Prevalence of subclinical thyroid disorders in type 2 diabetes mellitus

Background: Subclinical thyroid disorders usually do not produce symptoms of thyroid disease until they turn into over thyroid disease. Thyroid disease is more common in people with diabetes mellitus than in the general population and it is important to detect thyroid disorder before its clinical manifestation. Subclinical hypothyroidism (SCH) can produce dyslipidemia, obesity thus resulting increased predisposition to coronary artery disease. Subclinical hyperthyroidism can aggravate hyperglycemia and impair blood sugar control. Objectives: Our objective is to determine the prevalence of subclinical thyroid disorders in patients with type 2 diabetes mellitus (T2DM) and to analyze the clinical and metabolic profi le of patients with this dual endocrine disorder. Methods and Results: One hundred consecutive type 2 diabetic patients without clinical manifestations of thyroid disorders were screened for SCH and subclinical hyperthyroidism using serum free T3, free T4 and thyroid stimulating hormone (TSH) levels. Individuals of subclinical thyroid disease were further screened for thyroperoxidase (TPO) antibodies. SCH was detected in 13% of type 2 diabetic patients and none had subclinical hyperthyroidism in our study. SCH was common among females with type 2 diabetes (84.6%). Elevated TPO antibody levels were present in 84.6% SCH patients. Diabetic retinopathy among SCH patients showed signifi cant association with higher serum TSH levels. Left ventricular diastolic dysfunction was present in 30.8% of SCH patients. Conclusion: SCH is common among type 2 diabetic patients, especially in females. It is most commonly secondary to autoimmune thyroid disease. Microvascular complications are commonly observed in this group of patients with dual endocrinal disorder and treating physician should be aware of the impact and should routinely screen SCH to prevent complications.


INTRODUCTION
The prevalence of thyroid disease in the diabetic patients is signifi cantly higher than in the general population. [1]Apart from autoimmune etiology linked to the higher prevalence of thyroid disease in diabetes mellitus; it has also been observed that thyroid function is intrinsically linked to insulin resistance.It has also been stated that common factors simultaneously are responsible for increased thyroid stimulating hormone (TSH) levels and insulin resistance. [2] type 2 diabetes mellitus (T2DM), prevalence of thyroid disease has been found to be as high as 31%, the most common disorder being subclinical hypothyroidism, followed by subclinical hyperthyroidism, overt hypothyroidism and overt hyperthyroidism. [3]Subclinical hypothyroidism (SCH) is defined as a serum TSH level above normal despite normal levels of serum free thyroxine. [4,5]H, in various studies, has been shown to be associated with elevation in serum lipids, coronary artery disease and left ventricular (LV) diastolic dysfunction, LV systolic dysfunction with exercise, increased peripheral vascular resistance and mental depression.

MATERIALS AND METHODS
This study was done at department of general medicine, Kempegowda Institute of Medical Sciences, Bangalore.This is a cross-sectional observational descriptive study.A total of consecutive 100 type 2 diabetic patients (50 male and 50 female patients) aged >40 years, with no past history of thyroid disorder were included in the study.Patients younger than 40 years of age on drugs known to alter thyroid hormonal levels, seriously ill-patients, patients previously diagnosed with thyroid disorder and on medication, patients with the chronic conditions known to alter thyroid function, such as hepatic dysfunction, pregnancy and psychiatric illness were excluded from the study.Written informed consent was taken from all patients and the study was approved by institutional ethical committee.All the study participants underwent detailed history, clinical examination and laboratory investigations using pro forma designed for this study.Special emphasis was given to symptoms and signs of hypothyroidism and hyperthyroidism.
SCH was defi ned as serum TSH> 4.2 μIU/ml, with normal levels of serum free T 4 (0.93-1.7 ng/dl).Anti-TPO antibodies were measured by immunoenzymatic assay using 0.5 ml of patient's serum sample and values >9.0 IU/ml were interpreted as elevated.

