The Relationship of Glycemic Exposure (HbA1c) and Dyslipidemia with Subclinical Hypothyroidism in Patients with Type 2 Diabetes Mellitus
Hari Hendarto, Dante Saksono Harbuwono, Imam Subekti, Siti Setiati
Abstract
Type 2 diabetes mellitus (T2DM) is known to have an association with subclinical hypothyroidism (SCH). The number of cases for DMT2 with SCH is higher than that of T2DM without SCH. Here, patients with SCH have a high risk to suffer from dyslipidemia. This study aims at examining the association of dyslipidemia with retinopathy in patients with T2DM and SCH. The research in this study uses cross- sectional design. The samples are adult patients who have been diagnosed with T2DM for at least 1 year, have been admitted to the outpatient polyclinic of the Endocrine Metabolic Division at Dr. Cipto Mangunkusumo National Public Hospital, and have met the inclusion criteria. The data collected includes blood glucose control, TSHs lipid profile, fT4 and retinopathy. As the result, the study shows the proportion of SCH in T2DM patients is 7.2% and most of the patients are over 60 years old. T2DM patients with poor blood sugar control (HbA1c>7) have a 3.664 time risk to suffer from SCH compared to those who can control their blood sugar well (p: 0.010). In the case of T2DM patients with SCH who are associated with dyslipidemia, the risk of developing retinopathy is 2.76 times greater than those without dyslipidemia (p: 0.014). In conclusion, there is a significant relationship between SCH and blood sugar control in T2DM patients, SCH and dyslipidemia in T2DM patients, and dyslipidemia and retinopathy in T2DM patients with SCH respectively.
Keywords: Type 2 Diabetes Mellitus, Subclinical Hypothyroidism, Dyslipidemia, Retinopathy
INTRODUCTION
Hypothyroid disorders are endocrine diseases that are quite common in society. In 1979, Gray et. al.1 first examined the association of diabetics with thyroid hormone disorders. In subsequent studies, a significant relationship between patients with type 1 diabetes (T1DM) and thyroid disorders, especially hypothyroidism, has been proven. This relationship is understandable due to the fact that both are related to immune
system disorders. Tunbridge et. al.2 have found T1DM patients with thyroid disorders have 2-3 times more risk compared to the general population in their study. In the meantime, hypothyroid cases which are associated with Type 2 Diabetes Mellitus (T2DM) patients are still unknown.345 In Jordan, for example, 12.5% of treated T2DM patients are found to have thyroid disorders.6 In Saudi Arabia, 16% of T2DM patients also have thyroid disorders.7 In a study conducted on T2DM patients in Greece, 12.3% of them suffer from thyroid disorders.8 The three aforementioned studies also show the subclinical hypothyroidism (SCH) is the most common thyroid disorder for patients with T2DM. SCH is defined as a condition where the serum Thyroid Stimulating Hormone (TSH) concentration increases, but the serum thyroxine (T4) and serum triiodothyronine (T3) are within normal limits, and no typical clinical symptoms of hypothyroidism are found.910
Retinopathy is a micro-vascular complication which is often found in patients with T2DM. According to data from the World Health Organization (WHO) in 2002, the number of cases of blindness due to retinopathy reached 5% of the 37 million cases of blindness worldwide.11 Several causative factors including insulin resistance, chronic inflammation, and oxidative stress that occur in diabetes patients are known to be the factors causing damage to the endothelial cells of the retinal blood vessels in the eyes.12 However, not all diabetic patients with high sugar levels must be accompanied by retinopathy. In the case of diabetic patients whose blood sugar is controlled, but remains affected by retinopathy, other factors may influence the retinopathy disorder. In a study conducted to T2DM patients with retinopathy, the average total cholesterol and low- density lipoprotein (LDL) levels are found significantly increasing when compared to those without retinopathy.13 Interestingly, some studies claim besides glucose control, dyslipidemia improvement by consuming statins or fibrates in T2DM patients is proven to reduce the progressivity of retinopathy.14 This suggests that dyslipidemia may have a role in the process of retinopathy in T2DM patients.
