The Clinical Implications Of Thyroid Hormones Biology Essay

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Thyroid dysfunction is one of the major public health problems in Nepal. Laboratory tests facilitate early diagnosis before clinical features are obvious, increased sensitivity carries the price of decreased diagnostic specificity. Laboratory tests coupled with supportive clinical findings are frequently used to diagnose thyroid dysfunction. Historically, hypercholesterolemia and raised serum low density lipoprotein (LDL) cholesterol levels have been found to be associated with hypothyroidism. Therefore, assessment of altered lipid profile plays a supportive role in diagnosis of thyroid dysfunction. The aim of our study was to find out the variations of thyroid hormones and lipid profile in hyperthyroidism and hypothyroidism with their clinical implications.

Material and methods

It was a hospital based retrospective study carried out from the data retrieved from the register maintained in the Department of Biochemistry of the Manipal Teaching Hospital, Pokhara, Nepal between 1st July, 2009 and 30th June, 2010. The variables collected were age, gender, total T4, total T3, TSH, fT4, total cholesterol and triglyceride levels. Descriptive statistics and testing of hypothesis were used for the analysis of data.

Result

122 out of the 365 subjects selected for the study had some form of thyroid disorder. Of the 122 cases, 40 had hyperthyroidism, 42 had hypothyroidism and the remaining 40 were diagnosed to have subclinical hypothyroidism. The frequency of thyroid disorders was much higher in females as compared to their male counterparts. The mean value of each variable in cases except for age was statistically significant as compared to controls (p=0.001). Elevated levels of total T3 (CI 2.14 to 2.59),T4(CI 13.00 to 15.30) and fT4 (CI 2.51 to 2.81) associated with decreased TSH levels (CI 0.29 to 0.35) were found in cases of hyperthyroidism. The TSH values (CI 17.05 to 22.85) were markedly increased while T4 and T3 values were found to be less than the reference range in cases of hypothyroidism. There was significant increase in the mean concentration of total cholesterol (CI 268.83 to 289.79) and triglycerides (CI 154.81to 182.05) in cases of hypothyroidism. The fT4 (CI 1.08 to1.22) levels were in reference range and TSH levels (CI 9.59 to 10.50) were moderately raised in cases of subclinical hypothyroidism.

Conclusion

Thyroid dysfunction is common across all age groups and shows a strong female preponderance in Pokhara valley. It necessitates the measurement of thyroid hormones in women after the age of 50, in pregnancy and after delivery and in women and men with hypercholesterolemia. Therefore, timely screening and check up is necessary in order to curtail the problem of undiagnosed cases, giving specific consideration to patients who have high artherogenic profile. This will reduce the risk of future negative health events in older adults.

Key Words: Hyperthyroidism, Hypothyroidism, Subclinical Hypothyroidism, Thyroid hormones, Lipid profile

