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Archives of Endocrinology and Metabolism

Print version ISSN 2359-3997On-line version ISSN 2359-4292

Arch. Endocrinol. Metab. vol.59 no.6 São Paulo Dec. 2015  Epub Sep 25, 2015

http://dx.doi.org/10.1590/2359-3997000000065 

Original Articles

Effects of thyroid hormone replacement on glycated hemoglobin levels in non diabetic subjects with overt hypothyroidism

Sailaja Anantarapu1 

Suresh Vaikkakara1 

Alok Sachan1 

Bobbidi Venkata Phaneendra2 

Mustur Manohar Suchitra3 

Amaresh Ponnala Reddy4 

Sunil Epuri1 

Arun Mukka1 

Dharaneswari Vemvakam1 

1Department of Endocrinology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

2Department of Pathology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

3Department of Biochemistry, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

4Department of Endocrinology, Narayana Medical College, Nellore, Andhra Pradesh, India

ABSTRACT

Objective

Glycated hemoglobin (HbA1c) may not accurately reflect the level of glycemia in conditions of altered erythrocyte turnover. Hypothyroidism is one condition associated with sluggish erythropoesis. To assess changes in HbA1c, independent of changes in plasma glucose after initiation of thyroxine replacement in patients with overt hypothyroidism.

Materials and methods

In this prospective longitudinal study carried out in a tertiary care centre, adult non-diabetic patients with overt hypothyroidism recruited between March 2012 to August 2013 were rendered euthyroid on thyroxine. They underwent testing for hemoglobin, HbA1c, reticulocyte count, thyroxine, thyrotropin and a standard oral glucose tolerance test, both before and at 3 months after restoration to the euthyroid state. Main outcome assessed was the change in HbA1c independent of the change in glucose parameters.

Results

Thirty eight patients (35 female and 3 male) aged 37.8 ± 10.2 years with overt hypothyroidism (thyroxine 12.6 ± 13.4 ng/mL and thyrotropin -98.1 ± 63.7 µIU/mL respectively) were recruited. While HbA1c fell from 5.8 ± 0.7% to 5.6 ± 0.5% (p = 0.009) at 3 months following the correction of hypothyroidism, there were no changes in the fasting and the 2 hr post oral glucose tolerance test glucose (p = 0.67 and 0.56 respectively). The number of patients with dysglycemia diagnosed by HbA1c (i.e HbA1c≥ 5.7%) fell from 25 (65.78%) to 17 (44.7%) after treatment (p = 0.008). There were 7 (18.4%) patients with HbA1c ≥ 6.5% at baseline, but this fell to just 4 (10.5%) (p < 0.001) after 3 months of euthyroidism.

Conclusion

HbA1c is not a reliable diagnostic test for diabetes in the presence of hypothyroidism.

Key words: Glycated hemoglobin; hypothyroidism; thyroxine

INTRODUCTION

The American Diabetic Association has recently approved the use of glycated hemoglobin (HbA1c) as a screening as well as diagnostic test fordiabetes mellitus. A value ≥ 5.7% but < 6.5% was considered to represent pre-diabetes, while a value ≥ 6.5% was considered diagnostic ofdiabetes mellitus (1,2).

The glycated hemoglobin represents the fraction of hemoglobin that undergoes non-enzymatic glycation over the circulatory life span of the erythrocytes (usually 120 days) (3,4). It not only depends on the ambient level of glycemia over the preceeding 2-3 months (5), but also on the average period of exposure of the circulatory red blood cells (RBCs) to this glycemia i.e on the erythrocyte turnover in circulation (3,5). Conditions which are associated with a low RBC turnover, with a predominance of older cells (and a paucity of younger RBCs and reticulocytes) in circulation are associated with a falsely elevated HbA1c. Proven examples include iron (6,7) and vitamin B12 deficiency (6), and renal failure (8).

Among the hypoplastic anaemias, an important and common etiological factor is hypothyroidism (9,10). In response to the diminished metabolism and the reduced requirements for oxygen, there is reduced erythropoietin production from the proximal renal tubules (11).

