Prevalence of Sub-Clinical Hypothyroidism among Diabetes Mellitus Patients with Vascular Complications

 

Sai Saran Thokada, Harsha Kandregula, Vinodkumar Mugada

Vignan Institute Pharmaceutical Technology, Duvvada, Andhra University Visakhapatnam

 

ABSTRACT:

Diabetes mellitus and thyroid dysfunction are the two most commonly seen endocrine disorders in outpatient care with reported global prevalence ranging from 2.2 to 17%. Thyroid dysfunction is a spectrum of disorders of the thyroid gland which manifests either as hyper or hypothyroidism. In this case, we notice different circulating levels of TSH. Studies have found that thyroid dysfunction is much common in diabetic population compared to non-diabetic population, diabetes and thyroid disorders have been shown to influence each other mutually because of various pathological reasons. The prevalence of hypothyroidism is also based on gender, age, and other genetical factors. Publications were identified through keyword searches of electronic databases and the internet. The databases included are Pubmed, Medline, Trip Medical Database, Embase, Cochrane Library, and Science Direct. Data extraction included Information about Study information, Interventions, Search strategy, Type of review. The extraction was carried out from the studies that were identified for inclusion. Type 2 diabetic patients with subclinical hypothyroidism are associated with an increased risk of nephropathy and cardiovascular events. The clinical importance of the biochemical abnormalities is not clear. Microvascular complications have been most commonly observed.

 

 

 

 

 

INTRODUCTION:

Hypothyroidism is a condition in which the thyroid gland fails to produce a sufficient amount of thyroid hormone to meet the metabolic demands of the body. In laboratory testing, overt hypothyroidism is classified as an elevated level of serum thyrotropin-stimulating hormone (TSH) in combination with low thyroxine (T3) or triiodothyronine (T4) levels. Subclinical hypothyroidism is a biochemical diagnosis defined by a normal free T4 level and an elevated TSH level. Isolated hypothyroxinemia is characterized by a normal serum TSH and low serum FT4 levels. Thyroid hormones exert profound effects in the regulation of glucose homeostasis, and hypothyroidism can have profound effects on glucose metabolism and insulin secretion ^{[1, 2]}.

 

The association between type 2 diabetes mellitus and SCH is well known, with the reported prevalence of SCH in diabetes varying between 2.0 and 17% ^{[3, 4]}. Although SCH is common in patients with type 2 diabetes, the clinical importance of the biochemical abnormalities is unclear. SCH has been reported to be associated with endothelial dysfunction independent of other well-known atherosclerotic risk factors^[5]. Numerous epidemiological studies indicate the higher prevalence of overt hypothyroidism in type 2 diabetes mellitus (T2DM) population than in the general population ^[6,7]. However, the relationship between subclinical hypothyroidism (SCH) and T2DM is controversial.

 

Diabetes mellitus and thyroid dysfunction are the two most common endocrine disorders seen in outpatient care with reported global prevalence ranging from 2 to 17%. Thyroid dysfunction is a spectrum of disorders of the thyroid gland which manifests either as hyper or hypothyroidism and is reflected in circulating levels of TSH. There is a deep, fundamental relation between diabetes mellitus and thyroid dysfunction ^[8]. Hyperthyroidism impairs glycemic control in diabetic subjects, while hypothyroidism increases susceptibility to hypoglycemia thus complicating diabetes management ^[10]. An association between type 2 diabetes mellitus and SCH is not uncommon, with an SCH prevalence of 2.2–17% reported in previous studies ^[9,11].

 

METHODOLOGY:

Search like Pubmed, Medline, Trip Medical Database, Embase, Cochrane Library, and Science Direct. Studies having patients with age between 18 to 60 years, gender among both males and females are considered, both inpatients and outpatients are monitored, only diabetic patients are included. Studies having patients with comorbid conditions, pregnant and lactating women and patients of age below 18 and above 60 years are excluded. Three stages of screening was performed to include relevant studies. Stage 1 is title screening where in duplicate titles were excluded. Stage 2 is abstract screening where abstract was screened for inclusion into the review. Stage 3 is full paper screening where in full paper was screened for inclusion into the study.

 

DISCUSSION:

Vascular endothelial dysfunction is supposed to be an important factor in the pathogenesis of microvascular and macrovascular complications in diabetes. Endothelial dysfunction has also been described in subclinical hypothyroidism as well as in those with upper normal TSH values ^{[12, 13]}. The association between microvascular complications and subclinical hypothyroidism and TSH values has not been comprehensively studied. Among the few studies done on the subject, the findings have been opposing. A cross-sectional study with a case-control analysis revealed a 19.1% prevalence of subclinical hypothyroidism in type 2 diabetic patients, and this is higher than data reported by Gao et al ^[14]. NHANES III, a population study, reported a high prevalence of subclinical hypothyroidism was in females (5.8%).

