age at delivery after controlling for DM, CKD, and pre-eclampsia was not significantly younger (P = 0.119). There was no difference in congenital malformations or perinatal death and no difference in the total number of infants born between groups (P = 0.518). Conclusion: The majority of women with chronic hypoPT had normal pregnancy outcomes, and the overall risks appear low. Maternal chronic hypoPT is, however, associated with higher risk of induction of labor and slightly lower infant birth weight.Peer reviewe

Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease

Background No reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal. Objective To explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD. Methods Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. Results Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and levels of ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. Conclusions We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.publishedVersio

Discovering gender and inflection. A view from Icelandic

In this dissertation, I investigate the nature of generalizations in grammatical gender and inflectional morphology from a learning perspective. Cross-linguistic differences in children’s learning trajectories have been at the forefront of research on the acquisition of grammatical gender. Transparency has been argued to be predictive of children’s behavior in gender acquisition (Slobin, 1977). Hitherto, however, it has been unclear what it means for a gender system to be either transparent or opaque to the child learner. I argue that in order to get to the root of the cause, a theory of grammatical gender acquisition must explain the conditions under which children generalize in gender assignment – and when these conditions are not met. In a series of corpus studies that approximate a child’s lexical experience in gender acquisition in Icelandic, I formulate predictions for children’s behavior using two contrasting models of productivity, Baayen’s P and P* metrics (1989; 1991; 1993) and Yang’s Tolerance Principle (2005; 2016). These predictions were put to the test in an elicited production task on children and adults with two conditions: Productive and unproductive. I argue that the empirical results demonstrate that children and adults draw a categorical distinction between productive and unproductive processes in gender assignment in Icelandic. I argue that cross-linguistic differences in gender acquisition reflect a learning process that is guided by the search for productive patterns. In two subsequent studies, using the same corpus-based and experimental methods, I investigate how knowledge of gender facilitates the induction of other inflectional forms or vice versa, using plural formation in Icelandic as a test case. Noun pluralization in Icelandic crosscuts both gender and inflection classes, which raises the question of how children can extract the relevant generalizations given syncretism both within and across the inflectional paradigm. I demonstrate how children and adults were at a loss to pluralize nouns that they were unable to assign gender to. In other words, productivity in gender assignment correlates with productivity in plural formation. Since knowledge of gender is contingent on the knowledge of productive nominative singular forms, I propose that gender may be a developmental prerequisite for the acquisition of plural formation in Icelandic due to the statistical primacy of singular forms in the input. I discuss the theoretical implications of the empirical findings, both for language acquisition and for linguistic theory. I propose that an understanding of children’s discovery procedure in acquisition may offer solutions to otherwise intractable problems in linguistic theory. I further propose that learning considerations may shed light on the nature of the variation attested in heritage grammars. In a longitudinal corpus case study, I study how generalizations about gender assignment may undergo change as the result of attrition. I argue that the nature of the changes attested in the corpus as a function of time suggest difficulties with lexical access and retrieval, rather than a systematic re-analysis of the gender system, although the non-target forms are not entirely unconstrained

The Effects of Attrition on Grammatical Gender: A View from North American Icelandic

Heritage grammars have been argued to differ with respect to whether they are an instantiation of divergent attainment or attrition. Attrition and divergent attainment are not mutually exclusive and can even co-exist with respect to the same or different grammatical phenomena, but teasing these apart requires longitudinal studies or carefully selected cross-sectional data (Montrul, 2008; 2016; Polinsky, 2011). In this article we present data from a longitudinal corpus of letters written by a speaker of North American Icelandic over a span of seventy-two years. The earliest letters suggest that the writer acquired Icelandic consistent with the baseline. However, in the last thirty years of writing, non-target forms emerge in the corpus. Morphosyntax, notably grammatical gender and inflectional morphology, is the most affected domain of grammar. In this article we focus on the nature of the changes attested for grammatical gender across time. Our results show that gender assignment does not undergo a systematic re-analysis. However, the non-target gender agreement indicates the overuse of an agreement default, which may reflect a trend towards a systematic reduction of the gender agreement system

A prospective study on insect bite hypersensitivity in horses exported from Iceland into Switzerland

Abstract Background Insect bite hypersensitivity (IBH) is an IgE-mediated dermatitis caused by bites of Culicoides spp., which occurs frequently in horses imported from Iceland to continental Europe. IBH does not occur in Iceland because Culicoides species that bite horses are not present. However, Simulium vittatum (S. vittatum) are found in Iceland. In Europe, blood basophils from IBH-affected horses release significantly more sulfidoleukotrienes (sLT) than those from healthy controls after in vitro stimulation with Culicoides nubeculosus (C. nubeculosus) and S. vittatum. Aims of the study were: (I) using the sLT release assay, to test if horses living in Iceland were sensitized to S. vittatum and (II) to determine in a longitudinal study in horses imported from Iceland to Switzerland whether the sLT release assay would allow to predict which horses would develop IBH. Results Horses in Iceland, even when living in high S. vittatum areas, were usually not sensitized to S. vittatum or C. nubeculosus. Incidence of IBH in the 145 horses from the longitudinal study was 51% and mean time until IBH developed was 2.5 ± 1 year. Before import and after the first summer following import, there were no significant differences in sLT release between the endpoint healthy (H) and IBH groups. After the 2nd summer, when the number of clinically affected horses increased in the endpoint IBH group, a significantly higher sLT release after stimulation with C. nubeculosus but not with S. vittatum was observed. After the 3rd and 4th summer, the endpoint IBH group had a significantly higher sLT release with C. nubeculosus and S. vittatum than the endpoint H group. Some of the horses that remained healthy became transiently positive in the sLT release assay upon stimulation of their peripheral blood leucocytes with C. nubeculosus. Conclusions Horses in Iceland are not sensitized to S. vittatum. In horses that develop IBH, sensitization to S. vittatum is secondary to sensitization to C. nubeculosus and probably a result of an immunological cross-reactivity. A sLT release assay cannot be used to predict which horses will develop IBH. A transient positive reaction in the sLT release assay observed in horses that remained healthy suggests that immunoregulatory mechanisms may control an initial sensitization of the healthy horses

