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Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.

PurposeIn clinical practice, currently one reference range for serum immunoglobulin (Ig) A, G, and M is applied to all adults, although various factors may influence Ig serum levels. Population-based data on determinants of IgA, IgG, and IgM and recommendations for subgroup specific reference ranges are lacking. We aimed to provide an overview of determinants of IgA, IgG, and IgM in community-dwelling middle-aged and elderly individuals and explore determinants that influence Ig reference ranges.MethodsWithin the Rotterdam Study, we performed linear regression analyses for the association of demographic, lifestyle, and cardiovascular factors with serum IgA, IgG, and IgM. We furthermore calculated Ig reference ranges (based on percentiles), both overall and within relevant subgroups.ResultsWe included 8768 participants (median age 62 years). IgA and IgG increased non-linearly with higher age (P < .0001 for both). Women had lower IgA (beta: − 0.24; 95% confidence interval [95% CI]: − 0.29; − 0.20) and IgG (beta: − 0.33; 95% CI: − 0.44; − 0.23), but higher IgM levels (beta: 0.08; 95% CI: 0.04;0.13) than men. Former and particularly current smoking were associated with lower IgA and IgG (betas between − 0.07 and − 1.03). Higher alcohol consumption was associated with lower IgG (beta for heavy drinking: − 0.70; 95% CI: − 0.91; − 0.48). Corticosteroid use was associated with lower IgG (beta: − 1.12; 95% CI: − 1.58; − 0.66). Associations with cardiovascular factors were heterogeneous and differed between sexes.ConclusionAge, sex, smoking, alcohol consumption, corticosteroid use, and cardiovascular factors are determinants that should be considered when interpreting serum Ig levels in middle-aged and elderly individuals and may require adjusted reference ranges.

Background The association of thyroid function with risk of type 2 diabetes remains elusive. We aimed to investigate the association of thyroid function with incident diabetes and progression from prediabetes to diabetes in a population-based prospective cohort study. Methods We included 8452 participants (mean age 65 years) with thyroid function measurement, defined by thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and longitudinal assessment of diabetes incidence. Cox-models were used to investigate the association of TSH and FT4 with diabetes and progression from prediabetes to diabetes. Multivariable models were adjusted for age, sex, high-density lipoprotein cholesterol, and glucose at baseline, amongst others. Results During a mean follow-up of 7.9 years, 798 diabetes cases occurred. Higher TSH levels were associated with a higher diabetes risk (hazard ratio [HR] 1.13; 95 % confidence interval [CI], 1.08–1.18, per logTSH), even within the reference range of thyroid function (HR 1.24; 95 % CI, 1.06–1.45). Higher FT4 levels were associated with a lower diabetes risk amongst all participants (HR 0.96; 95 % CI, 0.93–0.99, per 1 pmol/L) and in participants within the reference range of thyroid function (HR 0.96; 95 % CI, 0.92–0.99). The risk of progression from prediabetes to diabetes was higher with low-normal thyroid function (HR 1.32; 95 % CI, 1.06–1.64 for TSH and HR 0.91; 95 % CI, 0.86–0.97 for FT4). Absolute risk of developing diabetes type 2 in participants with prediabetes decreased from 35 % to almost 15 % with higher FT4 levels within the normal range. Conclusions Low and low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes. Future studies should investigate whether screening for and treatment of (subclinical) hypothyroidism is beneficial in subjects at risk of developing diabetes.