Several studies have shown SCH is one of the risk factors to increase blood cholesterol levels.15161718 SCH Patients who are older than 60 years old has higher risk to suffer from dyslipidemia.19 In the meantime, some other studies have found the risk of dyslipidemia increases as the TSH levels go higher.20 According to some studies, hypothyroid patients with dyslipidemia can actually reduce their cholesterol and LDL
levels by doing hypothyroidism (levothyroxine) therapy, unless there are other predisposing factors causing the increased cholesterol levels in their blood.21 Other researchers have found SCH patients who get levothyroxine therapy decrease their total of cholesterol by an average of 9-15 mg/dL and LDL by 11 mg/dL respectively.2223
According to the ATA/AACE guidelines, SCH patients with TSH levels
>10 μIU/mL can get hypothyroidism therapy, levothyroxine, for example, to reduce the risk of death from cardiovascular disorders or other causes. Meanwhile, hypothyroid therapy is not recommended for hypothyroid patients with TSH levels still below 10 μIU / mL. Here, observing as well as assessing clinical deterioration or new additional examination data is more than sufficient.24 However, some studies show a significant reduction in mortality for hypothyroid patients who have low TSH levels below 10 μIU/mL and get levothyroxine therapy, compared to those who do not do the therapy.25
Parle et. al.26 claim SCH patients who do not receive levothyroxine therapy have only 5% of their TSH levels returned to normal after 1 year, the remaining TSH levels would remain high. Another study finds 33% to 55% of SCH patients who are left without treatment would develop clinical hypothyroidism.27 Further, some other studies mention the factor that plays a role in changing SCH to overt hypothyroidism is high TSH levels.28 This suggests lowering TSH levels is an important goal in the initial procedures for SCH patients to prevent further abnormalities or complications.
THEORETICAL REVIEW
Subclinical Hypothyroidism (SCH) is a condition where serum Thyroid Stimulating Hormone (TSH) increases above the normal values, but the free T3 and T4 levels are within normal limits.29 Generally happening without clinical symptoms, SCH is often undiagnosed. Therefore, SCH diagnostics can only be made through laboratory examination. The upper limit value of the normal TSH value used in this study is 4.0 μIU/mL, adjusted to the value limit used by most studies on hypothyroidism in diabetic patients.30 In addition, 4,0 μIU/mL is the standard reference value used by various laboratories.3132 Inadequate production of thyroid hormone in SCH causes compensation for elevated TSH levels to keep thyroid hormones (T3 and T4) within normal limits. If the T3 and T4 levels, for example, remain low even though the TSH level is high, an overt
hypothyroid consequently occurs. Levothyroxine is a therapeutic option in hypothyroid patients.3334
Several studies have shown SCH that happens to T1DM patients is associated with autoimmune disorders, but it is considered unclear in T2DM. In their study, Celani et. al.35 find anti-TPO positive in 61.3% of T2DM patients with SCH. This indicates the same result as in T1DM disease. In T2DM, the autoimmune disorders involved cannot be ruled out. Another method to detect thyroiditis is thyroid ultrasound.
According to Yamashiro et. al.36, the thyroid ultrasound examination is a very useful to diagnose thyroiditis disorders in addition to clinical and laboratory examinations.
The function of the thyroid gland has long been known to have an association with blood sugar homeostasis, fat metabolism and enzymes that play a role in the lipoprotein transport process.37 The relationship between carbohydrate consumption and thyroid hormone production was first suggested by Danforth et al.38 In diabetic patients, thyroid hormone response decreases due to the TSH, resulting in a hypothyroid state.3940 The hypothyroid patients often suffer from dyslipidemia.4142434445 According to the research conducted by Zhang et. al.46, the TSH receptors in addition to the thiorid gland are also present in the liver, indicating the involvement of thyroid hormone in regulating the functions of liver. Thyroid hormones are known to be able to inhibit cholesterol synthesis by inhibiting hydroxy-methylglutaryl coenzyme A (HMG-coA) reductase which consequently causes it inactive.