It is conceivable that this reduced erythropoiesis may result in a false elevation of HbA1c (12) resulting in some cases in an erroneous diagnosis of pre diabetes or diabetes. We planned to assess changes in patient categorization between euglycemia, prediabetes anddiabetes mellitus based on HbA1c levels, resulting from thyroxine replacement to hypothyroid patients- an aspect not studied before.

MATERIALS AND METHODS

Study design

The study was a prospective study conducted in the Department of Endocrinology and Metabolism at a tertiary care centre in India. The study period was from March 2012 to August 2013. Patients aged more than 20 years with a biochemical diagnosis of overt hypothyroidism (i.e TSH > 15 µIU/mL and T4 < 55 ng/mL) were recruited for the study. Patients satisfying glucose based criteria for diabetes mellitus as recommended by the American Diabetes Association (ADA) (13) in 2009, were excluded from the study. Suspected or known case of chronic kidney disease, abnormal haemoglobinopathy, haemolytic disorder, reticulocytosis (reticulocytes > 2.5% of all erythrocytes), bone marrow disorders like aplastic anaemia, myelodysplastic syndrome or recent (< 3 months) blood transfusion were excluded from the study.

Written informed consent was obtained from all patients for participation in the study. The study was cleared by the Institutional Ethics Committee. Weight and height of recruited patients was recorded. Blood samples of the enrolled patients were obtained in the morning between 0800–0900 hr after an overnight fast for fasting plasma glucose (FPG), serum creatinine, hemoglobin (Hb), HbA1c, reticulocyte count and serum T4 and TSH. Patients were categorized on HbA1c alone into euglycemia (HbA1c < 5.7%), prediabetes (HbA1c≥ 5.7 but < 6.5) and diabetes mellitus (HbA1c ≥ 6.5%) based on diagnostic cutoffs of HbA1c advocated by the American Diabetes Association (2). Dysglycemia based only on HbA1c was defined as HbA1c ≥ 5.7%, i.e. it included patients with both prediabetes and diabetes mellitus diagnosed on HbA1c.

Each patient then was given 75 gm anhydrous glucose mixed in 200 mL water and asked to drink slowly over 3 minutes. Repeat samples for plasma glucose were collected after 2 hours. Patients with fasting plasma glucose (FPG) ≥ 100 mg/dL were labeled as having impaired fasting glucose (IFG), while those with 2 hrs post OGTT plasma glucose (PGPG) ≥ 140 mg/dL were labeled having impaired glucose tolerance (IGT). Prediabetes based on plasma glucose measurements was diagnosed by the presence of either IFG or IGT or both. Patients with FPG ≥ 126 mg/dL or PGPG ≥ 200 mg/dL were excluded from the study as previously stated, with the intention of excluding patients satisfying glucose based criteria fordiabetes mellitus.

Biochemical assays

T4 was measured by radioimmunoassay (RIA) method by using BRIA MAG 4 kits [Broad of Radiation and Isotope Technology (BRIT), Mumbai, India]. The minimum and maximum detectable limits for serum T4 was 15-240 ng/mL. TSH was measured by immunoradiometric assay (IRMA) method by using IRMAK-9 kits [Broad of Radiation and Isotope Technology (BRIT), Mumbai, India]. The minimum and maximum detectable limits for serum TSH was 0.15-100 mIU/L. The intra assay and inter assay CV (%) ranges from 2.79-6.92 and 1.80-8.21 respectively. HbA1c was analysed using commercially available HPLC kits (D-10 HemoglobinA1c Prog, Bio-Rad Laboratories, California, United States). The intra and inter assay CV (%) was 0.78 and 0.52 respectively. Plasma glucose and serum creatinine were measured using autoanalyzer CX5 (Beckman Coulter, California, United States of America). Glomerular filtration rate was calculated using the Cockcroft Gault formula (14) and corrected to 1.73 m2 BSA. Haemoglobin was estimated on an automated haematology analyzer by colorimetric method (Shenzhen Mindray Biomedical Electronics Co Ltd, Hamburg 20537, Germany). Reticulocytes were counted by a trained observer after staining of peripheral blood smear with a supravital stain (new methylene blue) and expressed as a percentage of total red blood cells.