Introduction

Thyroid hormones are crucial for growth and regulation for the protein, carbohydrate and fat metabolism. Thyroid disorders are commonly separated into two major categories, hyperthyroidism and hypothyroidism, depending on whether serum thyroid hormone levels (T4 and T3) are increased or decreased respectively. These disorders may be due to congenital factors, genetic predisposition, inadequate levels of dietary iodine intake, pregnancy, radiotherapy, viral infection, surgery, underlying disease such as infiltrative disorders, or autoimmunity1-3. Graves Disease (diffuse toxic goitre) is a common cause of hyperthyroidism due to overactivity of the immune system (autoimmunity). Other causes are sub-acute (painful, viral) thyroiditis, silent thyroiditis (painless or postpartum thyroiditis) and toxic multinodular goiter4. In the UK, hyperthyroidism has a prevalence of around 2.7% in females, which is approximately 10 times more than the prevalence in males. Thyroid disorders remain undiagnosed in nearly 0.5% of the female population in the UK5. In a community survey comprising of 1210 participants (age ≥60 years) from the UK, the prevalence of undiagnosed overt hyperthyroidism was very low6. In a similar study conducted in Sweden, out of 1442 participants (age ≥ 60 yrs), only 2% of subjects were diagnosed to have thyrotoxicosis7. The leading cause of primary hypothyroidism in iodine deficient areas is Hashimoto's disease (chronic autoimmune thyroiditis)8. Pathophysiologically, there is cell-mediated and antibody-mediated destruction of the thyroid gland9. Other causes are mainly due to iodine deficiency, over treated Graves disease, anti-thyroid drugs and radioactive therapy. The prevalence of subclinical hypothyroidism ranges from 1% to 10% worldwide and is more common in women than men, with prevalence in women above 60 years of age approaching 20% in some reports5. In the United States National Health and Nutrition Examination Survey (NHANES III), the prevalence of overt hypothyroidism and subclinical hypothyroidism was found to be 0.3% and 4.3% respectively10. The annual incidence of primary hypothyroidism in women is 3.5 per 1000 and in men 0.6 per 1000 in the UK11. Women are 10 times at higher risk of developing hypothyroidism compared to men, with the difference being significant after thirty-four years of age. This is because the symptoms of hypothyroidism and menopause go hand in hand, leaving behind more chances of missing hypothyroid cases12. The changing immune environment and the requirements of a growing fetus make pregnancy and the postpartum period complicated and it could result in thyroid dysfunction13. Nepal is a mountainous landlocked area, situated far away from the sea. The geographical placement of the country along with high annual rainfall leads to low soil iodine content. These factors lead to a very high incidence of iodine deficiency disorders. The detection of hyperthyroidism and hypothyroidism in hospital based thyroid screening of suspected patient in eastern part of Nepal was reported to be 13.68% and 17.19% respectively in 2002 and 8.3% in 2010 for each disorder14.

Both hypothyroidism and hyperthyroidism have potentially fatal systemic manifestations. Therefore, accurate diagnosis of thyroid abnormalities is critical for clinicians as well as medical laboratories worldwide for appropriate management. Laboratory measurements of T3, T4 and TSH are crucial in helping clinicians to diagnose thyroid abnormalities. Historically, hypercholesterolemia and elevated serum low density lipoprotein cholesterol levels have been found to be associated with hypothyroidism. Therefore, assessment of altered lipid profile plays a supportive role in diagnosis of thyroid dysfunction 15. The aim of the current study was to find out the variations of thyroid hormones and lipid profile in hyperthyroidism, subclinical hypothyroidism and hypothyroidism.

Materials and Methods

It was a hospital based retrospective study carried out using data retrieved from the register maintained in the Department of Biochemistry of the Manipal Teaching Hospital, Pokhara, Nepal between 1st July, 2009 and 30th June, 2010. The variables collected were age, gender, T3, T4, TSH, fT4, total cholesterol and triglycerides.

Analysis of T3, T4, TSH and fT4 levels was done by ELISA (HUMAN) 16-18. Estimation of total cholesterol and triglycerides was done by semi autoanalyser Human 3500, Germany19. The commercially available kits of Human, Germany were used for estimation of all biochemical parameters.

Selection of Subjects:

Inclusion Criteria: Patients with abnormal thyroid profile

Exclusion Criteria: Patients having hepatic or renal dysfunction; history of heart failure, diabetes mellitus, stroke or ischemic heart disease; malignancy; alcohol or drug abuse were excluded from the study. Patients who had used any medications (within the previous six months) that might have contained corticosteroids, antifolates or lipid lowering agents were also excluded from the study.

The data collected was analyzed using Excel 2003, R 2.8.0, Statistical Package for the Social Sciences (SPSS) for Windows Version 16.0 (SPSS Inc; Chicago, IL, USA) and EPI Info 3.5.1 Windows Version. Z-test was used to compare the significance difference between two variables. A p-value of <0.05 (two-tailed) was used to establish statistical significance.

Result

122 out of the 365 subjects selected for the study had some form of thyroid disorder. Of 122 cases, 40 had hyperthyroidism, 42 had hypothyroidism and the remaining 40 were diagnosed to have subclinical hypothyroidism.

