Subclinical hypothyroidism: summary of evidence in 2014

Subclinical hypothyroidism, which is defined as elevated thyroid-stimulating hormone (TSH) levels with free thyroxine concentrations within the reference range, is a common disorder that increases with age and affects up to 18% of the elderly, with a higher prevalence in women compared to men. Prospective data have shown an increased risk of coronary heart disease events, heart failure, and cardiovascular mortality among affected adults. Conflicting results have been found on the association between subclinical hypothyroidism and cognitive impairment, depression and the risk of fractures. Management strategies including screening and treatment of subclinical hypothyroidism are still controversial, while the ongoing European randomised controlled trial "TRUST" targets to solve these uncertainties. This narrative review aims to assess current evidence on the clinical aspects, as well as screening and treatment recommendations in adults with subclinical hypothyroidism.

Subclinical thyroid dysfunction and the risk of stroke: a systematic review and meta-analysis

Subclinical thyroid dysfunction has been associated with coronary heart disease, but the risk of stroke is unclear. Our aim is to combine the evidence on the association between subclinical thyroid dysfunction and the risk of stroke in prospective cohort studies. We searched Medline (OvidSP), Embase, Web-of-Science, Pubmed Publisher, Cochrane and Google Scholar from inception to November 2013 using a cohort filter, but without language restriction or other limitations. Reference lists of articles were searched. Two independent reviewers screened articles according to pre-specified criteria and selected prospective cohort studies with baseline thyroid function measurements and assessment of stroke outcomes. Data were derived using a standardized data extraction form. Quality was assessed according to previously defined quality indicators by two independent reviewers. We pooled the outcomes using a random-effects model. Of 2,274 articles screened, six cohort studies, including 11,309 participants with 665 stroke events, met the criteria. Four of six studies provided information on subclinical hyperthyroidism including a total of 6,029 participants and five on subclinical hypothyroidism (n = 10,118). The pooled hazard ratio (HR) was 1.08 (95 % CI 0.87-1.34) for subclinical hypothyroidism (I (2) of 0 %) and 1.17 (95 % CI 0.54-2.56) for subclinical hyperthyroidism (I (2) of 67 %) compared to euthyroidism. Subgroup analyses yielded similar results. Our systematic review provides no evidence supporting an increased risk for stroke associated with subclinical thyroid dysfunction. However, the available literature is insufficient and larger datasets are needed to perform extended analyses. Also, there were insufficient events to exclude clinically significant risk from subclinical hyperthyroidism, and more data are required for subgroup analyses.

How do Swiss family physicians treat subclinical hypothyroidism?

Subclinical hypothyroidism is a common condition, and its prevalence increases with age. Currently, guidelines regarding the screening and treatment of subclinical hypothyroidism are controversial. An international survey of general practitioners (GPs), to which Swiss GPs also contributed, showed large inter-country variations in treatment strategies for subclinical hypothyroidism. These differences are mainly explained by the lack of strong evidence for the management of this condition. The European randomized-controlled clinical trial TRUST should help clarify recommendations for screening and thyroxin replacement for the elderly with subclinical hypothyroidism. Working in close collaboration with GPs in Switzerland for the recruitment of patients will ensure that the findings from this study will be applicable to primary care settings.

Third-Generation-Cephalosporin-Resistant Klebsiella pneumoniae Isolates from Humans and Companion Animals in Switzerland: Spread of a DHA-Producing Sequence Type 11 Clone in a Veterinary Setting.

Characterization of third-generation-cephalosporin-resistant Klebsiella pneumoniae isolates originating mainly from one human hospital (n = 22) and one companion animal hospital (n = 25) in Bern (Switzerland) revealed the absence of epidemiological links between human and animal isolates. Human infections were not associated with the spread of any specific clone, while the majority of animal infections were due to K. pneumoniae sequence type 11 isolates producing plasmidic DHA AmpC. This clonal dissemination within the veterinary hospital emphasizes the need for effective infection control practices.

Serum folate, cobalamin, homocysteine and methylmalonic acid concentrations in pigs with acute, chronic or subclinical Lawsonia intracellularis infection.