Patients were then started on thyroxin supplements for 3 months. The dose of the drug was increased periodically (every 4-6 weeks) step wise, based on TSH estimations till the patients were rendered euthyroid, i.e had TSH between 0.5-5 µIU/ml. Once the patient had been restored to the euthyroid state, the patient was allowed to continue the same dose of thyroxin and recalled after three months. After three months of documentation of euthyroidism, the following investigations were repeated as before: serum T4 and TSH, fasting plasma glucose and post glucose load 2 hr plasma glucose, HbA1c, haemoglobin and reticulocyte percentage. Reticulocyte percentage was determined by the same expert, who performed the same determination at baseline.

Sample size

The study was planned to detect change in HbA1c before and after restoration of the euthyroid state with a power of 80% and a significance level at a p < 0.05. The standard deviation of HbA1c (σ) in the normal population, as represented by the normal healthy control subjects in the study by Kim and cols. (12) was 0.31%. In that study the correction of hypothyroidism lead to fall of 0.2% in the HbA1c. Expecting to demonstrate a similar or greater change in our patients, the minimal sample size required to demonstrate a change (δ) of 0.2% in the HbA1c was obtained as given below (15):

where Zα (coefficient of α error) assumes a value of 1.96 and Z1-β (coefficient of β error) takes a value of 0.8416 for a statistical power of 80% and at a significance level of p < 0.05 for comparison of means of HbA1c before and after the correction of hypothyroidism by a 2 tailed paired t test. Substituting the values of σ and δ as mentioned above the required sample size was 37.

Statistical analysis

Data was recorded on a pre designed proforma and managed using Microsoft Excel 2007 (Microsoft Corp, Redmond, WA). Continuous variables were compared with same parameters measured 3 months after the restoration of euthyroidism using two tailed paired t test with a p value of < 0.05 being considered as significant. Baseline proportions were compared with those measured 3 months after the restoration of euthyroidism by the McNemar χ2 test. Statistical software SPSS version 15 (SSPS Inc., Chicago, IL) was used for statistical analysis.

RESULTS

Baseline clinical features

A total of 38 consecutive patients with confirmed overt hypothyroidism (i.e TSH > 15 µIU/ml and T4 < 55 ng/mL) were recruited for the study over a period of one and a half years. Baseline patient characteristics are given below in table 1.

Table 1 Baseline characteristics of recruited patients 

Patient parameter Value (n = 38)
Age 37.8 ± 10.2 years
Female : Male ratio 35: 3
Weight 61.0 ± 13.2 kg
BMI 25.0 ± 4.2 kg/m2
Number of obese patients (% of total) 20 (46.51%)
Serum creatinine 0.79 ± 0.20 mg/dL
Estimated GFR 104.93 ± 29.40 mL/min/1.73 m2BSA
Thyroxine 12.6 ± 13.4 ng/mL
Thyrotropin 98.1 ± 63.7 µIU/mL

BMI: body mass index; GFR: glomerular filtration rate.

Normal values thyroxine: 55-135 ng/mL; thyrotropin 0.5-5.0 µIU/mL.

Effect of thyroxine replacement

Patients were re-evaluated 3 months after restoration to the euthyroid state. The recorded changes are given in table 2.

