Contemporary Medical Management of Primary Hyperparathyroidism:A Systematic Review

IntroductionPrimary hyperparathyroidism is increasingly an asymptomatic disease at diagnosis, but the recognized guidelines for management are based on evidence obtained from studies on patients with symptomatic disease, and surgery is not always indicated. Other patients are unable to undergo surgery, and thus a medical treatment is warranted. This systematic review provides an overview of the existing literature on contemporary pharmaceutical options available for the medical management of primary hyperparathyroidism.MethodsDatabases of medical literature were searched for articles including terms for primary hyperparathyroidism and each of the included drugs. Data on s-calcium, s-parathyroid hormone, bone turnover markers, bone mineral density (BMD) and hard endpoints were extracted and tabulated, and level of evidence was determined. Changes in s-calcium were estimated and a meta-regression analysis was performed.ResultsThe 1,999 articles were screened for eligibility and 54 were included in the review. Weighted mean changes calculated for each drug in s-total calcium (mean change from baseline ± SEM) were pamidronate (0.31 ± 0.034 mmol/l); alendronate (0.07 ± 0.05 mmol/l); clodronate (0.20 ± 0.040 mmol/l); mixed bisphosphonates (0.16 ± 0.049 mmol/l); and cinacalcet (0.37 ± 0.013 mmol/l). The meta-analysis revealed a significant decrease of effect on s-calcium with time for the bisphosphonates (Coef. −0.049 ± 0.023, p = 0.035), while cinacalcet proved to maintain its effect on s-calcium over time. Bisphosphonates improved BMD while cinacalcet had no effect.DiscussionThe included studies demonstrate advantages and drawbacks of the available pharmaceutical options that can prove helpful in the clinical setting. The great variation in how primary hyperparathyroidism is manifested requires that management should rely on an individual evaluation when counseling patients. Combining resorptive agents with calcimimetics could prove rewarding, but more studies are warranted

PREVALENCE AND PREDICTORS OF ADEQUATE TREATMENT OF OVERT HYPOTHYROIDISM - A POPULATION-BASED STUDY

The aim of this study is to evaluate the adequacy of treatment, and to identify factors influencing treatment of hypothyroidism. Patients newly diagnosed with overt hypothyroidism (n=345) were identified via a register linked to a laboratory database. In selected periods with staff available, 165 patients were invited, and 113 (68.5 %) accepted participating in a comprehensive program including blood tests and completion of questionnaires. We performed a longitudinal follow-up on thyroid function tests 10 years after the diagnosis. Time to reach a serum TSH level of 0.2-10 mU/L (termed as clinically acceptable) and biochemical normalization (TSH: 0.2-5.0 mU/L), respectively, were analyzed using Kaplan Meier survival analysis. Predictors for longer duration to reach the normal TSH range were identified using cox proportional hazards regression. Only 67.7 % of the patients were in the euthyroid range on the long term after diagnosis of overt hypothyroidism (2 years: 59.4 %; 10 years: 67.7 %). Median time to the first normal TSH was 8.9 months (95 % CI: 7.6-10.2 months). The factors associated with longer duration until normalization of TSH after multivariate analysis were age (HR 0.79 per 10 years; 95 % CI: 0.66-0.94; P = <0.01), smoking (HR 0.47; 95 % CI: 0.26-0.83; P = <0.01), serum TSH at diagnosis (HR 0.96 per 10 mU/L; 95 % CI: 0.93-0.99; P = 0.02) and BMI (HR 0.96 per kg/m(2); 95 % CI: 0.91-0.99; P = 0.03). A considerable number of hypothyroid patients remained inadequately treated. When treating hypothyroid patients, special attention should be addressed to those patients who never or lately obtain euthyroid status

Associations between trabecular bone score and biochemistry in surgically vs conservatively treated outpatients with primary hyperparathyroidism:A retrospective cohort study

Purpose: Trabecular Bone Score (TBS) is a software-based method for indirect assessment of trabecular bone structure of the spine, based on analysis of pixels in dual energy x-ray absorptiometry (DXA) images. Few studies describe the use of TBS in patients with primary hyperparathyroidism (PHPT). This study aimed at further describing this relationship, investigating possible correlations between biochemistry, body mass index (BMI), fracture incidence and TBS. Methods: Cross-sectional study of 195 patients with verified PHPT, surgically (27) or conservatively (168) treated at the Department of Endocrinology, Aalborg University Hospital. TBS was acquired by reanalyzing DXA-images of the included subjects from the outpatient clinic. Biochemical variables were obtained from clinical routine blood samples taken in relation to the DXA-scans. History of fractures and medical history was obtained from radiology reports and medical charts. Results: Patients with active PHPT had a TBS-score signifying a partly degraded bone structure, whereas surgically treated patients had a normal bone structure as judged by TBS, though the difference in TBS-score was not statistically significant. Use of antiresorptive treatment was negatively associated with BMD but not TBS. No correlations between the biochemical variables and TBS were found. A negative correlation between TBS and BMI in patients with PHPT was present. Patients experiencing a fragility fracture had a significantly lowered TBS, BMD and T-Score. Conclusion: Biochemistry does not seem to predict bone status in terms of TBS in patients with PHPT. TBS is negatively correlated to BMI, which is also seen in patients not suffering from PHPT. The lack of a predictive value for antiresorptive treatment for TBS may raise concern. TBS appears to have a predictive value when assessing risk of fracture in patients with PHPT. Mini abstract: This cross-sectional study investigates possible correlations between biochemical variables, body mass index (BMI) and trabecular bone score (TBS) in 195 patients with primary hyperparathyroidism. It finds no correlation between biochemical variables and TBS, but finds a negative correlation between TBS and BMI and a clear association between fracture incidence and low TBS-score. Keywords: Primary hyperparathyroidism, Trabecular bone score, Body mass index, Osteoporosis, Osteopenia, Biochemical variable