The thyroid hormones also help the liver clear excess cholesterol from the bloodstream. Here, the blood cholesterol is transported to the bile and, in turn, excreted with feces. In addition, the thyroid hormones can reduce cholesterol absorption in the intestine. When their levels decrease, the liver is unable to clear excess cholesterol, fatty acids and blood triglycerides. The hypothyroid condition also stimulates HMG-coA activity which consequently increases cholesterol in the blood.47 Some studies shows SCH patients have a high risk of developing heart disease due to disturbances in the endothelium of blood vessels and increasing the cholesterol levels in the blood. Other studies find SCH patients with dyslipidemia and diabetes have a higher risk of atherosclerosis and coronary heart disease compared to those without diabetes. In patients without insulin sensitivity disorders, according to Bakker et. al.48, the increase in TSH is not always followed by an increase in LDL cholesterol. However, different conditions are
found in patients with insulin resistance, a strongly positive correlation between the increase in TSH and the high levels of LDL cholesterol.
In T2DM patients with SCH, retinopathy complications in the eyes are often found. Here, the insulin resistance that occurs in diabetes and SCH causes a decrease in the dilatation of blood vessels in the retina and the formation of fibrosis. The long-term effect is damage to the blood vessels in the retina.49 In addition, an increase in serum C- reactive protein (CRP) is also detected in patients with SCH or diabetes. This protein is a marker of a non-specific inflammatory reaction in the body,50 which causes damage to the endothelial cells of small blood vessels in the retina.51
Some experts believe patients with uncontrolled diabetes and dyslipidemia are required to conduct a screening examination for the possibility of hypothyroidism.5253 For this reason, it is essential to know and understand the factors that influence the severity of retinopathy. In this study, the risk factors to examine include chronic hyperglycemia which is measured through HbA1c examination, and serum lipid levels consisting of cholesterol, triglyceride, LDL and HDL levels.
RESEARCH METHODS
Cross-sectional study is used as the research design in this study. The study was conducted at the diabetes polyclinic, Endocrine Metabolic Division, Department of Internal Medicine, Dr. Cipto Mangunkusumo National Public Hospital in March-April 2016. The number of study population is 278 adult patients with T2DM. The samples are the same patients who participated in the Diagnostic score of hypothyroidism in Type 2 Diabetes Patients study conducted at the diabetes polyclinic, Endocrine Metabolic Division, Department of Internal Medicine, Dr. Cipto Mangunkusumo National Public Hospital and was completed in August 2015. The samples are those who have met the acceptance criteria, not the rejection criteria. The data used in this study includes the history of T2DM diagnosis, age, sex, occupation, education and glucose control. In addition, the data which is specifically drawn for this study is lipid profiles, TSHs, fT4 and retinopathy disorders.
Acceptance Criteria
a. Patients diagnosed with T2DM for at least 1 year.
b. Over 18 years old (adult).
c. Ability to communicate and be interviewed to complete the data variables needed in this study.
Rejection Criteria a. T1DM patients.
b. Pregnant patients. Anti-thyroid or thyroid hormone medications and other drugs may affect the patients’ thyroid status.
All T2DM patients who have been admitted to the diabetes polyclinic, Endocrine Metabolic Division in the Department of Internal Medicine and have met the acceptance criteria, not the rejection criteria, were included during the study period until the sample size was found.
Before data entry, data editing is carried out. The editing here is intended to facilitate the data entry stage which is completed through a coding process. The SPSS 16.0 is used to calculate and analyze the data. Univariate analysis, for example, is applied to each variable in order to see the distribution and percentage of each category. In addition, bivariate analysis is also performed to find the relationship between the two variables, independent and dependent variables, using chi-square test (X2). The level of significance is α = 0.05, which means the variables are said to be significantly related if the p value is <0.05. Further, the data obtained are presented in a narrative, textual, and tabular manner. Each variable is interpreted descriptively and analytically.
