Een zeer groot aantal nationale en internationale instituten/ziekenhuizen hebben aan dit onderzoek deelgenomen.
The Relation Between Thyroid Function and Anemia: A Pooled Analysis of Individual Participant Data
Daisy M. Wopereis,1,2* Robert S. Du Puy,1* Diana van Heemst,2 John P. Walsh,3,4 Alexandra Bremner,5 Stephan J. L. Bakker,6 Douglas C. Bauer,7,8 Anne R. Cappola,9 Graziano Ceresini,10 Jean Degryse,11,12 Robin P. F. Dullaart,6 Martin Feller,13,14 Luigi Ferrucci,15 Carmen Floriani,13 Oscar H. Franco,16 Massimo Iacoviello,17 Georgio Iervasi,18 Misa Imaizumi,19 J. Wouter Jukema,20 Kay-Tee Khaw,21 Robert N. Luben,21 Sabrina Molinaro,22 Matthias Nauck,23 Kushang V. Patel,24 Robin P. Peeters,16,25 Bruce M. Psaty,26,27 Salman Razvi,28 Roger K. Schindhelm,29 Natasja M. van Schoor,30 David J. Stott,31 Bert Vaes,11,12 Mark P. J. Vanderpump,32 Henry V¨olzke,33 Rudi G. J. Westendorp,34 Nicolas Rodondi,13,14 Christa M. Cobbaert,35 Jacobijn Gussekloo,1,2 and Wendy P. J. den Elzen,35 for the Thyroid Studies Collaboration
1 Department of Public Health and Primary Care, Leiden University Medical Center, Leiden 2300RC, Netherlands;
2 Department of Internal Medicine, Gerontology and Geriatrics Section, Leiden University Medical Center, Leiden 2300RC, Netherlands;
3 Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Perth 6009, Western Australia;
4 Medical School, The University of Western Australia, Crawley, Perth 6009, Western Australia;
5 School of Population Health, The University of Western Australia, Crawley, Perth 6009, Western Australia;
6 Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen 9700RB, Netherlands;
7 Department of Medicine, University of California San Francisco, San Francisco, California 94143;
8 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94143;
9 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania19104;
10 Department of Clinicaland Experimenta lMedicine, Geriatric Endocrine Unit, University Hospital of Parma, Parma43126,Italy;
11 Institute of Health and Society, Universit´le catholique de Louvain, Brussels B1200, Belgium;
12 Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Leuven B3000, Belgium;
13 Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern3010,Switzerland;
14 Institute of Primary Health Care,UniversityofBern,Bern3012,Switzerland;
15 National Instituteon Aging,Baltimore,Maryland20892;
16 Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015GE, Netherlands;
17 University Cardiology Unit, Cardiothoracic Department, University Policlinic Hospital, Bari 70124, Italy;
18 National Council Research Institute of Clinical Physiology/Tuscany Region G. Monasterio Foundation, Pisa 56126, Italy;
19 Department of Clinical Studies, Radiation Effects Research Foundation, Nagasaki850-0013,Japan;
20 Department of Cardiology, Leiden University Medical Center, Leiden 2300RC, Netherlands;
21 Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, England;
22 National Council Research Institute of Clinical Physiology, Pisa 56124, Italy;
23 Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald D-17489, Germany;
24 Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98195;
25 Department of Internal Medicine, Rotterdam Thyroid Center, Erasmus MC, Rotterdam 3015GD, Netherlands;
26 Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98101;
27 Kaiser Permanente Washington Health Research Institute, Seattle, Washington 98101;
28 Department of Endocrinology, Gateshead Health Foundation NHS Trust, Gateshead, Tyne and Wear NE9 6SX, England;
29 Department of Clinical Chemistry, Haematology and Immunology, Northwest Clinics, Alkmaar 1815JD, Netherlands;
30 Department of Epidemiology and Biostatistics,EMGO Institute for Health and Care Research, Amsterdam 1081BT, Netherlands;
31 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom;
32 The Physicians’ Clinic, London W1G 7AE, England;
33 Institute for Community Medicine, Study of Health in Pomerania/Clinical-Epidemiological Research and German Centre of Cardiovascular Research, University of Greifswald, Greifswald D-17489, Germany;
34 Department of Public Health and Center of Healthy Aging, University of Copenhagen, Copenhagen DK-2200, Denmark;
and 35 Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden 2300RC, Netherlands
Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce.
To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.
Individual participant data meta-analysis.
Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162).
Main Outcome Measures:
Primary outcome measure was anemia (hemoglobin ,130 g/L in men and ,120 g/L in women).
Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants [overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87)].
Hemoglobin levels were lower in all groups compared with participants with euthyroidism.
In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for over thypothyroidism,1.18(1.00to1.38) for subclinical hypothyroidism, 1.15(0.94to1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism.
Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results.
No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.
Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function.
In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia. (J Clin Endocrinol Metab 103: 3658–3667, 2018
Thyroid diseases and anemia are common disorders, and their prevalence increases with age (1–4).
Hypothyroidism and anemia can each cause nonspecific symptoms of ill health like fatigue, and both lead to decreased quality of life.