Table 2 Comparison of anthropometry, hematological parameters, thyroid profile, glycemic indices and proportion of patients with abnormal glycemic parameters before and 3 months after the correction of hypothyroidism in 38 patients 

Parameter Pre therapy N = 38 Post therapy N = 38 P value
Weight (kg) 61.0 ± 13.2 57.5 ± 14.3 0.004
BMI (kg/m2 ) 25.0 ± 4.2 24.1 ± 4.3 0.039
T4 (ng/mL) 12.6 ± 13.4 105.7 ± 36.9 < 0.001
TSH (µIU/mL) 98.1 ± 63.7 2.5 ± 3.5 < 0.001
Hb (gm/dL) 11.7 ± 1.9 12.1 ± 1.6 0.044
Reticulocyte (as % of total RBCs) 0.9 ± 0.6 1.2 ± 0.7 0.046
FPG (mg/dL) 86.8 ± 11.0 87.5 ± 9.1 NS
PGPG (mg/dL) 123.4 ± 35.6 127.0 ± 28.8 NS
HbA1c (%) 5.8 ± 0.7 5.6 ± 0.5 0.009
No. (%) of patients with IFG (FPG ≥ 100 mg/dL) 4 (10.5%) 5 (13.1%) NS
No. (%) of patients with IGT (PGPG ≥ 140 mg/dL) 11 (29%) 11 (29%) NS
No. (%) of patients with IFG and /or IGT 12 (31.6%) 15 (39.4%) NS
No. (%) of patients with HbA1c ≥ 5.7 25 (65.7%) 17 (44.7%) 0.008
No. (%) of patients with HbA1c ≥ 5.7 with normal FPG and PGPG 16 (42.1%) 7 (18.4%) 0.035
No. (%) of patients with HbA1c ≥ 6.5% 7 (18.4%) 4 (10.5%) < 0.001

BMI: body mass index; T4: thyroxin; TSH: thyroid stimulating hormone; Hb: hemoglobin; FPG: fasting plasma glucose; PGPG: post glucose tolerance test 2 hours plasma glucose; HbA1c: glycated hemoglobin; IFG: impaired fasting glucose; IGT: impaired glucose tolerance; NS: not significant (p > 0.05).

Normal values T4: 55-135 ng/mL, TSH 0.5-5.0 µIU/mL, Hb: 12-14 gm/dL in females and 14-16 gm/dL in males, Reticulocyte (%)-0.5-1.5%. FPG < 100 mg/dL, PGPG < 140 mg/dL, HbA1c < 5.7%.

Following correction of T4 and TSH to 105.7 ± 36.9 ng/mL and 2.5 ± 3.5 µIU/mL respectively, there was a reduction in the mean body weight by 3.5 kg (p = 0.004). Likewise, there was improvement in the hemoglobin from 11.7 ± 1.9 gm/dL to 12.1 ± 1.6 gm/dL (p = 0.044). This was accompanied by a rise in the reticulocyte percentage from 0.9 ± 0.6% to 1.2 ± 0.7% (p = 0.046).

Changes in glycemic indices

Table 2 shows the comparison between the HbA1c, FPG and PGPG at baseline and at 3 months after the correction of hypothyroidism. While there was a fall in the HbA1cfrom 5.8 ± 0.7% to 5.6 ± 0.5% (p = 0.009) following the correction of hypothyroidism, there were no corresponding changes in the fasting and the 2 hr post OGTT plasma glucose (p > 0.05) .

Changes in the proportion of patients with abnormal glycemic indices in OGTT before and after treatment is also shown in table 2. The proportion of patients with IFG and those with IGT did not change (p > 0.05 for both). The proportion of patients with prediabetes based on plasma glucose values (i.e having IFG or IGT or both) also did not change (p > 0.05). However the number of patients with dysglycemia diagnosed by HbA1c (i.e HbA1c ≥ 5.7%) fell from 25 (65.78%) to 17 (44.7%) after treatment (p = 0.008). Likewise the number of patients with HbA1c ≥ 5.7 % but having normal plasma glucose both in the fasting and the 2 hrs post OGTT state (i.e false diagnosis of dysglycemia by HbA1c) also fell from 16 (42.1%) to 7 (18.42%) (p = 0.035).

No patient fulfilled glucose criteria for diabetes at baseline, due to exclusion of such patients at baseline. Nevertheless there were 7 (18.4%) patients with HbA1c ≥ 6.5% at baseline (representing false diagnosis of DM by HbA1c), but this fell to just 4 (10.5%) (p < 0.001) after 3 months of euthyroidism.