The impact of non-communicable diseases (NCDs) in populations extends beyond ill-health and mortality with large financial consequences. To systematically review and meta-analyze studies evaluating the impact of NCDs (including coronary heart disease, stroke, type 2 diabetes mellitus, cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease and chronic kidney disease) at the macro-economic level: healthcare spending and national income. Medical databases (Mediine, Embase and Google Scholar) up to November 6th 2014. For further identification of suitable studies, we searched reference lists of included studies and contacted experts in the field. We included randomized controlled trials, systematic reviews, cohorts, case-control, crosssectional, modeling and ecological studies carried out in adults assessing the economic consequences of NCDs on healthcare spending and national income without language restrictions. All abstracts and full text selection was done by two independent reviewers. Any disagreements were resolved through consensus or consultation of a third reviewer. Data were extracted by two independent reviewers using a pre-designed data collection form. Studies evaluating the impact of at least one of the selected NCDs on at least one of the following outcome measures: healthcare expenditure, national income, hospital spending, gross domestic product (GDP), gross national product, net national income, adjusted national income, total costs, direct costs, indirect costs, inpatient costs, outpatient costs, per capita healthcare spending, aggregate economic outcome, capital loss in production levels in a country, economic growth, GDP per capita (per capita income), percentage change in GDP, intensive growth, extensive growth, employment, direct governmental expenditure and non-governmental expenditure. From 4,364 references, 153 studies met our inclusion criteria. Most of the studies were focused on healthcare related costs of NCDs. 30 studies reported the economic impact of NCDs on healthcare budgets and 13 on national income. Healthcare expenditure for cardiovascular disease (12-16.5 %) was the highest; other NCDs ranged between 0.7 and 7.4 %. NCD-related healt costs vary across the countries, regions, and according to type of NCD. Additionally, there is an increase in costs with increased severity and years lived with the disease. Low- and middle-income (LMI) countries were the focus of just 16 papers, which suggests an information shortage concerning the true economic burden of NCDs in these countries. NCDs pose a significant financial burden on healthcare budgets and nations' welfare, which is likely to increase over time. However further work is required to standardize more consistently the methods available to assess the economic impact of NCDs and to involve (hitherto under-addressed) LMI populations across the globe.

An up-to-date overview of determinants of serum immunoglobulins in adults is pivotal for clinical practice and research, but currently lacking. We therefore performed a systematic review and meta-analysis to identify determinants of serum immunoglobulin levels. Embase, Web of Science, Medline, Cochrane, and Google Scholar were searched from inception to July 11 , 2019 for articles reporting on determinants of serum immunoglobulin A, G or M (IgA, IgG or IgM) in adult humans. Random and fixed effect models were applied to obtain pooled mean differences (MDs) and 95% confidence intervals (CIs) for the association of age and sex with serum immunoglobulins. We retrieved 117 articles reporting on determinants of serum immunoglobulins, of which 28 could be meta-analyzed. Older compared to younger individuals had higher IgA (MD: 0.38; CI: 0.18 - 0.58), but lower IgM levels (MD: -0.40; 95%: -0.66 - -0.14). Men had higher IgA (MD: 0.22; CI: 0.03 - 0.42), but lower IgM levels (MD: -0.21; CI: -0.32 - -0.10) than women. Age and sex did not influence IgG. Caucasian ethnicity was associated with lower IgA, IgG, and IgM. Smoking and corticosteroid use were associated with lower IgG. Positive associations were reported of probiotics with IgG, alcohol with IgA, hypertension with IgA and IgG, and acute psychological stress with IgA, IgG, and IgM. Older age and male sex are associated with higher IgA, but lower IgM, and urge investigation of age- and sex-specific reference ranges of immunoglobulins. Other identified determinants were ethnicity, diet, lifestyle and cardio-metabolic factors.

Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Mediine, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case-control, cross-sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured in DALYs, productivity costs, and labor market participation, including unemployment, return to work and sick leave. From 4542 references, 126 studies met the inclusion criteria, many of which focused on the impact of more than one NCD on productivity. Breast cancer was the most common (n = 45), followed by stroke (n = 31), COPD (n = 24), colon cancer (n = 24), DM (n = 22), lung cancer (n = 16), CVD (n = 15), cervical cancer (n = 7) and CKD (n = 2). Four studies were from the WHO African Region, 52 from the European Region, 53 from the Region of the Americas and 16 from the Western Pacific Region, one from the Eastern Mediterranean Region and none from South East Asia. We found large regional differences in DALYs attributable to NCDs but especially for cervical and lung cancer. Productivity losses in the USA ranged from 88 million US dollars (USD) for COPD to 20.9 billion USD for colon cancer. CHD costs the Australian economy 13.2 billion USD per year. People with DM, COPD and survivors of breast and especially lung cancer are at a higher risk of reduced labor market participation. Overall NCDs generate a large impact on macro-economic productivity in most WHO regions irrespective of continent and income. The absolute global impact in terms of dollars and DALYs remains an elusive challenge due to the wide heterogeneity in the included studies as well as limited information from lowand middle-income countries.

