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Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism.

ABSTRACT: BACKGROUND: Subclinical hypothyroidism (SCH) is not a rare condition in females, the elderly, or patients with chronic kidney disease (CKD). Even though previous studies have demonstrated that thyroid hormone replacement therapy (THRT) improves cardiac function and dyslipidemia in patients with SCH, it remains unclear as to whether THRT can improve renal function in CKD patients with SCH. This study investigated the impact of THRT on changes in estimated glomerular filtration rates (eGFR) in this patient population. METHODS: A total of 113 CKD patients with SCH who were treated with L-thyroxine and had eGFR available for at least 24 months before and after THRT were enrolled between January 2005 and December 2011. A linear mixed model was used to compare patients' clinical and biochemical parameters at various time points. The slope of the decline in eGFR over time, both before and after THRT, was also calculated and compared using a linear mixed model. RESULTS: The mean age of the study participants was 63.2±12.7 years, and 36 patients (31.9%) were men. The mean follow-up duration before and after THRT was 28.6±4.5 and 30.6±6.4 months respectively. After 24 months of THRT, serum thyrotropin (TSH) levels were significantly reduced-8.86±0.49 versus 1.41±0.73??IU/mL, p<0.001-but there were no significant changes in triiodothyronine and free thyroxine concentrations. Serum albumin, calcium, phosphate, cholesterol, and triglyceride levels were also comparable before and after THRT. The rates of decline in eGFR were significantly attenuated by THRT (-4.31±0.51 vs.-1.08±0.36 [mL/min]/[year·1.73 m²], p<0.001), even after adjustment for age, sex, diabetes, mean arterial pressure, and serum albumin, cholesterol, and triglyceride concentrations (p<0.001). CONCLUSION: THRT attenuated the rate of decline in renal function in CKD patients with SCH, suggesting that THRT may delay reaching end-stage renal disease in these patients.

SUBMITTER: Shin DH

PROVIDER: S-EPMC3675831 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism.

Shin Dong Ho DH Lee Mi Jung MJ Lee Hye Sun HS Oh Hyung Jung HJ Ko Kwang Il KI Kim Chan Ho CH Doh Fa Mee FM Koo Hyang Mo HM Kim Hyoung Rae HR Han Jae Hyun JH Park Jung Tak JT Han Seung Hyeok SH Yoo Tae-Hyun TH Kang Shin-Wook SW

Thyroid : official journal of the American Thyroid Association 20130528 6

<h4>Background</h4>Subclinical hypothyroidism (SCH) is not a rare condition in females, the elderly, or patients with chronic kidney disease (CKD). Even though previous studies have demonstrated that thyroid hormone replacement therapy (THRT) improves cardiac function and dyslipidemia in patients with SCH, it remains unclear as to whether THRT can improve renal function in CKD patients with SCH. This study investigated the impact of THRT on changes in estimated glomerular filtration rates (eGFR) ...[more]

PMID: 23281965

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Project description:BACKGROUND:Subclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH. METHODS:Participants are community-dwelling subjects aged ?65 years with SCH, diagnosed by elevated TSH levels (?4.6 and ?19.9 mU/L) on a minimum of two measures???three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p?=?0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients. Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture. DISCUSSION:This large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition. TRIAL REGISTRATION:Clinicaltrials.gov NCT01660126 ; registered 8th June 2012.

Project description:A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment.Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force.We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones.We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.

Project description:OBJECTIVE:To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. DESIGN:Retrospective cohort study. SETTING:The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. PARTICIPANTS:Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. EXPOSURE:TSH concentration in patients with hypothyroidism. MAIN OUTCOME MEASURES:Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. RESULTS:162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). CONCLUSIONS:In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

Project description:Thyroid hormone is a potent stimulator of metabolism, playing a critical role in regulating energy expenditure and in key physiological mechanisms, such as growth and development. Although administration of thyroid hormone in the form of levo thyroxine (l-thyroxine) has been used to treat hypothyroidism for many years, the precise molecular basis of its physiological actions remains uncertain. Our objective was to define the changes in circulating protein levels that characterize alterations in thyroid hormone status. To do this, an integrated untargeted proteomic approach with network analysis was used. This study included 10 age-matched subjects with newly diagnosed overt hypothyroidism. Blood was collected from subjects at baseline and at intervals post-treatment with l-thyroxine until they reached to euthyroid levels. Plasma protein levels were compared by two-dimensional difference in gel electrophoresis (2D-DIGE) pre- and post-treatment. Twenty differentially expressed protein spots were detected. Thirteen were identified, and were found to be unique protein sequences by MALDI-TOF mass spectrometry. Ten proteins were more abundant in the hypothyroid vs. euthyroid state: complement C2, serotransferrin, complement C3, Ig κ chain C region, α-1-antichymotrypsin, complement C4-A, haptoglobin, fibrinogen α chain, apolipoprotein A-I, and Ig α-1 chain C region. Three proteins were decreased in abundance in the hypothyroid vs. euthyroid state: complement factor H, paraneoplastic antigen-like protein 6A, and α-2-macroglobulin. The differentially abundant proteins were investigated by Ingenuity Pathway Analysis (IPA) to reveal their associations with known biological functions. Their connectivity map included interleukin-6 (IL-6) and tumour necrosis factor α (TNF-α) as central nodes and the pathway identified with the highest score was involved in neurological disease, psychological disorders, and cellular movement. The comparison of the plasma proteome between the hypothyroid vs euthyroid states revealed differences in the abundance of proteins involved in regulating the acute phase response.

Project description:Importance:The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses. Objective:To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism. Data Sources:PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018. Study Selection:Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers. Data Extraction and Synthesis:Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied. Main Outcomes and Measures:General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months. Results:Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high. Conclusions and Relevance:Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.

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Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism.

Publications

Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism.

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