Table 1: Comparison of biochemical variables in cases and controls

Variables

Controls

(243)

Thyroid

p value

cases

Mean ± SD

Age

37.95 ± 15.54

Hyper

34.85 ± 16.59

0.248

Hypo

40.88 ± 15.32

0.258

Schypo

39.08 ± 17.4

0.678

T3

1.03 ± 0.42

Hyper

2.37 ± 0.74

0.001**

Hypo

0.37 ± 0.19

0.001**

Schypo

1.00 ± 0.29

0.571

T4

7.62 ± 1.75

Hyper

14.15 ± 3.7

0.001**

Hypo

2.21 ± 0.85

0.001**

Schypo

6.27 ± 1.17

0.001**

TSH

3.0 ± 1.99

Hyper

0.32 ± 0.10

0.001**

Hypo

20.5 ± 11.4

0.001**

Schypo

10.04 ± 1.46

0.001**

fT4

1.38 ± 0.36

Hyper

2.66 ± 0.48

0.001**

Hypo

0.56 ± 0.29

0.001**

Schypo

1.15 ± 0.21

0.001**

TCHO

167.21 ± 25.90

Hyper

143.12 ± 9.43

0.001**

Hypo

279.31 ± 34.65

0.001**

Schypo

257.88 ± 22.29

0.001**

TG

123.53 ± 22.66

Hyper

87.32 ± 18.31

0.001**

Hypo

168.43 ± 45.02

0.001**

Schypo

152.35 ± 53.55

0.001**

No. of cases : Hyper - 40, Hypo - 42, Schypo - 40

Hyper (Hyperthyroidism), Hypo (Hypothyroidism), Schypo (SubClinical Hypothyroidism)

T CHO (Total Cholesterol), TG (Triglycerides)

** Statistically significant (p value < 0.05)

Table 1 depicts that mean value of each variable in cases except for age was statistically significant as compared to controls (p=0.001). Elevated levels of total T3 (CI 2.14 to 2.59), T4 (CI 13.00 to 15.30) and fT4 (CI 2.51 to 2.81) associated with decreased TSH levels (CI 0.29 to 0.35) were found in cases of hyperthyroidism. The mean values of total cholesterol (CI 140.20 to 146.04) and triglycerides (CI 81.65 to 92.99) were lowered in cases of hyperthyroidism. The TSH values (CI 17.05 to 22.85) were markedly increased while T4 and T3 values were lowered in cases of hypothyroidism. There was significant increase in the mean concentration of total cholesterol (CI 268.83 to 289.79) and triglycerides (CI 154.81to 182.05) in cases of hypothyroidism. The fT4 (CI 1.08 to1.22) levels were in reference range and TSH levels (CI 9.59 to 10.50) were moderately raised in cases of subclinical hypothyroidism. The mean values of levels of total cholesterol (CI 250.97 to 264.78) and TG (CI 135.65 to 168.84) was increased as compared to controls in cases of subclinical hypothyroidism.

Table 2: Comparison of gender in cases and controls

Male

Female

p value

Cases(Hyper)

10

30

0.001**

Cases(Hypo)

6

36

0.001**

Cases(Schypo)

6

34

0.001**

Controls

58

185

0.001**

** Statistically significant (p value <0.05)

Table 2 shows that the frequency of thyroid disorders was much higher in females than males in both cases and controls. In the suspected cases, prevalence of thyroid disorders was 27.5% in males, 35.09% in females and 33.42% overall. It was found to be statistically significant.