The global economic impact of non-communicable diseases (NCDs) on household expenditures and poverty indicators remains less well understood. To conduct a systematic review and meta-analysis of the literature evaluating the global economic impact of six NCDs [including coronary heart disease, stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on households and impoverishment. Medline, Embase and Google Scholar databases were searched from inception to November 6th 2014. To identify additional publications, reference lists of retrieved studies were searched. Randomized controlled trials, systematic reviews, cohorts, case-control, cross-sectional, modeling and ecological studies carried out in adults and assessing the economic consequences of NCDs on households and impoverishment. No language restrictions. All abstract and full text selection was done by two independent reviewers. Data were extracted by two independent reviewers and checked by a third independent reviewer. Studies were included evaluating the impact of at least one of the selected NCDs and on at least one of the following measures: expenditure on medication, transport, co-morbidities, out-of-pocket (OOP) payments or other indirect costs; impoverishment, poverty line and catastrophic spending; household or individual financial cost. From 3,241 references, 64 studies met the inclusion criteria, 75 % of which originated from the Americas and Western Pacific WHO region. Breast cancer and DM were the most studied NCDs (42 in total); CKD and COPD were the least represented (five and three studies respectively). OOP payments and financial catastrophe, mostly defined as OOP exceeding a certain proportion of household income, were the most studied outcomes. OOP expenditure as a proportion of family income, ranged between 2 and 158 % across the different NCDs and countries. Financial catastrophe due to the selected NCDs was seen in all countries and at all income levels, and occurred in 6-84 % of the households depending on the chosen catastrophe threshold. In 16 low- and middle-income countries (LMIC), 6-11 % of the total population would be impoverished at a 1.25 US dollar/day poverty line if they would have to purchase lowest price generic diabetes medication. NCDs impose a large and growing global impact on households and impoverishment, in all continents and levels of income. The true extent, however, remains difficult to determine due to the heterogeneity across existing studies in terms of populations studied, outcomes reported and measures employed. The impact that NCDs exert on households and impoverishment is likely to be underestimated since important economic domains, such as coping strategies and the inclusion of marginalized and vulnerable people who do not seek health care due to financial reasons, are overlooked in literature. Given the scarcity of information on specific regions, further research to estimate impact of NCDs on households and impoverishment in LMIC, especially the Middle Eastern, African and Latin American regions is required.

Variations in thyroid function within reference ranges are associated with increased risk of diseases and death. However, the impact of thyroid function on life expectancy (LE) with and without noncommunicable diseases (NCDs) remains unknown. We therefore aimed to investigate the association of thyroid function with total LE and LE with and without NCD among euthyroid individuals. The study was embedded in the Rotterdam Study, a prospective population-based study carried out in the Netherlands. In total, 7,644 participants without known thyroid disease and with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels within reference ranges were eligible. NCDs were defined as presence of cardiovascular disease, diabetes mellitus type 2, or cancer. We used the demographic tool of multistate life tables to calculate LE estimates at the age of 50 years, using prevalence, incidence rates, and hazard ratios for three transitions (healthy to NCD, healthy to death, and NCD to death). The total LE and LE with and without NCD among TSH and FT4 tertiles were calculated separately in men and women. Analyses were adjusted for sociodemographic and cardiovascular risk factors. The mean (standard deviation) age of the participants was 64.5 (9.7) years, and 52.3% were women. Over a median follow-up of 8 years (interquartile range 2.7-9.9 years), 1,396 incident NCD events and 1,422 deaths occurred. Compared with those in the lowest TSH tertile, men and women in the highest TSH tertile were expected to live 1.5 years (95% confidence interval [CI] 0.8-2.3, p < 0.001) and 1.5 years (CI 0.8-2.2, p < 0.001) longer, respectively, of which 1.4 years (CI 0.5-2.3, p = 0.002) and 1.3 years (CI 0.3-2.1, p = 0.004) with NCD. Compared with those in the lowest FT4 tertile, the difference in LE for men and women in the highest FT4 tertile was -3.7 years (CI -5.1 to -2.2, p < 0.001) and -3.3 years (CI -4.7 to -1.9, p < 0.001), respectively, of which -1.8 years (CI -3.1 to -0.7, p = 0.003) and -2.0 years (CI -3.4 to -0.7, p = 0.003) without NCD. A limitation of the study is the observational design. Thus, the possibility of residual confounding cannot be entirely ruled out. In this study, we found that people with low-normal thyroid function (i.e., highest tertile of TSH and lowest tertile of FT4 reference ranges) are expected to live more years with and without NCD than those with high-normal thyroid function (i.e., lowest tertile of TSH and highest tertile of FT4 reference ranges). These findings provide support for a re-evaluation of the current reference ranges of thyroid function.