Statistical analysis
Descriptive statistics were presented as mean ± standard deviation for continuous measures while absolute values and percentages for categorical measures.All analyses were conducted using the Statistical Package for the Social Sciences (SPSS) 16 statistical software (SPSS Inc., Chicago, Illinois, USA).A P < 0.05 was considered to be statistically signifi cant throughout the analysis.The difference between different parameters based on quantitative variables are compared using Student's t-test for independent samples and the difference is considered statistically signifi cant when the P < 0.05.

RESULTS
In the present study, a total number of 100 patients of T2DM underwent thyroid function test including serum free T 3 , free T 4 and TSH.Based on the above biochemical values, it was determined that out of the 100 patients [Table 1], 84 were euthyroid (serum TSH, serum free T 4 , serum free T 3 within normal limits), 13 patients had SCH (serum TSH > 4.2IU/ml with normal levels of serum free T 4 ) and the remaining 3 had overt primary hypothyroidism (serum TSH > 4.2IU/ml and serum Free T 4 < 0.93 ng/dl) [Table 1].None had subclinical or overt hyperthyroidism.
Among the 13 patients of subclinical hypothyroidism, 11 were female and 2 were male patients.Therefore, the percentages of SCH among female and male patients were 22% and 4% respectively.
The mean age in SCH patients was 58.77 ± 5.47 years, whereas the mean age in euthyroid patients was 56.98 ± 7.49 years, the difference was not statistically signifi cant (P value: 0.304).

Clinical profi le of subclinical hypothyroid patients
Among the 13 subclinical hypothyroid patients detected in the study, 3 (23%) patients had clinical features suggestive of hypothyroidism.Goiter was detected in 2 (15.4%) patients of SCH.Table 2 enlists the clinical profi le of patients SCH patients who presented with each clinical feature of hypothyroidism.
SCH patients having symptoms/signs of hypothyroidism were compared with SCH patients without symptoms/signs of hypothyroidism with respect to serum free T 3 , free T 4 and TSH values [Table 3].Statistically signifi cant difference was noted in all the above three biochemical variables between the two groups.

Blood pressure
The mean SBP of the 13 SCH patients was 137.38 ± 11.59 mm Hg, whereas, the mean DBP was 79.69 ± 8.40 mm Hg.Systemic hypertension was present in 6 (46%) of the 13 SCH patients.All the above 6 patients were known cases of hypertension and were on regular antihypertensive drug treatment; and had a mean duration of hypertension of 5.5 ± 3.94 years.

Body mass index (BMI)
BMI, which was calculated for all 100 T2DM patients was used to compare the 13 SCH patients with 84 euthyroid subjects.SCH patients had a mean BMI of 29.70 ± 3.77 kg/m 2 whereas euthyroid patients had a mean BMI of 27.35 ± 4.36 kg/m 2 , which was not statistically signifi cant (P value 0.054).

Macrovascular complications of DM
Among 13 SCH patients, coronary artery disease was evident in 1 (7.7%)SCH patient with a positive history of ischemic heart disease and was confi rmed by 2D echocardiography.There was no clinical evidence of peripheral arterial disease or cerebrovascular disease in any of the thirteen SCH patients in the study.

Glycemic profi le
The glycemic profi le including FBS, PPBS and serum HbA1c, of SCH patients of T2DM was compared with that of euthyroid counterparts in the study.Among the

Antidiabetic medications
Among the 13 SCH patients, 2 (15.4%) patients were on insulin therapy along with oral hypoglycemic agents, 4 (30.8%)patients were on more than 2 classes of oral hypoglycemic drugs, the remaining 7 (53.8%)SCH patients were on not more than 2 classes of oral hypoglycemic drugs.