Lawsonia intracellularis is the causative agent of porcine proliferative enteropathy. The clinical presentation can be acute (i.e. proliferative hemorrhagic enteropathy, PHE), chronic (i.e. porcine intestinal adenomatosis, PIA) or subclinical. In humans with chronic enteropathies, low serum folate (vitamin B(9)) and cobalamin (vitamin B(12)) concentrations have been associated with increased serum concentrations of homocysteine and methylmalonic acid (MMA), which reflect the availability of both vitamins at the cellular level. The aim of this study was to evaluate serum folate, cobalamin, homocysteine and MMA concentrations in serum samples from pigs with PHE, PIA or subclinical L. intracellularis infection, and in negative controls. Serum folate, cobalamin, homocysteine and MMA concentrations differed significantly among pigs in the PHE, PIA, subclinical and negative control groups. Serum folate concentrations in the PHE and PIA groups were lower than in the subclinical and negative control groups, while serum cobalamin concentrations were lower in the PIA group than in other groups. Serum concentrations of homocysteine were higher in the PHE, PIA and subclinical groups than in the negative control group. Serum concentrations of MMA were higher in the subclinical and PIA groups than in the control group. These data suggest that pigs infected with L. intracellularis have altered serum cobalamin, folate, homocysteine and MMA concentrations.

A naturally occurring prfA truncation in a Listeria monocytogenes field strain contributes to reduced replication and cell-to-cell spread

Listeria (L.) monocytogenes is an environmental bacterium that may become an intracellular pathogen upon ingestion to cause gastroenteritis, septicaemia, abortions, and/or fatal infections of the central nervous system. We here describe a L. monocytogenes field strain (JF5171) isolated from a bovine placenta in the context of abortion, which exhibited attenuation in bovine brain-slice cultures. The whole genome of strain JF5171 was sequenced, and the invasion, replication, and intercellular spread of JF5171 were further analyzed by quantification of colony forming units and immunofluorescence studies. Phospholipase and hemolysis activity of JF5171 were also quantified along with transcription levels of actA, hly and prfA. The data obtained were compared to those of the widely used L. monocytogenes reference strain, EGD-e. JF5171 exhibited reduced replication and lower levels of phospholipase and hemolysis activity. Invasion and cell-to-cell spread was strongly decreased compared to EGD-e, and actin polymerization was absent. A frame shift deletion was identified in the JF5171 coding region of the major regulator for virulence, prfA. This resulted in a truncated C-terminus sequence (WEN* vs. WGKLN*). In addition, a point mutation resulted in a lysine to arginine substitution at amino acid position 197. Complementation with prfA from EGD-e and with (EGD-e) prfA-K197N increased the replication and spread efficiency of JF5171. In contrast, complementation with the truncated version of prfA had no effect. Taken together, these results suggest that the truncated C-terminus of prfA considerably contributes to the strongly attenuated phenotype observed in vitro.

Extensive Copy-Number Variation of Young Genes across Stickleback Populations

Duplicate genes emerge as copy-number variations (CNVs) at the population level, and remain copy-number polymorphic until they are fixed or lost. The successful establishment of such structural polymorphisms in the genome plays an important role in evolution by promoting genetic diversity, complexity and innovation. To characterize the early evolutionary stages of duplicate genes and their potential adaptive benefits, we combine comparative genomics with population genomics analyses to evaluate the distribution and impact of CNVs across natural populations of an eco-genomic model, the three-spined stickleback. With whole genome sequences of 66 individuals from populations inhabiting three distinct habitats, we find that CNVs generally occur at low frequencies and are often only found in one of the 11 populations surveyed. A subset of CNVs, however, displays copy-number differentiation between populations, showing elevated within-population frequencies consistent with local adaptation. By comparing teleost genomes to identify lineage-specific genes and duplications in sticklebacks, we highlight rampant gene content differences among individuals in which over 30% of young duplicate genes are CNVs. These CNV genes are evolving rapidly at the molecular level and are enriched with functional categories associated with environmental interactions, depicting the dynamic early copy-number polymorphic stage of genes during population differentiation.

Holocene vegetation development in the catchment of Sagistalsee (1935 m asl), a small lake in the Swiss Alps

Pollen and plant macrofossils were analysed at Sägistalsee (1935 m asl), a small lake near timber-line in the Swiss Northern Alps. Open forests with Pinus cembra and Abies alba covered the catchment during the early Holocene (9000–6300 cal. BP), suggesting subcontinental climate conditions. After the expansion of Picea abies between 6300 and 6000 cal. BP the subalpine forest became denser and the tree-line reached its maximum elevation at around 2260 m asl. Charcoal fragments in the macrofossil record indicate the beginning of Late-Neolithic human impact at ca. 4400 cal. BP, followed by a extensive deforestation and lowering of the forest-limit in the catchment of Sägistalsee at 3700 cal. BP (Bronze Age). Continuous human activity, combined with a more oceanic climate during the later Holocene, led to the local extinction of Pinus cembra and Abies alba and favoured the mass expansion of Picea and Alnus viridis in the subalpine area of the Northern Alps. The periods before 6300 and after 3700 cal. BP are characterised by high erosion activity in the lake's catchment, whereas during the phase of dense Picea-Pinus cembra-Abies forests (6300–3700 cal. BP) soils were stable and sediment-accumulation rates in the lake were low. Due to decreasing land-use at higher altitudes during the Roman occupation and the Migration period, forests spread beween ca. 2000 and 1500 cal. BP, before human impact increased again in the early Middle Ages. Recent reforestation due to land-use changes in the 20th century is recorded in the top sediments. Pollen-inferred July temperature and annual precipitation suggest a trend to cooler and more oceanic climate starting at about 5500 cal. BP.