 

Perros et al., ^[3] found that the occurrence of subclinical hypothyroidism was 3.3% in men and 4.6% in women with Type 2 diabetes. Amira et al., ^[38] reported a high prevalence of subclinical hypothyroidism in females (14.5%) with Type 2 diabetes and revealed a dominance of females than the above-said studies. The patients with SCH had a significantly longer duration of diabetes in comparison to the euthyroid group (p=0.007).

 

Gao et al., ^[14] concluded that there is no association between subclinical hypothyroidism and microvascular complications in type II diabetes. It is known that thyroid hormone plays an important role in kidney growth and preservation of many of its functions ^[17]. In view of the extremely high prevalence of hypothyroidism in those with T1DM, screening for thyroid disease

 

Should be done in a systematic fashion. Regular screening will unmask a substantial number of individuals with asymptomatic thyroid dysfunction. Current guidelines advise screening type 1 diabetic subjects at the time of diagnosis or initial contact ^[15,16]. In other words, the glomerular filtration rate in hypothyroid patients is approximately one-third lower than the corresponding values in euthyroid individuals ^[19]. The presence of undiagnosed hypothyroidism may increase cardiovascular risk by aggravating dyslipidemia, insulin resistance, obesity and vascular endothelial dysfunction^[18,21]. Suher et al., ^[22] suggested that subjects with hypothyroidism may have increased urinary albumin excretion rate which came consistency to our result as there was a significant increase in the mean of albuminuria in patients with SCH. Yasuda et al., ^[23] subclinical hypothyroidism was associated with albuminuria in type 2 diabetic patients and the TSH level was found to be an independent risk factor for the presence of albuminuria. In our study, the prevalence of IHD was significantly higher in patients with SCH than in patients without SCH.

 

Jim et al., ^[47] provide evidence that SCH in patients with Type 2 diabetes is associated with a high prevalence of CHD. This issue can be explained by overt thyroid hormone deficiency which leads to increases in total cholesterol and LDL–C levels ^[23] which is evident in our result. Also, thyroid hormone deficiency can also damage vascular function directly ^{[24, 25]}. Furthermore, several researchers have stated that SCH impairs the relaxation of vascular smooth muscle cells, thereby inducing increased arterial stiffness and systemic vascular resistance ^[26], as well as changes in endothelial function due to decreased nitric oxide availability ^{[27, 28]}. Endothelial dysfunction in SCH could be due to inflammation ^[29].

 

The case for annual screening in patients with T2DM is less clear-cut. A number of guidelines are either not specific regarding routine monitoring or explicitly recommend against routine annual screening in patients with T2DM^[30]. Hollander et al., ^[31] demonstrated that renal function was better in 32 patients with hypothyroidism after thyroxin treatment, and it does not follow the impact of treatment of subclinical hypothyroidism on risk reduction of diabetic vascular complication. Whether the management of patients with subclinical hypothyroidism affects important cardiovascular outcomes remains an unanswered question ^{[31, 32]}. Chu and Crapo suggested that there was a little or no benefit of thyroxine therapy in most patients with subclinical hypothyroidism ^[33]. However, they also concluded that thyroxine treatment may be beneficial in selected patients with certain clinical circumstances ^{[34, 35]}.

 

Kim et al., ^[36] didn’t find any significant difference in the duration of diabetes between euthyroid and SCH patients. Although obesity affects hypothalamic-pituitary-thyroid axis directly or indirectly leading to variations in thyroid function tests, ^[36] there was no significant difference in BMI between SCH diabetic patients and euthyroid group (P=0.092). In this cross-sectional analysis of type 2 diabetes mellitus, subclinical hypothyroidism was associated with a higher frequency of microvascular (diabetic nephropathy, and retinopathy) and macrovascular complication (IHD). Chen et al., study which showed that type 2 diabetic patients with subclinical hypothyroidism are associated with an increased risk of nephropathy and cardiovascular events, but not with retinopathy ^[37].

 

 

 

Kim et al., ^[36] showed that SCH was associated with sight-threatening diabetic retinopathy, but not associated with diabetic nephropathy. However, he did not analyze the relationship between SCH and prevalence of macrovascular complications. He explained the link between SCH and diabetic retinopathy by insulin resistance that was higher in the SCH than the euthyroid group.

