Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study.

BACKGROUND: Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir. METHODS AND RESULTS: Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir. CONCLUSIONS: Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established.

Changes in sleeping and basal energy expenditure and substrate oxidation induced by short term thyroxin administration in man.

The present study was designed to explore the thermogenic effect of thyroid hormone administration and the resulting changes in nitrogen homeostasis. Normal male volunteers (n = 7) received thyroxin during 6 weeks. The first 3-week period served to suppress endogenous thyroid secretion (180 micrograms T4/day). This dose was doubled for the next 3 weeks. Sleeping energy expenditure (respiratory chamber) and BMR (hood) were measured by indirect calorimetry, under standardized conditions. Sleeping heart rate was continuously recorded and urine was collected during this 12-hour period to assess nitrogen excretion. The changes in energy expenditure, heart rate and nitrogen balance were then related to the excess thyroxin administered. After 3 weeks of treatment, serum TSH level fell to 0.15 mU/L, indicating an almost complete inhibition of the pituitary-thyroid axis. During this phase of treatment there was an increase in sleeping EE and sleeping heart rate, which increased further by doubling the T4 dose (delta EE: +8.5 +/- 2.3%, delta heart rate +16.1 +/- 2.2%). The T4 dose, which is currently used as a substitutive dose, lead to a borderline hyperthyroid state, with an increase in EE and heart rate. Exogenous T4 administration provoked a significant increase in urinary nitrogen excretion averaging 40%. It is concluded that T4 provokes an important stimulation of EE, which is mostly mediated by an excess protein oxidation.

Subclinical hypothyroidism and functional mobility in older adults.

BACKGROUND: Health risks associated with subclinical hypothyroidism in older adults are unclear. Our objective was to compare the functional mobility of people aged 70 to 79 years by thyroid function categorized by thyrotropin (TSH) level as euthyroid (>or=0.4 to <4.5 mIU/L), mild subclinical hypothyroid (>or=4.5 to <7.0 mIU/L), or moderate subclinical hypothyroid (>or=7.0 to <or=20.0 mIU/L with a normal free thyroxine level) cross-sectionally and over 2 years. METHODS: A total of 2290 community-dwelling residents participating in the year 2 clinic visit (July 1998-June 1999) of the Health, Aging, and Body Composition (Health ABC) Study, who had measured TSH level, had the capacity to walk 20 m unaided, and were not taking thyroid medication or had TSH levels consistent with hyperthyroidism or hypothyroidism. Main outcome measures included self-reported and performance-based measures of mobility (usual and rapid gait speed and endurance walking ability) assessed at study baseline (year 2) and 2 years later. RESULTS: In age- and sex-adjusted analyses, the mild subclinical hypothyroid group (vs the euthyroid group) demonstrated better mobility (faster mean usual and rapid gait speed [1.20 vs 1.15 m/s and 1.65 vs 1.56 m/s, respectively; P < .001] and had a higher percentage of those with good cardiorespiratory fitness and reported walking ease [39.2% vs 28.0% and 44.7% vs 36.5%, respectively; P < .001]). After 2 years, persons with mild subclinical hypothyroidism experienced a similar decline as the euthyroid group but maintained their mobility advantage. Persons with moderate subclinical hypothyroidism had similar mobility and mobility decline as the euthyroid group. CONCLUSION: Generally, well-functioning 70- to 79-year-old individuals with subclinical hypothyroidism do not demonstrate increased risk of mobility problems, and those with mild elevations in TSH level show a slight functional advantage.

Thyroid function in severely traumatized patients with or without head injury.

The pattern of thyroid function changes following severe trauma was assessed prospectively in 35 patients during the first 5 days after injury. Patients were divided into 2 groups to evaluate the effect of head injury: group I, patients with severe head injury; group II, patients with multiple injuries without head injury. The results demonstrate a low T3 and low T4 syndrome throughout the study, with decreases in both total and free levels of T3 and T4, normal or increased rT3 levels, and normal TSH levels. The presence of severe head injury was associated with lower levels of TSH and free T3. Mortality was 37%. Survival was associated with higher TSH and T3 levels, but not with higher T4 levels. TSH levels exceeding 1 mU/l on the first day were only observed in survivors. These findings show that a typical low T3 and low T4 syndrome is present after severe trauma in patients with multiple injury as well as with head injury. Primary hypothyroidism can be excluded, pituitary or hypothalamic hypothyroidism is likely in these patients.

Activation of electrical triggers of atrial fibrillation in hyperthyroidism.