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Variation in treatment strategies of Swiss general practitioners for subclinical hypothyroidism in older adults.

QUESTIONS UNDER STUDY As the best management of subclinical hypothyroidism is controversial, we aimed to assess variations in treatment strategies depending on different Swiss regions, physician and patient characteristics. METHODS We performed a case-based survey among general practitioners (GPs) in different Swiss regions, which consisted of eight hypothetical cases presenting a female patient with subclinical hypothyroidism and nonspecific complaints differing by age, vitality status and thyroid-stimulating hormone (TSH) concentration. RESULTS A total of 262 GPs participated in the survey. There was considerable variation in the levothyroxine starting dose chosen by GPs, ranging from 25 µg to 100 µg. Across the Swiss regions, GPs in the Bern region were significantly more inclined to treat, with a higher probability of initiating treatment (60%, p = 0.01) and higher mean starting doses (45 µg, p <0.01) compared with the French-speaking region (44%, 36 µg); the Zurich region had intermediate values (52%, 39 µg). We found no association between treatment rate and other physician characteristics. GPs were more reluctant to initiate treatment in 85-year-old than in 70-year-old women (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.63-0.94), and more likely to treat women with a TSH of 15 mU/l than those with a TSH of 6mU/l (OR 8.71, 95% CI 6.21-12.20). CONCLUSIONS There are strong variations in treatment strategies for elderly patients with subclinical hypothyroidism across different Swiss regions, including use of higher starting doses than the recommended 25 µg in the Swiss guidelines, which recommend a starting dose of 25 µg. These variations likely reflect the current uncertainty about the benefits of treatment, which arise from the current lack of evidence from adequately powered clinical trials.

What are the causes for the spread of GLE parameters deduced from NM data?

Investigations have shown that the analysis results of ground level enhancements (GLEs) based on neutron monitor (NM) data for a selected event can differ considerably depending the procedure used. This may have significant consequences e.g. for the assessment of radiation doses at flight altitudes. The reasons for the spread of the GLE parameters deduced from NM data can be manifold and are at present unclear. They include differences in specific properties of the various analysis procedures (e.g. NM response functions, different ways in taking into account the dynamics of the Earth’s magnetospheric field), different characterisations of the solar particle flux near Earth as well as the specific selection of NM stations used for the analysis. In the present paper we quantitatively investigate this problem for a time interval during the maximum phase of the GLE on 13 December 2006. We present and discuss the changes in the resulting GLE parameters when using different NM response functions, different model representations of the Earth’s magnetospheric field as well as different assumptions for the solar particle spectrum and pitch angle distribution near Earth. The results of the study are expected to yield a basis for the reduction in the spread of the GLE parameters deduced from NM data.

Jejunitis and brown bowel syndrome with multifocal carcinogenesis of the small bowel

This is the first report describing a case where prolonged, severe malabsorption from brown bowel syndrome progressed to multifocally spread small bowel adenocarcinoma. This case involves a female patient who was initially diagnosed with chronic jejunitis associated with primary diffuse lymphangiectasia at the age of 26 years. The course of the disease was clinically, endoscopically, and histologically followed for 21 years until her death at the age 47 due to multifocal, metastasizing adenocarcinoma of the small bowel. Multiple lipofuscin deposits (so-called brown bowel syndrome) and severe jejunitis were observed microscopically, and sections of the small bowel showed dense lymphoplasmacytic infiltration of the lamina propria as well as blocked lymphatic vessels. After several decades, multifocal nests of adenocarcinoma cells and extensive, flat, neoplastic mucosal proliferations were found only in the small bowel, along with a loss of the mismatch repair protein MLH1 as a long-term consequence of chronic jejunitis with malabsorption. No evidence was found for hereditary nonpolyposis colon carcinoma syndrome. This article demonstrates for the first time multifocal carcinogenesis in the small bowel in a malabsorption syndrome in an enteritis-dysplasia-carcinoma sequence.