The combination of anemia and abnormal thyroid function may therefore be accompanied by serious morbidity and further effects on quality of life.
The co-occurrence of anemia and hypothyroidism is not only a challenging diagnostic problem in allocating symptoms to one of the diseases, but may also point to a causal relationship between thyroid disease and anemia (5).
Indeed, relationships between thyroid disease and anemia have already been documented in experimental animal studies in the distant past (5).
For instance, hypophysectomized mammals were found to have decreased red bloodcellcounts that corrected after administration of thyroid hormones(6,7).
Additionally, mice deficientinthe thyroid hormone receptor TRa have been found to have decreased hematocrit values (8).
However, human data regarding relationships between thyroid disease and hematologic anomalies are scarce. Researchers investigating potential altered erythropoiesis as a result of thyroid dysfunction found red cell abnormalities and a reduced proliferative potential of hematopoietic progenitor cells in both patients with hypothyroidism and hyperthyroidism, but the total number of studied participants was low (9, 10).
In addition, a higher prevalence of anemia was identified in older male patients with subclinical hypothyroidism (11) and in patients with clinical hypothyroidism (12), but incidence estimates were not available due to the cross-sectional study design.
Additionally, a rise of thyroid hormone levels or a decrease in levels of TSH within the reference ranges was associated with higher erythropoietic activity(13),but the low number of studied participants precluded stratification by hyperthyroid subgroups. I none population-based cohort, both hypothyroidism and hyperthyroidism were associated
Table 1. Baseline Characteristics of Individuals in Included Studies (N = 42,162)
Anemia was defined according to the World Health Organization criteria (hemoglobin concentration ,130 g/L in men and ,120 g/L in women) (22). In 14 cohorts, a follow-up measurement of hemoglobin was available.
TSH and freeT4concentrations were measured at baseline inall cohorts.
Cohort-specific cutoff values were applied for free T4 concentrations (Supplemental Table 1).
Participants with a TSH level of 0.45 to 4.5 mIU/L were categorized as euthyroid.
Overt hypothyroidism was defined as a TSH level .4.5 mIU/L in combination with reduced free T4 concentration.
Subclinical hypothyroidism was defined as a TSH level .4.5mIU/L in combination with a normal free T4 concentration.
A TSH level ,0.45 mIU/L with normal free T4 levels was defined as subclinical hyperthyroidism.
Overt hyperthyroidism was defined as a TSH level ,0.45 mIU/L with an elevated free T4 concentration (2).
Table 2. The Risk of Having Anemia at Baseline According to Thyroid Hormone Status (N = 42,162 From 16 Cohorts)
Table 3. The Risk of Developing Anemia During Follow-up According to Thyroid Hormone Statusat Baseline (N = 25,466 From 14 Cohorts)
Figure 1. The pooled ORs of the risk of having anemia at baseline with the 95% CI and P value for trend. Logistic regression models corrected for age and sex; reference group is euthyroidism.
Figure 2. The pooled hazard ratios of developing anemia during follow-up in the thyroid function groups with the 95% CI and P value for trend. Cox regression models corrected for age and sex; reference group is euthyroidism
Some limitations of this study have to be acknowledged as well.
First, a limitation of this pooled analysis is that TSH and free T4 were only measured once at baseline.
Because subclinical hypothyroidism has been shown to normalize in one-third of cases (40), in guidelines, it is often recommended that measurements of these parameters are repeated.
Unfortunately, repeated TSH and free T4 measurements were not available in many cohorts.
Erroneously classifying patients with euthyroidism based on one measurement may have led to an underestimation of the associations found.
Second, the statistical power was more limited in the longitudinal models than in the baseline, cross-sectional analysis. The association between overt and subclinical hyperthyroidism and the risk of developing anemia did not reach statistical significance, but the results of the longitudinal analyses followed a similar pattern.
Third, we did not apply age-adjusted reference ranges as per current consensus and usual practice. However, evidence in favor of age-specific TSH reference ranges is starting to accumulate (41); so, too, is evidence to the contrary (42–44).
This is an important topic of future research.
Fourth, we performed sensitivity analyses excluding participants with high CRP levels as a proxy for chronic diseases that might predispose to anemia, but this only excluded diseases as sociated with inflammation.
Particularly in the group of participants with subclinical hypothyroidism, the possibility of the presence of nonthyroidal illness cannot be fully excluded.
As a result, possible residual errors caused by residual bias and confounding may have deflated the results.
Unfortunately, information on additional potential confounding factors, like thyroid medication dose titrations, other diseases relating to anemia (cancer ,chronic kidney disease, leukemia, gastric ulcers, arthritis, or chronic obstructive pulmonary disease), menopausal state, nonthyroidal illness, concomitant medications, and iron or vitamin supplements, was not available for most cohorts.
In conclusion, we observed higher odds of anemia in both participants with hypothyroid and hyperthyroid function.
In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up.
It remains to be assessed in a randomized controlled trial whether treatment of (subclinical) hypothyroidism is effective in reducing anemia.
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