The Ethics in clinical research (with human as subjects) refer to the Helsinki Declaration in 1964. This guideline is summarized in the “Medical research combined with professional care (clinical research)” item in the Indonesian Medical Research Ethics. In this study, the researchers have asked for ethical clearance (ethical approval) from the Medical Research Ethics Committee in the Faculty of Medicine, University of Indonesia. They use patients as samples, who have undergone examination according to the applicable protocol. Patients or their families are given an explanation regarding the aims and objectives of the research and the benefits expected from it. After understanding the aims and objectives, they are asked to sign a letter of consent to be included in the research. Ethical review and statement of passing the ethical review have been approved
by the Standing Committee for Research Ethics in the Faculty of Medicine, University of Indonesia. All data obtained and used in this research has remained confidential.
RESULTS AND DISCUSSION
The study subjects are diabetic patients who have been admitted to the diabetes polyclinic, Endocrine Metabolic Division, Department of Internal Medicine, Dr.
Cipto Mangunkusumo National Public Hospital and have met the predetermined acceptance criteria. A total of 278 patients have met the criteria and have stated their consent to be included in this study. For subjects who required some treatment, a treatment and evaluation were carried out according to patient service standards at the hospital. The basic characteristics of the study subjects are illustrated in table 1 on the following page.
Table 1. Basic Characteristics of the Study Subjects.
Characteristics N (%)
Gender
Man 116 (41.7)
Woman 162 (58.3)
Age (Years), Median 60 (37 – 86) Age Group
≥60 years 140 (50.4)
<60 years 138 (49.6)
Occupation
Unemployed 8 (2.9)
Housewife 115 (41.4)
Retired 89 (32.0)
Self-employed 32 (11.5)
Private Employee 11 (4.0)
State Employee 23 (8.3)
Education
Not in school 2 (0.7)
Primary School 44 (15.8)
Junior High School 34 (2.2)
Senior High School 118 (42.4)
Diploma 3 27 (9.7)
Higher Education 53 (19.1)
Family History of Thyroid
Yes 11 (4.0)
No 267 (96.0)
SCH Proportion in T2DM patients
Based on the operational definition, SCH patients are subjects with a TSHs value above the normal range value and their fT4 value is within the normal range. In the meantime, overt hypothyroid is addressed to subjects with a TSHs value above the normal range value and fT4 value below the normal range. The SCH proportion in T2DM patients is described in table 2 and table 3.
Table 2. The SCH Proportion in T2DM Patients by Gender
Total Number
of Patients
SCH (%) Overt Hypothyroid (%)
Euthyroid (%)
Man 116 (41.7) 10 (3.6) 0 (0) 106 (38.1)
Woman 162 (58.3) 10 (3.6) 2 (0.72) 150 (55.7)
Total 278 (100) 20 (7.2) 2 (0.72) 259 (93.8)
The table shows the SCH proportion in T2DM patients who have been admitted to have treatment in Endocrine, Metabolic and Diabetic Policlinic is 7.2%, greater than the overt hypothyroid proportion (0.72%). Here, the number of SCH proportion in man and woman is not different.
Table 3. The SCH Proportion in T2DM Patients by Age
Total Number of Patients
SCH (%) Overt
Hypothyroid (%)
Euthyroid (%)
Man 116 (41.7) 12 (4.32) 1 (0.36) 127 (45.68)
Woman 162 (58.3) 8 (2.88) 1 (0.36) 129 (46.4)
Total 278 (100) 20 (7.2) 2 (0.72) 259 (93.8)
According to the table, T2DM patients over 60 years old get more number of the SCH proportion.