Bacterial Community Composition and its Functional Potential in Ulcerative Colitis Patients:A Case Study

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease characterized by recurring inflammation in the colon. This study aimed to showcase the challenges related to the characterization of the enteric microbial community structure using 16S rRNA gene amplicon sequencing and its functional potentialusing metagenomic sequencing in five patients with UC during active disease and remission. The results revealed inter-individual and intra-individual differences in the microbial community composition. Differential abundance analysis identified specific genera associated with disease state, such asFaecalibacterium and Anaerostipes, which showed positive- and negative correlations, respectively. Prevotella was observed only during active disease. The high level of inter-individual taxonomicdifferences makes it difficult to link the changes to the disease. Functional analysis identified genes related to virulence and inflammatory bowel disease specifically during active disease. Although the approach showed great potential, it was limited by the vast amount of sequencing effort used on host DNA. Further research with a larger cohort and optimized DNA extraction protocols is needed in order validate the results and explore the functional roles of relevant epithelial-associated bacteria which is essential for unravelling the intricate host-microbiota interactions underlying disease pathogenesis

Long-term methimazole therapy in Graves' hyperthyroidism and adverse reactions: a Danish multicenter study

PURPOSE: In this prospective multicenter study with patients newly diagnosed with Graves’ hyperthyroidism (GH), we studied the timing and characteristics of adverse drug reactions in patients treated with anti-thyroid drugs (ATD) for up to 48 months. METHODS: Patients with GH were treated with ATD until remission and hereafter with a low-dose regime to keep the patients in remission. The patients were followed with blood samples and recording of adverse events approximately every second month for the first 2 years and every third month for the following 2 years. RESULTS: We included 208 patients and the patients were treated for a median of 22 (range: 0.5–49) months. Ten percent of the patients experienced adverse drug reactions and 75% of the cases occurred during the first 6 months. After 24 months, the methimazole dose was lowered to 5 mg/day, and after this time point, no further adverse drug reactions were recorded. Skin reactions were the most prominent reaction, comprising 68% of the registered reactions, and no hepatic and bonemarrow affection was recorded. CONCLUSION: With this study, we report the frequency, timing of occurrence, and characteristics of adverse drug reactions when treating GH with the ATD drug methimazole for up to 48 months. Long-term low-dose methimazole treatment can be a cost-effective and straightforward treatment option if adverse drug reactions such as severe hepatic and bone marrow affection are kept in mind

The Frequency of Focal Thyroid Incidental Findings and Risk of Malignancy Detected by 18F-Fluorodeoxyglucose Positron Emission Tomography in an Iodine Deficient Population

Incidental focal uptake of 18F-fluorodeoxyglucose (FDG) in the thyroid on positron emission tomography (PET/CT) is rare but often associated with malignancy. The epidemiology of thyroid incidentalomas has only to some extent been described in countries with iodine deficiency. Here we report data from Denmark, a country with known iodine deficiency and wide access to PET/CT. All FDG PET/CT comprising the head and neck region, during 2014, were retrospectively reviewed, and patients with focal FDG uptake in the thyroid gland were identified. A total of 2451 patients had an FDG PET/CT of which 59 (2.4%) patients presented with FDG-avid focal lesions in the thyroid gland. Among the 59 patients with FDG-avid lesions, 33 patients (56%) received work up with ultrasound, thyroid technetium scintigraphy, fine needle aspiration, and/or histology of which 20 patients had a conclusive pathology report. Ten patients with FDG-avid lesions were identified with thyroid malignancy. The risk of thyroid malignancy was 16.9% among patient with incidental FDG-avid thyroid lesions. Our findings indicated a similar frequency of FDG thyroid incidentalomas and malignancy rates in an iodine deficient population compared to summary data from prior studies, studies mostly performed in geographical areas of normal or excess iodine supplementation

Absorption rate of subcutaneously infused fluid in ill multimorbid older patients