On multiple linear regression analysis, none of the following parameters: namely the change in the hemoglobin, reticulocyte percentage, body mass index or the fasting or post OGTT plasma glucose were independently predictive (p > 0.05) of the change in the HbA1c between the baseline and final follow up.

DISCUSSION

Recently the American Diabetes Association has recommended the use of HbA1cfor the diagnosis of diabetes mellitus (2). However there has always been concern about the use of HbA1c in certain conditions, where this does not accurately reflect the level of glycemia. Disorders associated with changes in the RBC turnover can affect the HbA1c independently from the glycemic status, by altering the relative proportion of young and old RBCs in circulation i.e the average age of the RBCs (3,4). Thus disorders with reduced RBC turnover and a preponderance of older RBCs in circulation, like iron deficiency (6,7), vitamin B12 deficiency (6), or renal failure (8), can have a falsely elevated HbA1c.

Among the latter group of disorders, one which is widely prevalent is hypothyroidism. Indeed studies in our country show that overt hypothyroidism is found in 3.9% to 10.95% of the general population (16,17). These prevalence rates are much higher than that found in the Western population, where the prevalence of overt hypothyroidism is only 0.3-0.4% of the adult population (18,19). Thus, India seems to be having a much higher burden of hypothyroidism. Thus any impact of hypothyroidism on HbA1c is likely to be a bigger issue in India than in the Western countries.

We enrolled newly diagnosed patients with overt hypothyroidism. Those patients with FPG or PGPG in the diabetic range (i.e FPG ≥ 126 mg/dL and PGPG ≥ 200 mg/dL were excluded from the study since they would require anti-diabetic medication or therapeutic lifestyle change, in addition to thyroxin treatment – thus introducing a confounding factor of impact of diabetes treatment on HbA1c, while studying HbA1c alterations with thyroxin replacement. Only patients with normal glucose values or patients with IFG/ IGT were thus included. The reason for choosing three months follow up was on account of the approximately 120 days lifespan of the RBCs in circulation (3,4).

Our study showed mild anaemia with a low reticulocyte count at baseline in concordance with other studies (12,20). In our patients, following thyroid hormone replacement, the haemoglobin and the reticulocyte count rose. Likewise Bashir and cols. (20), in a retrospective study showed that as compared to a Hb of 10.73 ± 0.86 gm/dL in untreated primary hypothyroid patients it was 12.64 ± 1.33 in treated primary hypothyroid patients (p < 0.001).

Though there was a mean weight loss of approximately 3.5 kg from baseline following the correction of hypothyroidism, the plasma glucose values remained unaltered (Table 2). Further the proportion of patients with dysglycemic states IGT or IFG or prediabetes based on plasma glucose (either IGT and/or IFG) did not change. These findings are similar to what was observed by Kim and cols. (12) who showed that there were no changes observed in FPG or in 1,2 an hydroglycitol (an index of postprandial hyperglycemia) following the correction of hypothyroidism.

Despite the mean FPG and PGPG being normal, the mean HbA1c at baseline was already in the prediabetes range. A significant proportion of patients had a false diagnosis of dysglycemia (42%) or diabetes (18.4%) by HbA1c.Thus in hypothyroidism there is a very high false positive rate for the diagnosis of dyglycemia, if HbA1c alone is used as the diagnostic test.

This false elevation of HbA1c was also demonstrated by Kim and cols. (12) who showed that HbA1c in 45 hypothyroid patients was higher than that in control subjects (5.54 ± 0.43%vs. 5.34 ± 0.31% in hypothyroid patients and controls respectively; p < 0.001), despite the lower level of plasma fasting glucose in the hypothyroid individuals. Christy and cols. (21) selected 30 hypothyroid (TSH > 14 mIU/L) non diabetic (FPG < 100 mg/dL) patients with normocytic normochromic anemia and compared these patients with 30 euthyroid non diabetic patients also with normocytic normochromic anemia. HbA1c in the hypothyroid patients was 6.32 ± 0.75 %vs. 5.87 ± 0.46% in the euthyroid group, the difference being statistically significant. Despite all subjects in this study being euglycemic, the odds ratio for HbA1c > 6.5% in hypothyroid patients with anemia was 3.16 in comparison to euthyroid persons.

