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, which include the spectrum of thyroid dysfunction diseases. The aim of the study was to find out the variations of thyroid hormones and lipid profile in hyperthyroidism, subclinical hypothyroidism and hypothyroidism.
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, sex, total T4, total T3, TSH, fT4, total cholesterol and triglycerides.
Result
122 out of the 365 subjects selected for the study had some form of thyroid disorder. Among these 122 cases, 40 had hyperthyroidism, 42 had hypothyroidism and the remaining 40 were diagnosed to have subclinical hypothyroidism. Our results showed that all the variables (T3, T4, TSH, fT4, total cholesterol and triglycerides) except for age were statistically significant when compared to cases. The frequency of thyroid disorders was much higher in females as compared to their male counterparts.
Conclusion
Thyroid dysfunction is very common both in elderly and younger age groups. Therefore, timely screening and check up is a must in order to curtail the problem of undiagnosed cases, giving specific consideration to patients who have high artherogenic profile.
Key Words: Hyperthyroidism, Hypothyroidism, Subclinical Hypothyroidism, Thyroid hormones
Introduction
Thyroid hormones are crucial for growth, and to regulate the metabolism of protein, carbohydrates and fat. Endocrine disease of the thyroid may result in either under- or overactivity of the gland and 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 autoimmunity 1-3. Graves Disease (diffuse toxic goitre) is the most common condition of hyperthyroidism and is caused by overactivity of the immune system (autoimmunity). Other subtypes are sub-acute (painful, viral) thyroiditis, silent thyroiditis (painless or postpartum thyroiditis) and toxic multinodular goiter 4. 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 UK 5. In a community survey comprising of 1210 participants (age≥ 60 years) from the UK, the prevalence of undiagnosed overt hyperthyroidism was very low 6. In a similar study conducted in Sweden, out of 1442 participants (age ≥ 60 yrs), only 2% of subjects were diagnosed to have thyrotoxicosis 7. Hypothyroidism is more common among elderly females, having 15 to 20 times higher risk for developing the disease when compared to men and its incidence is 0.3 to 5 people/1000/yr in America 8. The prevalence of hypothyroidism has been found to be between 0 and 7·8/1000 men and between 0 and 20·5/1000 women, and for hyperthyroidism, between 2·0 and 19·4/1000 women in Caucasian populations mainly from Scandinavia, Spain, the UK and the USA 9.
The major cause of hypothyroidism is Hashimoto's disease (chronic autoimmune thyroiditis). Other causes are mainly due to iodine deficiency, over treated Graves disease, anti-thyroid drugs and radioactive therapy 13.
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 cases 9. Pregnant women are also at higher risk 10. The increase in TSH levels with fT4 in reference range defines the grading of subclinical hypothyroidism. The prevalence of subclinical hypothyroidism ranges from 1% to 10% worldwide, with prevalence in women above 60 years of age approaching 20% in some reports 12. About 6.5 million Americans have undiagnosed and underactive or subclinical hypothyroidism and majority are at the risk of progression to overt hypothyroidism. Subclinical hypothyroidism is a more common disorder than overt hypothyroidism, with a prevalence of 1.4-7.8% in elderly population and even greater percentiles among women 17. A recent study by Walsh et al. confirmed that subclinical hypothyroidism, but not subclinical hyperthyroidism, is associated with an increased risk of fatal and nonfatal coronary heart disease18.
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, which include the spectrum of thyroid dysfunction diseases 14. About 172 million people, or 12% of the population of South East Asia, are affected by goiter and prevalence in Nepal surpasses all South East Asian countries. 41% of the general population here is at higher risk of developing goiter and improvement is anticipated by the increased consumption of iodized salt. The majority of patients with thyroid dysfunction fall within the 21-40 year age group 15. A survey done in Nepal in 1996 indicated that 55% of the population with goiter was localized to mountainous regions like Khumbhu and Jumla 16.