Fasting lipid profi le
Among the 13 SCH patients, 6 (46%) patients had dyslipidemia.All the 6 patients were known cases of dyslipidemia and were on medication for the same.The fasting lipid profi le of SCH patients of T2DM was compared with that of euthyroid counterparts.Among the 13 SCH patients, the mean serum total cholesterol was 175.69 ± 28.05 mg%, mean serum low-density lipoprotein (LDL) was 102.30 ± 27.3 mg%, mean serum high-density lipoprotein (HDL) was 38.14 ± 4.12 mg%, mean serum triglycerides (TG) was 178 ± 66.03 mg%.Among the 84 euthyroid subjects, the mean serum total cholesterol was 164.35 ± 32.73 mg%, mean serum LDL was 94.64 ± 28.87 mg%, mean serum HDL was 40.06 ± 6.94 mg%, mean serum TG was 151.10 ± 77.03 mg%.Although SCH patients had higher mean values of serum total cholesterol, LDL, TG and lower mean value of serum HDL, compared with euthyroid subjects, the difference was not statistically signifi cant.

Serum levels of anti-TPO antibodies
Among the 13 SCH patients, serum level of anti-TPO antibodies was elevated in 11 patients (84.6% of SCH patients).10 SCH patients with elevated anti-TPO antibody were female, one was male.The remaining 2 SCH patients had serum levels of anti-TPO antibodies within normal limits.Therefore, serum anti-TPO antibody levels were elevated in 91% of female SCH patients and in 50% of male SCH patients.

DISCUSSION
SCH is defi ned as a serum thyroid-stimulating hormone (TSH) level above the upper limit of normal despite normal levels of serum free thyroxine. [6]SCH or mild thyroid failure is a common problem, with a prevalence of 3-8% in the population without known thyroid disease. [7,8]The prevalence increases with age and is higher in women.After the sixth decade of life, the prevalence in men approaches that of women, with a combined prevalence of 10%.Antithyroid antibodies can be detected in 80% of patients with SCH and 80% of patients with SCH have a serum TSH of less than 10 mIU/L.
Although studies have pointed to some adverse effects of SCH, no consensus exists as to the clinical importance of the adverse effects and the benefi ts of levothyroxine therapy, particularly for the 80% of patients with SCH who have a TSH of less than 10 mIU/L, because of the different levels of TSH and degrees of thyroid dysfunction in these studies. [9,10]tients with SCH have a high rate of progression to clinically overt hypothyroidism, 2.6% each year if TPO antibodies are absent and 4.3% if they are present. [11]e Colorado Health Fair study showed that the mean total cholesterol level was 216 mg/dL for euthyroid patients and 224 mg/dL for patients with SCH. [12]Several randomized studies have shown reduction of LDL cholesterol by levothyroxine therapy.However, most of the studies showing benefi t are not categorized for serum TSH levels of 5.0-10.0mIU/L.A meta-analysis of 13 studies concluded that the lipid profi le improved with therapy. [13]n a 2004 review, data were considered insuffi cient to show benefi ts of levothyroxine therapy on lipid levels. [14][17]  rate of postpartum thyroiditis in diabetic patients is three times that in normal women.A number of reports have also indicated a higher than normal prevalence of thyroid disorders in type 2 diabetic patients, with hypothyroidism being the most common disorder. [1]evalence of thyroid disease in the general population is 6.6%. [1]erros et al. [18] found that the prevalence of thyroid disease in diabetics is 13.4% and was highest in type 1 diabetic females and lowest in type 2 diabetic males.Celani et al. [3] found that prevalence of thyroid disease in type 2 diabetics was 31.4%, out of which SCH was most common form (48.3%), followed by subclinical hyperthyroidism (24.2%), overt hypothyroidism (23.1%) and overt hyperthyroidism (4.4%).The study even reported that 33% of type 2 diabetics with thyroid disease had high levels of anti-TPO antibodies.Fernández-Real et al. [2] reported that thyroid function tests are intrinsically linked to variables of insulin resistance and endothelial function, therefore implying the possibility that underlying factors lead simultaneously to increased serum TSH, insulin resistance, ensuing dyslipidemia and altered endothelial function.
In hypothyroidism, glucose homeostasis is also affected although its clinical impact is less obvious.Decreased glucose disposal (as compared with euthyroid subjects) has been proved in hypothyroid patients.Hypothyroidism results in unimpaired or decreased liver glucose output thereby compensating for insulin resistance present in peripheral tissues and accounting for the diminished insulin requirement for glycemic control in hypothyroid diabetic patients.Insulin resistance has been also reported in subclinical hypothyroidism, adding one more possible mechanism to the association of sub-clinical hypothyroidism and cardiovascular risk.
Only a few studies have explored the effects of sub-clinical thyroid dysfunction in the diabetic population.Patients with SCH had a higher prevalence of retinopathy, especially the sight-threatening form, when compared with their type 2 diabetic euthyroid counterparts. [19]Both SCH and hyperthyroidism have been linked to increased cardiovascular risk.
In the present study, serum TPO antibody elevation was seen in 11 (84.6%)SCH patients, indicating thyroid disease of autoimmune etiology.In a study by Celani et al., [3] it was observed that 61.3% SCH patients with T2DM had elevated serum anti-TPO antibody levels.
Celani et al. [3] also observed that the remaining 38.7% SCH patients who were negative for anti-TPO antibody, showed decreased serum TSH concentrations when retested after 2 months of adequate treatment for DM.