Following correction of hypothyroidism and maintenance of the euthyroid state for up to 3 months, the initially elevated mean HbA1c was found to fall to a normal value despite there being no change in the FPG and the PGPG. Similar findings were reported by Kim and cols. (12) in their 30 hypothyroid patients who were resumed on thyroxin replacement. In their study, HbA1c fell from 5.57 ± 0.26% at baseline to 5.37 ± 0.32% 1 month after commencing thyroxin replacement; a magnitude of fall similar to that seen in our study.

Change in the HbA1c cannot be attributed to the fall in the BMI as there was no significant association between these parameters on multiple linear regression. Moreover there is no mechanism by which the BMI can influence the HbA1c other than through the level of glycemia, which has remained unaffected between baseline time point and post 3 months follow up.

Similar reduction of HbA1c without attempting to control glucose has also been observed in patients with vitamin B12 deficiency treated with vitamin B12 or iron deficiency individuals treated with iron (7) or renal failure patients treated with erythropoietin (8). In all these cases the fall in HbA1c was attributed to the appearance of newly formed young RBCs in circulation. In our patients also, this process is reflected in the observed rise in the reticulocyte percentage. However there was no statistical association between the change in the HbA1c and the change in the reticulocyte percentage or the hemoglobin. This may be due to the following reasons. Firstly, though the study is adequately powered to detect changes in HbA1c between pre and post treatment time points, it may not be adequately powered to assess causal associations with changes in the reticulocyte percentage. Secondly the reticulocytes only represent the “youngest” red blood cells, but do not fully reflect the the entire population of “young” RBCs in circulation. There is currently no satisfactory method to study the average age of the RBCs in circulation at two different points in time, which would have been the ideal tool in this study.

In our study the diagnosis (based on HbA1c) of dysglycemia (HbA1c ≥ 5.7%) made earlier was subsequently changed to euglycemia in nearly one third of the patients initially diagnosed as dysglycemia. Similar reduction was observed in the proportion of patients with the wrong diagnosis (based on HbA1c) of dysglycemia (i.e HbA1c ≥ 5.7 despite normal FPG and PGPG) and diabetes mellitus. Thus a very small reduction in HbA1c of only 0.2% nevertheless has a significant impact on the HbA1c based diagnostic categorization of hypothyroid patients. This aspect has not been studied earlier.

To conclude, levels of HbA1c are falsely elevated, out of proportion to the level of glycemia in patients with hypothyroidism. However it is lowered without any change in plasma glucose after correction of hypothyroidism. Consequently false diagnosis of dysglycemia may be made if HbA1c alone is used for diagnosis in patients with overt hypothyroidism. Therefore in hypothyroid patients, reliance should be placed only on fasting plasma glucose or the oral glucose tolerance test (OGTT) to diagnose prediabetes or type 2 diabetes.

The study is limited by having only a small number of patients, a relatively short follow up duration of 3 months and by the absence of a control group. A larger study with a longer follow up may be of use to confirm our results.

Acknowledgements

we thank Sri Balaji Aarogya Varaprasadini Scheme (SBAVP), Tirumala Tirupati Devasthanams (TTD), Tirupati for funding the research project with grant of Rs 25,000/-.

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This work was supported by the Sri Balaji Aarogya Varaprasadini Scheme (SBAVP), Tirumala Tirupati Devasthanams (TTD), Tirupati.

Received: April 26, 2015; Accepted: May 6, 2015

Correspondence to: Suresh Vaikkakara. Department of Endocrinology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India.sureshvdrsmailbox@rediffmail.com

Disclosure: no potential conflict of interest relevant to this article was reported.

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