BACKGROUND: Subcutaneous (SC) hydration is a valuable method for treating dehydration in the very old patients. Data are absent on the absorption rate, and the availability of SC infused fluid in the circulation in this group of patients where SC hydration is particularly relevant. METHODS: We performed an explorative study on ill very old (range 78–84 years old) geriatric patients with comorbidities who received an SC infusion of 235 ml isotonic saline containing a technetium-99m pertechnetate tracer. The activity over the infusion site was measured using a gamma detector to assess the absorption rate from the SC space. The activity was measured initially every 5 minutes, with intervals extended gradually to 15 minutes. Activity in blood samples and the thyroid gland was measured to determine the rate of availability in the circulation. RESULTS: Six patients were included. The mean age was 81 years (SD 2.1), the number of comorbidities was 4.6 (SD 1.3), and the Tilburg frailty indicator was 3.8 (SD 2.4). When the infusion was completed after 60 minutes, 53% (95% CI 50–56%) of the infused fluid was absorbed from the SC space, with 88% (95% CI 86–90%) absorbed one hour later. The absorption rate from the SC space right after the completion of the infusion was 127 ml/h (95% CI 90–164 ml/h). The appearance of the fluid into the blood and the thyroid gland verified the transfer from SC to circulation. CONCLUSION: This first explorative study of absorption of SC infused fluid in the very old found an acceptable amount of fluid absorbed from the SC space into the circulation one hour after infusion had ended. Results are uniform but should be interpreted cautiously due to the low sample size. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04536324

Interpretation of TSH and T4 for diagnosing minor alterations in thyroid function:a comparative analysis of two separate longitudinal cohorts

BACKGROUND: Minor alterations in thyroid function are frequent, and interpretation of thyroid function tests in the individual patient can be challenging. Furthermore, the choice of thyroid function test is debatable. To inform the debate, we performed a comparative evaluation of the variation in thyrotropin (TSH) and thyroxine (T4) in two different cohorts to illustrate the precision of TSH and T4 in the diagnosis and monitoring of thyroid dysfunction. METHODS: A comparative analysis of two separate longitudinal studies previously surveyed with monthly blood sampling for one year among 35 subjects. Participants were included based on T4 within the reference range and TSH either within (euthyroid; n = 15) or above (subclinical hypothyroidism; n = 20) the laboratory reference range on two independent blood samplings before inclusion. Exclusion criteria were known thyroid disease or use of thyroid interfering medication. TSH and T4 in individual samples were measured in a single batch to prevent between-batch variation. The distributions TSH and T4 were compared among euthyroid and subclinical hypothyroid individuals, and bootstrap estimates were used to calculate area under the curve (AUC). RESULTS: Collection of twelve, monthly blood samples in the 35 participants provided 420 samples, and data completeness was 100%. The mean TSH was 1.27/7.19 mIU/L and the mean total T4 was 106/85 nmol/L in euthyroid/subclinical hypothyroid participants. The subclinical hypothyroidism state deviated from the euthyroid by 20% for total T4 and by 466% for TSH. The overlap between the euthyroid and subclinical hypothyroid groups was 92.6% (389/420) for total T4 and 9.0% (38/420) of test results for TSH. The estimated AUC was 0.999 (95%-CI: 0.995; 1.00) for TSH and 0.853 (0.736; 0.935) for total T4. There was no confidence interval overlap between participant groups for TSH while there was a considerable overlap for total T4 (p < 0.001). CONCLUSION: The distributions of thyroid function tests illustrated how TSH outperforms T4 for detecting delicate differences in thyroid function in an individual. Thus, TSH was markedly better than T4 to discriminate between the subtle differences in thyroid function corroborating that TSH is the more sensitive and accurate index of thyroid function status in the individual patient

Application of ecosystem-specific reference databases for increased taxonomic resolution in soil microbial profiling

Intensive agriculture systems have paved the way for a growing human population. However, the abundant use of mineral fertilizers and pesticides may negatively impact nutrient cycles and biodiversity. One potential alternative is to harness beneficial relationships between plants and plant-associated rhizobacteria to increase nutrient-use efficiency and provide pathogen resistance. Plant-associated microbiota profiling can be achieved using high-throughput 16S rRNA gene amplicon sequencing. However, interrogation of these data is limited by confident taxonomic classifications at high taxonomic resolution (genus- or species level) with the commonly applied universal reference databases. High-throughput full-length 16S rRNA gene sequencing combined with automated taxonomy assignment (AutoTax) can be used to create amplicon sequence variant resolved ecosystems-specific reference databases that are superior to the traditional universal reference databases. This approach was used here to create a custom reference database for bacteria and archaea based on 987,353 full-length 16S rRNA genes from Askov and Cologne soils. We evaluated the performance of the database using short-read amplicon data and found that it resulted in the increased genus- and species-level classification compared to commonly use universal reference databases. The custom database was utilized to evaluate the ecosystem-specific primer bias and taxonomic resolution of amplicon primers targeting the V5–V7 region of the 16S rRNA gene commonly used within the plant microbiome field. Finally, we demonstrate the benefits of custom ecosystem-specific databases through the analysis of V5–V7 amplicon data to identify new plant-associated microbes for two legumes and two cereal species