CONCLUSION
SCH is common among type 2 diabetic patients, especially in females.
It is most commonly secondary to autoimmune thyroid disease.Microvascular complications are commonly observed in this group of patients with dual endocrinal disorder treating physicians should routinely screen SCH in patients with diabetes mellitus to prevent complications.
International Journal of Medicine and Public Health | Oct-Dec 2013 | Vol 3 | Issue 4

Table 1 : Gender distribution of thyroid dysfunction Gender
Diabetic nephropathy was observed in 3 SCH patients, comprising 23% of all the SCH patients in the study.All the above 3 patients had nephropathy in the form of microalbuminuria.Blood urea and serum creatinine levels were within normal range in all the SCH patients.Comparison was done between SCH patients with nephropathy and SCH patients without evidence of diabetic nephropathy, based on duration of DM, serum HbA1c levels and serum TSH level.
Total number of patients Euthyroidism, N (%) Subclinical hypothyroidism, N (%) Overt hypothyroidism, N (%) International Journal of Medicine and Public Health | Oct-Dec 2013 | Vol 3 | Issue 4 SCH patients with diabetic nephropathy had a mean serum TSH value of 7.29 ± 1.77 μIU/ml, mean serum HbA1c of 8.73 ± 2.45% and mean duration of DM being 8 ± 2.94 years.SCH patients without nephropathy had mean serum TSH of 5.57 ± 1.17 μIU/ml, mean serum HbA1c of 7.58 ± 1.57% and mean duration of DM being 5.6 ± 3.2 years.No statistically signifi cant difference was found between the two groups in any of the above study variables.

Table 3 : Comparison between the two groups of SCH patients based on presence/absence of clinical features of hypothyroidism, with respect to TFT parameters TFT parameters SCH patients Number of patients Mean value±SD
SCH = Subclinical hypothyroidism, SD = Standard deviation, TSH = Thyroid-stimulating hormone, TFT = Thyroid function tests

Table 4 : Comparison between SCH patients with diabetic microvascular complication and SCH patients without diabetic microvascular complication
SCH = Subclinical hypothyroidism, SD = Standard deviation, DM = Diabetes mellitus, TSH = Thyroid-stimulating hormone, HbA1C = Hemoglobin A1c International Journal of Medicine and Public Health | Oct-Dec 2013 | Vol 3 | Issue 4 Diabetic patients have a higher prevalence of thyroid disorders compared with the normal population.Because patients with one organ-specifi c autoimmune disease are at risk of developing other autoimmune disorders and thyroid disorders are more common in females, up to 30% of female type 1 diabetic patient have thyroid disease.The International Journal of Medicine and Public Health | Oct-Dec 2013 | Vol 3 | Issue 4