Dental health of patients with X-linked hypophosphatemia : A controlled study

ObjectiveThe present study compared the dental health of patients with X-linked hypophosphatemia (XLH) with healthy age- and gender-matched controls to increase our knowledge of the impact of XLH on oral health.Materials and methodsTwenty-two adult patients with XLH in the Stockholm region of Sweden were referred to the Department of Orofacial Medicine at Karolinska Institutet for an extended clinical and radiological examination. Pre-existing radiologic examinations of 44 healthy age- and gender-matched controls were retrieved from the Department of Oral Radiology, at Karolinska Institutet.ResultsThe 22 patients with XLH (15 females, median age 38 years, range 20-71; 7 males, median age 49 years, range 24-67) had a significantly higher number of root-filled teeth compared to healthy controls (p = .001). In the XLH group, females had significantly better oral health than males, especially concerning endodontic and cariological status (p's = .01 and .02, respectively). Periodontal status differed non-significantly between the XLH and control groups.ConclusionPatients with XLH had a significantly lower oral health status compared to a healthy population especially concerning endodontic conditions. Male patients with XLH had a higher risk of poor oral health compared to female patients with XLH.Peer reviewe

Kidney complications and hospitalization in patients with chronic hypoparathyroidism: A cohort study in Sweden

Context: Kidney complications may be considerably higher in patients with chronic hypoparathyroidism (hypoPT) treated with activated vitamin D and calcium supplementation. Objective: We aimed to investigate the risk of chronic kidney disease (CKD), urolithiasis, and hospitalization in patients with chronic hypoPT. Methods: In this population-based cohort study in Sweden, national registries (Swedish National Patient Register, Swedish Prescribed Drug Register, and Total Population Register, 1997–2018) were used to identify patients with chronic hypoPT and controls matched by sex, age, and county of residence. We determined time to CKD and urolithiasis diagnosis, and incidence rates of hospitalization. Results: A total of 1562 patients with chronic hypoPT without preexisting CKD and 15 620 controls were included. The risk of developing CKD was higher in patients with chronic hypoPT compared with controls (hazard ratio [HR] 4.45; 95% CI, 3.66-5.41). In people without prior urolithiasis (n = 1810 chronic hypoPT and n = 18 100 controls), the risk of developing urolithiasis was higher in patients with chronic hypoPT (HR 3.55; 95% CI, 2.84-4.44) compared with controls. Patients with chronic hypoPT had higher incidence rates for all-cause hospitalization (49.59; 95% CI, 48.50-50.70, per 100 person-years vs 28.43; 95% CI, 28.15-28.71, respectively) and for CKD (3.46; 95% CI, 3.18-3.76, per 100 person-years vs 0.72; 95% CI, 0.68–0.77, respectively), compared with controls. Men with hypoPT appear to have a higher risk of CKD than women. Conclusion: Patients with chronic hypoPT had an increased risk of CKD, urolithiasis, and hospitalization compared with controls.publishedVersio

Continuous Subcutaneous Hydrocortisone Infusion versus Oral Hydrocortisone Replacement for Treatment of Addison’s Disease: A Randomized Clinical Trial

Context: Conventional glucocorticoid replacement therapy fails to mimic the physiological cortisol rhythm, which may have implications for morbidity and mortality in patients with Addison’s disease. Objective: The objective of the study was to compare the effects of continuous sc hydrocortisone infusion (CSHI) with conventional oral hydrocortisone (OHC) replacement therapy. Design, Patients, and Interventions: This was a prospective crossover, randomized, multicenter clinical trial comparing 3 months of treatment with thrice-daily OHC vs CSHI. From Norway and Sweden, 33 patients were enrolled from registries and clinics. All patients were assessed at baseline and after 8 and 12 weeks in each treatment arm. Main Outcome Measures: The morning ACTH level was the primary outcome measure. Secondary outcome measures were effects on metabolism, health-related quality of life (HRQoL), sleep, and safety. Results: CSHI yielded normalization of morning ACTH and cortisol levels, and 24-hour salivary cortisol curves resembled the normal circadian variation. Urinary concentrations of glucocorticoid metabolites displayed a normal pattern with CSHI but were clearly altered with OHC. Several HRQoLindices in the vitality domain improved over time with CSHI.Nobenefit was found for either treatments for any subjective (Pittsburgh Sleep Quality Index questionnaire) or objective (actigraphy) sleep parameters. Conclusion: CSHI safely brought ACTH and cortisol toward normal circadian levels without adversely affecting glucocorticoid metabolism in the way that OHC did. Positive effects on HRQoL were noted with CSHI, indicating that physiological glucocorticoid replacement therapy may be beneficial and that CSHI might become a treatment option for patients poorly controlled on conventional therapy