Table 3: Gender wise comparison of biochemical variables in cases

Variables

Cases

Male

Female

p value

Mean ± SD

Mean ± SD

Age

Hyper

33.00 ± 20.07

35.47 ± 15.61

0.729

Hypo

53.33 ± 21.80

38.81 ± 13.26

0.168

Schypo

56.83 ± 25.57

35.94 ± 13.95

0.10

T3

Hyper

2.49 ±.77

2.33 ± 0.74

0.58

Hypo

0.40 ± 0.10

0.37 ± 0.20

0.66

Schypo

0.86 ± 0.29

1.02 ± 0.29

0.26

T4

Hyper

14.68 ± 4.76

13.97 ± 3.36

0.67

Hypo

2.65 ± 0.53

2.13 ± 0.88

0.08

Schypo

5.86 ± 0.60

6.33 ± 1.24

0.16

TSH

Hyper

0.34 ± 0.11

0.32 ± 0.10

0.62

Hypo

14.70 ± 5.40

21.48 ± 11.89

0.03**

Schypo

19.98 ± 9.00

15.34 ± 8.31

0.28

fT4

Hyper

2.5 ± 0.54

2.7 ± 0.47

0.41

Hypo

0.45 ± 0.25

0.58 ± 0 .30

0.28

Schypo

1.10 ± 0.60

1.15 ± 0.22

0.25

TCHO

Hyper

145.4 ± 10.12

142.37 ± 9.25

0.42

Hypo

265.00 ± 23.15

281.69 ± 35.89

0.16

Schypo

283.50 ± 16.15

265.12 ± 22.25

0.04**

TG

Hyper

84.40 ± 15.98

88.30 ± 19.18

0.53

Hypo

152.17 ± 42.16

171.14 ± 45.47

0.35

Schypo

167.50 ± 67.85

176.74 ± 50.59

0.35

No. of cases:Hyper M-10,F-30; Hypo M-6,F-36; Schypo M-6,F-34

** Statistically significant (p value<0.05)

Table 3 displays that there was quantitatively small but statistically not significant gender differences in each variable.

Discussion

Hyperthyroidism is associated with increased mortality in individuals over 60 years of age, particularly from circulatory incompetence and atrial fibrillation20. Other effects of hyperthyroidism include decreased systemic vascular resistance, reduced bone mineral density, increased cardiac contractility, cardiac output, heart rate, left ventricular mass causing diastolic dysfunction (delayed relaxation) and atrial arrhythmias. Laboratory tests facilitate early diagnosis before clinical features are obvious, increased sensitivity carries the price of decreased diagnostic specificity. Therefore, laboratory tests couple with supportive clinical findings are frequently used to diagnose thyrotoxicosis and it is best established by showing high circulating concentrations of the thyroid hormones thyroxine (T4) and triiodothyronine (T3)21.Thyroid stimulating hormone is undetectable in thyrotoxic patients and also normal in some people owing to insensitivity of the assay. The current study showed the rise in serum T3, T4 and fT4 (2.66 ± SD0.48 pg/ml), along with reduced levels of serum TSH (0.32 ± SD 0.10 mU/L). The similar findings were also observed in previous studies in cases of hyperthyroidism22. The present study revealed that total cholesterol (143.12 ± SD 9.43 mg/dl) and triglycerides (87.32 ± SD18.31 mg/dl) values were lowered in cases of hyperthyroidism. Thyroid hormones enhance the intravascular catabolism of VLDL triglyceride, modulate LDL receptor activity both in vitro and in vivo and hence lowers plasma cholesterol concentrations23. Furthermore, there is increased clearance of cholesterol from plasma , excessive conversion of cholesterol to bile acids in the liver and early removal of low density lipoprotein from the plasma in hyperthyroidism24. Thyroid hormones also lower triglyceride levels by promoting the clearance from plasma25.