CONTEXT: A shortening of the atrial refractory period has been considered as the main mechanism for the increased risk of atrial fibrillation in hyperthyroidism. However, other important factors may be involved. OBJECTIVE: Our objective was to determine the activity of abnormal supraventricular electrical depolarizations in response to elevated thyroid hormones in patients without structural heart disease. PATIENTS AND DESIGN: Twenty-eight patients (25 females, three males, mean age 43+/-11 yr) with newly diagnosed and untreated hyperthyroidism were enrolled in a prospective trial after exclusion of heart disease. Patients were followed up for 16 +/- 6 months and studied at baseline and 6 months after normalization of serum TSH levels. MAIN OUTCOME MEASURES: The incidence of abnormal premature supraventricular depolarizations (SVPD) and the number of episodes of supraventricular tachycardia was defined as primary outcome measurements before the start of the study. In addition, heart rate oscillations (turbulence) after premature depolarizations and heart rate variability were compared at baseline and follow-up. RESULTS: SVPDs decreased from 59 +/- 29 to 21 +/- 8 per 24 h (P = 0.003), very early SVPDs (so called P on T) decreased from 36 +/- 24 to 3 +/- 1 per 24 h (P < 0.0001), respectively, and nonsustained supraventricular tachycardias decreased from 22 +/- 11 to 0.5 +/- 0.2 per 24 h (P = 0.01) after normalization of serum thyrotropin levels. The hyperthyroid phase was characterized by an increased heart rate (93 +/- 14 vs. 79 +/- 8 beats/min, P < 0.0001) and a decreased turbulence slope (3.6 vs. 9.2, P = 0.003), consistent with decreased vagal tone. This was confirmed by a significant decrease of heart rate variability. CONCLUSION: Hyperthyroidism is associated with an increased supraventricular ectopic activity in patients with normal hearts. The activation of these arrhythmogenic foci by elevated thyroid hormones may be an important causal link between hyperthyroidism and atrial fibrillation.

Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality

BACKGROUND: Data on the association between subclinical thyroid dysfunction and coronary heart disease (CHD) and mortality are conflicting. PURPOSE: To summarize prospective evidence about the relationship between subclinical thyroid dysfunction and CHD and mortality. DATA SOURCES: MEDLINE (1950 to January 2008) without language restrictions and reference lists of retrieved articles were searched. STUDY SELECTION: Two reviewers screened and selected cohort studies that measured thyroid function and then followed persons prospectively to assess CHD or mortality. DATA EXTRACTION: By using a standardized protocol and forms, 2 reviewers independently abstracted and assessed studies. DATA SYNTHESIS: Ten of 12 identified studies involved population-based cohorts that included 14 449 participants. All 10 population-based cohort studies examined risks associated with subclinical hypothyroidism (2134 CHD events and 2822 deaths), whereas only 5 examined risks associated with subclinical hyperthyroidism (1392 CHD events and 1993 deaths). In a random-effects model, the relative risk (RR) for subclinical hypothyroidism for CHD was 1.20 (95% CI, 0.97 to 1.49; P for heterogeneity = 0.14; I(2 )= 33.4%). Risk estimates were lower when higher-quality studies were pooled (RR, 1.02 to 1.08) and were higher among participants younger than 65 years (RR, 1.51 [CI, 1.09 to 2.09] for studies with mean participant age <65 years and 1.05 [CI, 0.90 to 1.22] for studies with mean participant age > or =65 years). The RR was 1.18 (CI, 0.98 to 1.42) for cardiovascular mortality and 1.12 (CI, 0.99 to 1.26) for total mortality. For subclinical hyperthyroidism, the RR was 1.21 (CI, 0.88 to 1.68) for CHD, 1.19 (CI, 0.81 to 1.76) for cardiovascular mortality, and 1.12 (CI, 0.89 to 1.42) for total mortality (P for heterogeneity >0.50; I(2 )= 0% for all studies). LIMITATIONS: Individual studies adjusted for different potential confounders, and 1 study provided only unadjusted data. Publication bias or selective reporting of outcomes could not be excluded. CONCLUSION: Subclinical hypothyroidism and hyperthyroidism may be associated with a modest increased risk for CHD and mortality, with lower risk estimates when pooling higher-quality studies and larger CIs for subclinical hyperthyroidism

Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis.

CONTEXT: Subclinical hypothyroidism has been associated with increased risk of coronary heart disease (CHD), particularly with thyrotropin levels of 10.0 mIU/L or greater. The measurement of thyroid antibodies helps predict the progression to overt hypothyroidism, but it is unclear whether thyroid autoimmunity independently affects CHD risk. OBJECTIVE: The objective of the study was to compare the CHD risk of subclinical hypothyroidism with and without thyroid peroxidase antibodies (TPOAbs). DATA SOURCES AND STUDY SELECTION: A MEDLINE and EMBASE search from 1950 to 2011 was conducted for prospective cohorts, reporting baseline thyroid function, antibodies, and CHD outcomes. DATA EXTRACTION: Individual data of 38 274 participants from six cohorts for CHD mortality followed up for 460 333 person-years and 33 394 participants from four cohorts for CHD events. DATA SYNTHESIS: Among 38 274 adults (median age 55 y, 63% women), 1691 (4.4%) had subclinical hypothyroidism, of whom 775 (45.8%) had positive TPOAbs. During follow-up, 1436 participants died of CHD and 3285 had CHD events. Compared with euthyroid individuals, age- and gender-adjusted risks of CHD mortality in subclinical hypothyroidism were similar among individuals with and without TPOAbs [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.87-1.53 vs HR 1.26, CI 1.01-1.58, P for interaction = .62], as were risks of CHD events (HR 1.16, CI 0.87-1.56 vs HR 1.26, CI 1.02-1.56, P for interaction = .65). Risks of CHD mortality and events increased with higher thyrotropin, but within each stratum, risks did not differ by TPOAb status. CONCLUSIONS: CHD risk associated with subclinical hypothyroidism did not differ by TPOAb status, suggesting that biomarkers of thyroid autoimmunity do not add independent prognostic information for CHD outcomes.

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.

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.

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.