Background: Recently, a new biomarker index that reflects inflammation and protein energy malnutrition has emerged as a predictor of mortality in cardiovascular diseases. The metabolic vulnerability index (MVX) derives from blood-based inflammation (IVX) and malnutrition (MMX) markers measured by nuclear magnetic resonance (NMR) spectroscopy. We aimed to explore the association of subclinical hypothyroidism and thyroid-related parameters with IVX, MMX, and MVX scores. Methods: This cross-sectional study used the baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Individuals with normal thyroid function and subclinical hypothyroidism were included. Thyroid-related parameters—thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3–FT4 ratio, and antithyroperoxidase antibodies (TPOAb)—were the explanatory variables. The primary outcomes, MVX, MMX, and IVX scores, were analyzed as continuous variables. Linear regression analyses were performed for both univariate and multivariable models, with sensitivity and subgroup analyses applied to assess robustness. Findings: There were 3979 participants (51.4% female) with a mean age of 51.26 (SD: 9.02) years. After full adjustment for potential confounder variables, FT3 levels [B: −1.37 (−2.43;−0.31) p = 0.011] and the FT3–FT4 ratio [B: −0.90 (−1.79;−0.01) p = 0.047] were inversely associated with MVX scores. FT3 levels were also inversely associated with IVX [B: −1.32 (−2.39;−0.24) p = 0.017]. These results were consistent in euthyroid individuals and those with cardiometabolic diseases. In the sex-stratified analysis, FT3 levels were inversely associated with MVX, MMX, and IVX scores for men. Conclusion: Lower FT3 levels and the FT3–FT4 ratio were associated with a higher metabolic vulnerability in our cohort. Our study sheds light on the importance of metabolic surveillance in these patients, especially for men with cardiometabolic diseases.

IntroductionImmunoglobulins (Igs) play a pivotal role in host defense and prevention of pneumonia. Aging influences serum Ig levels, but the association between Igs and pneumonia in community-dwelling older individuals remains unknown. We evaluated the association of serum IgA, IgG, and IgM with pneumonia and lung function in middle-aged and older individuals.MethodsWe performed Cox and negative binomial regression analyses for the association of Igs with incident pneumonia and pneumonia-related mortality, and recurrent pneumonia respectively. We performed logistic regression analyses for the association between Igs and lung function values. Associations were adjusted for age, sex, smoking, comorbidities, and serum C-reactive protein.ResultsWe included 8,766 participants (median age 62.2 years, 57% women, median follow-up 9.8 years). Higher IgA (hazard ratio [HR]: 1.15; 95% confidence interval [95% CI]: 1.00-1.32) and IgG (HR: 1.13; 95% CI: 1.06-1.19) were associated with an increased pneumonia risk. Higher IgG was associated with an increased risk of pneumonia-related mortality (HR: 1.08; 95% CI: 1.01-1.16) and recurrent pneumonia (incidence rate ratio: 1.04; 95% CI: 1.00-1.09). Higher IgA and IgG were also associated with lower forced expiratory volume in one second (FEV1), lower forced vital capacity (FVC), and an increased odds of preserved ratio impaired spirometry (PRISm, i.e. FEV1 <80% and FEV1/FVC ratio ≥70%). No association was seen with an obstructive spirometry pattern.DiscussionHigher serum IgA and IgG levels were associated with pneumonia, pneumonia-related mortality, and PRISm in middle-aged and older individuals from the general population. Future studies should validate our findings and elucidate underlying pathophysiology.