Hypothyroidism was separated into either overt or subclinical disease. The most sensitive indicator for hypothyroidism was TSH, more than 10 mU/l, along with reduced levels of T426. The present study revealed the high values for serum TSH (20.5 ± SD11.4 mU/L) that almost certainly reflect a reduction in the circulating levels of thyroxine (T4) and triiodothyronine (T3). Hypothyroidism can affect people of all ages. Chronic autoimmune thyroiditis affects 3-5 times more frequently women than men, usually middle aged or older, as well as children. The mothers with very low serum T4 have higher incidence of still births, abortions and congenital abnormalities, contributing to the higher rate of perinatal deaths as T4 and T3 have strong modulating effect on the immune system. Decreased levels of T4 and T3 due to iodine deficiency during the first trimester could result in abnormal foetal development. Neurological cretinism is characterized by poor cognitive ability, deaf mutism, speech defects and proximal neuromotor rigidity27. In present study, there was significant increase in the mean concentration of total cholesterol (279.31 ± SD34.65mg/dl) and triglycerides (168.43 ± SD45.02mg/dl) in cases of hypothyroidism. A similar study done by Texeira et al in 2008 showed that hypothyroidism could significantly increase the levels of most of lipids, most importantly that of serum total cholesterol and LDL28. The previous study also showed similar mean values of serum total cholesterol (283 ± SD53 mg/dl) in hypothyroid subjects14. Hypothyroidism is a cause of secondary hyperlipidaemia. There is usually an increase in total cholesterol and furthermore, plasma triglycerides may also be increased. The mechanisms responsible for hypercholesterolemia are increased absorption of cholesterol from intestines, decreased clearance of cholesterol and low density lipoproteins from plasma and decreased synthesis of bile acids from cholesterol in the liver in hypothyroidism24. There is also significant association between thyroid antibodies, obesity, hypertension, diabetes and hypercholesterolemia. All these factors contribute to elevated risk of coronary heart disease23. Lipoprotein Lipase (LPL), a key enzyme in lipid metabolism, catalyzes the hydrolysis of triglycerides (TG) from TG-rich lipoproteins, and serves a bridging function that enhances the cellular uptake of lipoproteins. The triglycerides were elevated due to inactivity of lipoprotein lipase and hepatic lipase, reduced fractional clearance from plasma in cases of overt hypothyroidism. The previous study also revealed that elevation in plasma TG was less consistent than that of total cholesterol29. Therefore, abnormal lipid metabolism in hypothyroidism accelerates the process of atherogenesis and elevates cardiovascular risk30. The terminology subclinical hypothyroidism is gaining support, based on evidence that potentially important tissue abnormalities can occur during progressive thyroid failure before the serum T4 concentration becomes clearly subnormal. The increase in TSH levels with free thyroxine (fT4) in reference range defines the grading of subclinical hypothyroidism31. In present study, fT4 (1.15 ± SD0.21 pg/ml) levels were in reference range and TSH levels (10.04 ± SD1.46 mU/L) were moderately raised in cases of subclinical hypothyroidism. These values were quite close to values found in other studies i.e. TSH (11.43 ± SD5.50 mU/L) and fT4 (1.05 ± SD0.21 pg/ml)31. The current study showed that levels of total cholesterol (257.88 ± SD22.29 mg/dl) and TG (152.35 ± SD53.55 mg/dl) were increased as compared to controls. In similar studies done previously, the levels of serum total cholesterol and TG were found to be 237.50 ± SD1.01mg/dl and 168.53 ± SD 0.89 mg/dl respectively in cases of subclinical hypothyroidism31. The major concern with subclinical hypothyroidism has been risk of progression to overt hypothyroidism, hypercholesterolemia and increased risk of cognitive impairment particularly in elderly individuals32. Further, subclinical hypothyroidism may affect both diastolic and systolic cardiac function, worsen traditional risk factors for cardiovascular disease, including blood pressure, plasma lipid profile and endothelial function. Thus, it was seen that patients with thyroid dysfunction had significant reversible alterations in levels of serum total cholesterol and triglycerides.

Conclusion

Thyroid dysfunction is found to be common across all age groups and shows a strong female preponderance in Pokhara valley. Hypothyroidism is reasonably common in people with significant hypercholesterolaemia. It is eminently treatable and this could well result in lipid lowering. It necessitates the measurement of thyroid hormones in women after the age of 50, in pregnancy and after delivery and in women and men with hypercholesterolemia. Therefore, timely screening and check up is necessary in order to curtail the problem of undiagnosed cases, giving specific consideration to patients who have high artherogenic profile. This will reduce the risk of future negative health events in older adults.

Future Directions of the Study

Multi-centered randomized and population based studies are needed to get the association between hypothyroidism and cardiovascular disorders. Early screening is inexpensive and prevents the progression to hypothyroidism. Antenatal checkups (particularly in the first trimester) help in preventing the premature delivery and birth defects. Maternal iodine supplementation is necessary before or during pregnancy. Iodine deficiency continues to be a major problem in Nepal and demands a clear control strategy, combining ongoing iodine supplementation and education.

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