This project was undertaken with the aim of developing a method for the assay of iodoamino acids in human serum. The iodoamino acids were separated by an ion exchange technique, and the resulting solutions analyzed for iodine using neutron activation analysis. This analytical system was applied to the analysis.of a number of serum samples from hypothyroid and hyperthyroid subjects. This allowed the division of each of these conditions into a number of classes in terms of the deviation of the individual iodoamino acid concentration from their normal ranges. / Thesis / Doctor of Philosophy (PhD)

Individuals with chronic medical conditions are at an increased risk for adverse reproductive and perinatal outcomes. However, there is limited condition-specific information on the reproductive and perinatal implications of chronic conditions and their associated treatments. In this dissertation, we focus on thyroid disorders and migraines, two relatively common chronic conditions among females of reproductive age, and three distinct reproductive outcomes, spanning from preconception to delivery. In study one, we analyzed the association between thyroid disorders and fecundability, the per-cycle probability of conception among non-contracepting couples, using data from Pregnancy Study Online (PRESTO), a preconception cohort study of pregnancy planners in the United States and Canada. We did not find an association between a diagnosis of hypothyroid, hyperthyroid, thyroid autoimmunity, or thyroid nodules/thyroid cancer and fecundability. We also found no association between thyroid medication use or non-use among individuals with a thyroid disorder and fecundability. In the second study, we focused on migraines and spontaneous abortion (SAB), which is pregnancy loss before twenty weeks gestation, also using PRESTO data. We found that a history of migraines is not independently associated with SAB risk in females, but that routine use of medication for migraines during the preconception period may be associated with an increased risk of SAB. In the third study, we focused on the association between migraines and hypertensive disorders of pregnancy (HDOP), which include gestational hypertension and preeclampsia. We used data from the Clinical Practice Research Datalink Gold, a longitudinal database of de-identified patient records from hundreds of primary care practices in the United Kingdom. We found that while migraines overall are associated with a small increase in risk of HDOP, this increase is most substantial among those with pre-pregnancy migraines that persist in the first trimester of pregnancy. Overall, we observed that while a history of diagnosed thyroid disorder or migraines ascertained via self-report during the preconception period may not be associated with the reproductive and perinatal outcomes we studied, certain subgroups of individuals with migraines may be at increased risk of SAB or HDOP. Migraine severity and persistence in the first trimester are likely important factors in determining the magnitude of this increased risk. Nuanced research into chronic conditions with a disproportionate disease burden among females of reproductive age will guide and improve reproductive health care for individuals with chronic conditions. This dissertation aims to address these gaps in the literature by exploring the relationship between two chronic conditions and three reproductive and perinatal outcomes: thyroid disorders and fecundability, migraines and spontaneous abortion, and migraines and hypertensive disorders of pregnancy. / 2023-04-20T00:00:00Z

Hypertension is associated with end organ damage (EOD). Since EOD is a risk factor for cardio- and cerebrovascular complications, it is a major requirement for these to be detected, prevented and treated. A total of 147 consecutive patients with newly-diagnosed essential hypertension and attending the outpatient clinic were included in this study based on a set of inclusion and exclusion criteria (patients with co-morbid illnesses were excluded from the investigation). Among them, 86% (70 male (M) and 56 female (F)) had one or more EODs, an observation which was very close to statistically significance (P=0.054). The presence of one or more EODs in newly-detected hypertension indicates widespread vascular damage which carries the high risk for cardio- and cerebrovascular morbidity and mortality. Although thyroid dysfunctions exert significant effects on blood pressure (BP), published literature available has revealed contradictory data. Objective of our study was to explore the inter-relationships between selected thyroid dysfunctional status (hyper and hypothyroid) and established biomarkers [thyroid stimulating hormone (TSH) and thyroxine (T4)]; and BP components [specifically Systolic BP (SBP), Diastolic BP (DBP), and Mean Arterial Pressure (MAP), and uniquely SBP:DBP ratio]. We followed rigid criteria in order to select adults with hyperthyroidism (n=71) and hypothyroidism (n=300), together with healthy age-matched controls (n =300), and applied a series of statistical analyses on the datasets acquired. We have observed thyroid dysfunctional status is associated with elevated BP, and increasing BP is positively-correlated with elevated serum thyroid biomarkers, hyper and hypothyroid disorders should be recognized and treated early in order to avoid critical hazards presented by high BP. Also, we have studied awareness among public and physicians in managing hypertension. Overall, the levels of knowledge and awareness among both groups are sub-optimal. Hence there is an urgent need for empowerment among both groups to enhance awareness and to bring effective standard of care.

The aetiology of autoimmune disease is a complex interplay between genetics, environment and immunological regulation. Our understanding of the genetic aspects of autoimmunity has increased with recent findings from Genome Wide Association Studies (GWAS). There is now a movement towards meta-analyses of GWA studies in order to increase the number of genetic loci detected. There are also efforts to detect common genetic risk factors amongst groups of diseases that potentially share common aetiopathogenic pathways. Animal models have formed the basis of many genetic discoveries and the domestic dog presents a spontaneous model for many diseases, including autoimmunity. Through man’s efforts to create specific breeds, the dog has acquired a genomic architecture consisting of long haplotype blocks and extensive linkage disequilibrium. This means that a GWAS can be conducted in dog breeds with fewer samples and fewer markers than an equivalent study in humans, reducing costs, cohort collection times, and data handling/storage considerations. Successful canine GWA studies are now starting to be published. Building upon this success, the findings from GWA studies in three canine autoimmune diseases (across six different breeds), with equivalent human pathologies, are presented. Dogs with diabetes mellitus (similar to latent autoimmune diabetes of adulthood in man), lymphocytic thyroiditis (similar to Hashimoto’s thyroiditis), and anal furunculosis (similar to perianal Crohn’s disease) were compared to control dogs to identify genetic susceptibility loci underlying disease. Follow-up genotyping of the top hits from the GWAS analyses were conducted to replicate findings and to better characterise the diseases across a number of dog breeds. Typing of MHC class II genes, important in the immune response, was also undertaken in canine diabetes mellitus and canine lymphocytic thyroiditis. In anal furunculosis, high-throughput, next-generation sequencing was utilised to identify novel mutations and fine-map associations at discovered loci. Several genes were identified in all of these canine autoimmune diseases, many with good candidate function. Some of these genes indicated common genetic susceptibility loci and pathways between canine autoimmune diseases. Breed-specific genetic effects underlying canine diabetes mellitus and canine lymphocytic thyroiditis were identified, which has implications for disease diagnosis and clinical management. Novel loci for investigation in the corresponding human disease studies have been identified and future work will begin to genetically link the conditions in dog and man.