Biological and protective properties of immune sera directed to the influenza virus neuraminidase

The envelope of influenza A viruses contains two large antigens, hemagglutinin (HA) and neuraminidase (NA). Conventional influenza virus vaccines induce neutralizing antibodies that are predominantly directed to the HA globular head, a domain that is subject to extensive antigenic drift. Antibodies directed to NA are induced at much lower levels, probably as a consequence of the immunodominance of the HA antigen. Although antibodies to NA may affect virus release by inhibiting the sialidase function of the glycoprotein, the antigen has been largely neglected in past vaccine design. In this study, we characterized the protective properties of monospecific immune sera that were generated by vaccination with recombinant RNA replicon particles encoding NA. These immune sera inhibited hemagglutination in an NA subtype-specific and HA subtype-independent manner and interfered with infection of MDCK cells. In addition, they inhibited the sialidase activities of various influenza viruses of the same and even different NA subtypes. With this, the anti-NA immune sera inhibited the spread of H5N1 highly pathogenic avian influenza virus and HA/NA-pseudotyped viruses in MDCK cells in a concentration-dependent manner. When chickens were immunized with NA recombinant replicon particles and subsequently infected with low-pathogenic avian influenza virus, inflammatory serum markers were significantly reduced and virus shedding was limited or eliminated. These findings suggest that NA antibodies can inhibit virus dissemination by interfering with both virus attachment and egress. Our results underline the potential of high-quality NA antibodies for controlling influenza virus replication and place emphasis on NA as a vaccine antigen. IMPORTANCE The neuraminidase of influenza A viruses is a sialidase that acts as a receptor-destroying enzyme facilitating the release of progeny virus from infected cells. Here, we demonstrate that monospecific anti-NA immune sera inhibited not only sialidase activity, but also influenza virus hemagglutination and infection of MDCK cells, suggesting that NA antibodies can interfere with virus attachment. Inhibition of both processes, virus release and virus binding, may explain why NA antibodies efficiently blocked virus dissemination in vitro and in vivo. Anti-NA immune sera showed broader reactivity than anti-HA sera in hemagglutination inhibition tests and demonstrated cross-subtype activity in sialidase inhibition tests. These remarkable features of NA antibodies highlight the importance of the NA antigen for the development of next-generation influenza virus vaccines.

Subclinical Thyroid Dysfunction and Depressive Symptoms among Elderly: A Prospective Cohort Study

BACKGROUND Subclinical hypothyroidism has been associated with depressive symptoms in cross-sectional studies, but prospective data and data on subclinical hyperthyroidism are scarce. METHODS In the Leiden sub-study of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) among adults aged 70-82 years with pre-existing cardiovascular disease or known cardiovascular risk factors, TSH and free T4 levels were measured at baseline and repeated after 6 months to define persistent thyroid function status. Main outcome measures were depressive symptoms, assessed with the Geriatric Depression Scale 15 (GDS) at baseline and after 3 years. All analyses were adjusted for age, gender and education. RESULTS Among 606 participants (41% women, mean age 75 years) without anti-depressant medication, GDS scores at baseline did not differ for participants with subclinical hypothyroidism (n = 47; GDS 1.75, 95% CI 1.29-2.20, p = 0.50) or subclinical hyperthyroidism (n = 13; GDS 1.64 [0.78-2.51], p = 1.00) compared to euthyroid participants (n = 546, mean GDS 1.60 [1.46-1.73]). After 3 years, compared to euthyroid participants, change in GDS scores did not differ for participants with subclinical hypothyroidism (ΔGDS -0.03 [-0.50-0.44], p = 0.80), while subclinical hyperthyroidism was associated with an increase in GDS scores (ΔGDS 1.13 [0.32-1.93] p = 0.04). All results were similar for persistent subclinical thyroid dysfunction. CONCLUSIONS In this largest prospective study on the association of persistent subclinical thyroid dysfunction and depression, subclinical hypothyroidism was not associated with increased depressive symptoms among older adults at high cardiovascular risk. Persistent subclinical hyperthyroidism might be associated with increased depressive symptoms, which requires confirmation in a larger prospective study. © 2015 S. Karger AG, Basel.

Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis

OBJECTIVE The objective was to determine the risk of stroke associated with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45-4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5-19.9 mIU/L with normal T4 levels. DATA EXTRACTION AND SYNTHESIS We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972-2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91-1.21) for stroke events (combined fatal and nonfatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years, with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years old (HR, 1.00; 95% CI, 0.86-1.18) or ≥ 80 years old (HR, 1.31; 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. CONCLUSIONS Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.