The Association of Glucose Control with SCH in T2DM patients
The glucose control is measured using HbA1c levels with HbA1c <7% as the cutoff value, according to the Diabetes Melitus 2 Consensus target of the Perkumpulan Endokrinologi Indonesia-PERKENI (Indonesian Society of Endocrinology) in 2015.54
Table 4. The Association of HbA1c with SCH in T2DM patients
Variable SCH
PR (IK 95%) p
Yes No
HbA1c
≥ 7 16 (12.6) 127 (88.8) 3.664 0.010
< 7 4 (3.1) 127 (96.6) (1.257 – 10.680)
* In an analysis using Chi Square test, x is meaningful if the p value is <0.05
Table 4 indicates out of 20 T2DM patients with SCH, 16 subjects (12.6%) have HbA1c >7. Only 4 subjects (3.1%) get HbA1c <7. This means DM2 patients with HbA1c >7 have 3.664 times greater risk of getting SCH than those with HbA1c <7 (p:
0.010).
Dyslipidemia and Retinopathy in T2DM Patients with SCH
In this study, the dyslipidemia and retinopathy proportions in T2DM patients with SCH are examined. The association of dyslipidemia with retinopathy is then measured using the Fisher Exact test. The measurement result is shown in Table 5.
Table 5 The Association of Dyslipidemia with Retinopathy in T2DM Patients with SCH
Variable SCH
PR (IK 95%) p
Yes No
HbA1c
≥ 7 16 (12.6) 127 (88.8) 3.664 0.010
< 7 4 (3.1) 127 (96.6) (1.257 – 10.680)
* In an analysis using Fisher Exact test, x is meaningful if the p value is <0.05
Referring to table 5, 14 of 20 T2DM subjects with SCH suffer from dyslipidemia while 6 other subjects do not have any. Further, 13 of the 14 T2DM subjects with SCH and dyslipidemia also experience retinopathy. Only 1 subject with dyslipidemia do not suffer from retinopathy. In addition, table 5 also mentions T2DM patients with SCH and dyslipidemia have 2.8 times greater risk of developing retinopathy than those without dyslipidemia (p: 0.014).
DISCUSSION
As seen in table 1, the number of subjects by gender is evenly distributed, 116 men (41.7%) and 162 women (58.3%). The proportion by gender is not really different. However, the greater proportion of women than that of men is a common proportion found in T2DM patients.5556 Here, the study results are expected to be generalized for both men and women due to their similar characteristics as the study subjects.
The other basic characteristic as illustrated in table 1 is age. The youngest age of the study subjects is 37 years old while the oldest one is 86 years. This age range is in line with the characteristics of T2DM which are generally experienced at the age of 40 years and above.57 In this study, the median value by the age criteria is 60 years, which is in line with the age limit according to WHO and the Law No. 13/1998 on the Welfare
of the Elderly in article 1 paragraph (2).58 For this reason, the cut-off point by age used in this study is 60 years. The study shows 140 subjects (50.4%) are considered as the elderly (≥ 60 years), while 138 subjects (49.6%) are under 60 years old. In another word, the number of subjects over and under 60 years of age who have participated in this study is relatively similar.
In terms of socio-demographic characteristics; education and occupation, both do not have a direct association with the risk of diabetes and thyroid disorders.
However, the level of education, ranging from primary to higher education and most of the subjects are primary graduates, is very useful in helping them understand the questions asked during interviews. Regarding the occupation, this variable is rarely discussed in details considering it plays a small part in giving meaning to the study on T2DM and thyroid disorders. The majority of subjects are housewives (41.4%), followed by retirees (32%). It is suffice to say the influence of occupation on the study results can be neglected.
Further, family history of thyroid disorders is an important variable due to the genetic risk of various thyroid disorders. However, as the number of subjects with a history of thyroid disorders in the family is only 11 people (4%), compared to those who do not have any family history (267 people), its effect on this study can be ignored.
Referring to Table 2, the proportion of SCH in T2DM patients is 7.2% and overt hypothyroid only 0.72% respectively. The meta-analysis study conducted by Han et. al. finds people with T2DM are more at risk to suffer from SCH than those without diabetes. The proportion obtained in this study is lower than that of studies conducted in India (16.3%), but not much different from the one conducted in America.59 In addition, the proportion of overt hypothyroidism which is much lower than that of SCH in the study is also in line with the studies conducted in India and America. This result indicates that SCH, even though without any typical clinical complaints, needs special concern considering the risk of developing into overt hypothyroidism. In a study about untreated SCH patients for 10 to 20 years, it is found 33-55% of them will develop clinical hypothyroidism.