 

Diabetes Mellitus is a silent disease and is now recognized as one of the fastest growing threat to public health in almost all countries of the World. It is also called the disease of prosperities. ^[38] The prevalence of GDM is raising worldwide parallel to the increment in the prevalence of obesity and DM2. ^[39] The study revealed that the prevalence of Pre-diabetes and DM were 12.05% and 08.45% respectively. Age group (45-60 years) has the most cases of DM. ^[40] It is well recognized fact that diabetes mellitus is associated with increased morbidity and mortality. But, how this disease affects functional health status and sense of wellbeing is still not well established. ^[41] Diabetes mellitus (DM) was likely first described about 3500 years ago and given its name about 2200 years ago by Demetrios of Apamaia.^[42] Diabetes is generally considered as chronic disorder of metabolism that affects the insulin production capacity of body.^[43] Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose) levels that result from defects in insulin secretion, or action, or both.^[44] Diabetes Mellitus (Type 2) is a major health issue all over the world. It is rapidly growing metabolic disorder characterized by hyperglycaemia with disturbances in carbohydrate, fat and protein metabolism. ^[45] Diabetes mellitus is a very common metabolic disorder of endocrine system, every year large Number of people suffered from diabetes. ^[46] The mechanism of action of Saxagliptin hydrochloride and Glibenclamide is quite different. Saxagliptin hydrochloride inhibits the dpp-4 enzyme and promotes insulin synthesis and release. While Glibenclamide stimulation of insulin release from the B2 cells of the pancreas by blocking the ATP-sensitive k+channels. ^[47]

 

 

S. No.	Author and Year	Type of Study	No. of Subjects	Outcome Measures	Outcome
1	Amira et al., 2017[48]	Cross-sectional study	110	Age (years) , Sex (M/F) Duration of DM(years) ,BMI (kg/m2) ,HbA1c (%) ,Total cholesterol, Triglycerides, LDL cholesterol,  HDL cholesterol,  TSH , T4 , Dyslipidemia ,HTN, Smoking	SCH has a higher prevalence of vascular complications in type 2 diabetes.
2	Umpierrez et al., 2003[49]	Cross-sectional study	58	Sex, BMI, TSH, TPO antibodies, Age, diabetes onset , Age, hypothyroidism, Time between the onset of diabetes and hypothyroidism .	All subjects with type 1 diabetes should undergo annual screening by serum TSH measurement to detect asymptomatic thyroid dysfunction, particularly those with positive TPO antibodies.
3	Klaus et al,1974 [50]	Cross-sectional study	114	Age, decrease in total insulin, first diagnosis.	The association of diabetes mellitus with primary hypothyroidism is more common.
4	Vibha et al., 2013[51]	Cross-sectional study	24	Thyroid disorders Hypothyroid (primary) Hypothyroid (subclinical) Hyperthyroid (primary) Hyperthyroid (subclinical)	There is a higher prevalence of thyroid disorders in type 2 Diabetics. This finding is more common in diabetic females. The most common thyroid disorder is hypothyroidism
5	Christian et al., 2013[52]	Cross-sectional study	2274	Age (years), Duration of diabetes (years), BMI z-score, HbA1c (%) , TSH (mIU/l), FT4 (pmol/l), TT4 (nmol/l) ,FT3 (pmol/l) ,TT3 (nmol/l) ,Cholesterol (mg/dl) ,LDL-cholesterol (mg/dl) ,HDL-cholesterol (mg/dl).	SCH is associated with increased levels of total cholesterol, and LDL-cholesterol.
6	Fei et al., 2016[53]	Cross-sectional study	41	Age(years), Female gender Cigarette smoking, Duration of diabetes (years), Insulin treatment, metformin treatment, BMI (kg/m2),  Serum TC > 5.7 mmol/L Serum LDL-C > 3.1 mmol/L Positive TPO- Ab	Among the 1662 T2DM hospitalized patients, 113 had hypothyroidism, including 26 (23 %) with overt hypothyroidism and 87 (77 %) with subclinical hypothyroidism.
7	Iacopo et al., 2005[54]	Case-study	25	Age ; BMI ; Dyslipidaemia; Hypertension	Among diabetic patients, the presence of severe diabetes was significantly associated with SH
8	Jin et al., 2010[55]	Cross-sectional study	15	Age ; BMI ; Sex ; Diabetes duration ; Systolic blood pressure ; Triglycerides.	Type 2 diabetic patients with SCH are associated with an increased risk of STDR.

 

 

CONCLUSION:

Vascular endothelial dysfunction is an important factor in the pathogenesis of microvascular and macrovascular complications in diabetes. Prevalence of subclinical hypothyroidism was reported as 2.2–17 %. Endothelial dysfunction has also been described in subclinical hypothyroidism as well as in those with upper normal TSH values. The association between microvascular complications and subclinical hypothyroidism and TSH values has not been comprehensively studied. Type 2 diabetic patients with subclinical hypothyroidism are associated with an increased risk of nephropathy and cardiovascular events, but not with retinopathy. Hence thereby we can say that there is no association between Hypothyroidism and diabetes mellitus but recommend all type 2 diabetes mellitus should have baseline evaluation of TSH and TPO antibodies and further precise dosing and specific treatment algorithm for thyroid dysfunction.

 

ACKNOWLEDGEMENTS:

We are thankful for our principal Dr. Y. Srinivasa Rao for his guidance and support in completing this review.

 

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