In this study, the SCH cases in T2DM patients are mostly found at the age above 60 years. Such result is in line with the previous studies stating the risk of SCH increases by 20% at the age of 60 years. Here, the number of men and women with SCH is not different (Table 3).
As described in Table 4, T2DM patients with poor blood sugar control (HbA1c >7) experience 3.664 times greater risk of developing SCH compared to T2DM patients whose blood sugar is well controlled. Several previous studies say SCH has a relationship with poor glucose control in T2DM patients, although the exact mechanism is not yet known for sure.606162
Table 5 illustrates T2DM patients with SCH and dyslipidemia have 2.76 times greater risk of suffering from retinopathy than those without dyslipidemia. The association among hypothyroidism, dyslipidemia and vascular disorders has been known since 1967.63 Premature babies born under 27 weeks of gestation are often accompanied by hypothyroid disorders caused by hypothalamic-pituitary axis and thyroid disorders.64 In addition, the premature babies with hypothyroidism have a high risk of suffering from premature retinopathy.65 In mice, hypothyroidism can cause impaired permeability of blood vessels in the retina.66
ATA recommends screening tests for thyroid function only in children suffering from T2DM. For adults with T2DM, no specific recommendations concerning the need to screen-test the thyroid function has been made until now. This can cause SCH abnormality which is undetected since the beginning. It is different from overt hypothyroid which is easily detected early due to its typical clinical symptoms. The SCH diagnosis can only be confirmed through laboratory as it does not have any typical clinical symptoms.
The administration of thyroid hormone therapy according to the ATA recommendations is only given if the TSH level is >10 μIU/ml, while the TSH levels ranging from 4 to 10 μIU/ml are observable. This is risky because it can cause therapy for thyroid disorders, especially untreated SCH. According to some study, 75% of SCH patients have the TSH value <10 μIU/mL. In the case of 10-22 years without treatment, 33-55% of SCH patients develop overt hypothyroidism. Another study shows giving thyroid hormones to young rats can help the development of blood vessels in the retina.67
As described in Table 5, most of the T2DM patients with SCH suffer from dyslipidemia (14 of 20 subjects). Several previous studies have found the SCH rate is high in patients with dyslipidemia.6869 For this reason, patients with uncontrolled dyslipidemia should be screened for thyroid function. If, for example, hypothyroidism is detected, thyroid hormone therapy can be used to treat the dyslipidemia.
Based on the data, this study has several advantages, one of which is to report the association among SCH, T2DM, dyslipidemia and retinopathy. In addition, the study on the proportion of SCH in T2DM patients have been conducted in other countries, but it is the first in Indonesia. On the contrary, this study has a weakness. It is only conducted at one national diabetes reference hospital in Jakarta. Therefore, the results cannot fully brepresent the diabetes population in Indonesia. Further, the cross-sectional study as the research design cannot be used to conclude the existence of direct cause and effect relationship between the variables.
CONCLUSION
a. The proportions of SCH and overt hypothyroid diseases in T2DM patients are 7.2%
and 0.72%, respectively.
b. The association of poor glucose control with the SCH risk in T2DM patients is detected.
c. The association of SCH with dyslipidemia risk in T2DM patients is found.
d. The association of dyslipidemia with retinopathy risk in patients with T2DM and SCH is found.
SUGGESTIONS
a. This study has found the proportion of SCH in T2DM patients is high due to the serious complications. However, the clinical symptoms of SCH are not typical. To that end, it is necessary to consider early SCH screening in diabetic patients who suffer from dyslipidemia and poor glucose control.
b. Cohort studies are expected to conduct with a wider population scale and its results can be used as inputs to formulate clinical recommendations concerning early screening for thyroid disorders in T2DM patients.
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