Both hypothyroidism and hyperthyroidism have potentially fatal systemic manifestations. Therefore, accurate and timely 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 Low Density Lipoprotein cholesterol levels have been found to be associated with subclinical hypothyroidism, therefore assessment of altered lipid profile plays a supportive role in thyroid dysfunction. (REF) 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, sex, T3, T4, TSH, fT4, total cholesterol and triglycerides.
Analysis of T3, T4, TSH and fT4 levels was done by ELISA (HUMAN) 19-21. Estimation of total cholesterol and triglycerides was done by semi autoanalyser Human 3500, Germany 22. The commercially available kits of Human, Germany were used for 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 and 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. Among these 122 cases, 40 had hyperthyroidism, 42 had hypothyroidism and the remaining 40 were diagnosed to have subclinical hypothyroidism.
Our results showed that all the variables (T3, T4, TSH, fT4, total cholesterol and triglycerides) except for age were statistically significant when compared to cases. The TSH values were markedly increased while T4 and T3 values were found to be less than the reference range in cases of hypothyroidism. The increase in TSH levels with fT4 in reference range defines the grading of subclinical hypothyroidism. Elevated levels of T3 and T4 associated with decreased TSH levels were found in cases of hyperthyroidism. In hypothyroidism and subclinical hypothyroidism, the total cholesterol values were moderately increased and there was no gross derangement of TG levels. In hyperthyroidism, total cholesterol and triglycerides levels were mildly decreased but remained within the reference range.
Table 2: Comparison of gender in controls and cases
Variable
Male
Female
P value
hyper
10
30
0.001**
hypo
6
36
0.001**
schypo
6
34
0.001**
Normal
58
185
0.001**
** Statistically significant (p value<0.05)
The above results show that the frequency of developing thyroid disorders is much higher in females in comparison to males.
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
hyper M-10,F-30: Hypo M-6,F-36: schypo M-6,F-34
** Statistically significant (p value<0.05), T Cho (Total Cholesterol), TG (Triglycerides)
The results show that these variables of T3, T4, TSH, fT4, total cholesterol, triglycerides do not have any statistical significance with respect to gender. Males and females had almost equal variation among the biochemical parameters and the respective values do not show any significant difference.
Discussion
Hyperthyroidism is associated with increased mortality in individuals over 60 years of age, particularly from circulatory incompetence and atrial fibrillation19. (Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med. 1994;331:1249-1252.) Other effects of hyperthyroidism include decreased systemic vascular resistance, reduced bone mineral density, increased cardiac contractility cardiac output, heart rate, left ventricular mass to cause diastolic dysfunction (delayed relaxation) and atrial arrhythmias. Our study was to stress upon the essentiality of laboratory diagnosis before any further investigation or treatment for thyroid disorders. The single most important biochemical parameter for confirming hyperthyroidism was serum TSH levels. Our results showed low or undetectable serum TSH, well below the reference range, along with raised serum T4 and T3 levels in hyperthryoidism. The values obtained were specific for diagnosis of thyrotoxicosis20. (Jayne Franklyn, MD and James Parle, MD: Hyperthyroidism - aging , Chapter 8 December 16, 2006 ) . The total cholesterol and TG values were lowered but remained within normal range. The values obtained were 143.12 ± 9.43mg/dl, 87.32 ± 18.31 mg/dl which were quite close to the values found by Abrams et al i.e.155±10mg/dl, 106±10mg/dl, of total cholesterol and TG respectively in hyperthyroidism.21.( J J Abrams and S M Grundy; Cholesterol metabolism in hypothyroidism and hyperthyroidism in man. J. Lipid Res. 1981 22:(2) 323-338. art23) There was increase in post-heparin plasma hepatic lipase activity which led to decrease in serum total cholesterol while lipoprotein lipase activity and serum triglycerides levels were normal in cases of hyperthyroidism (KAREN S. L. LAM, MAN KAM CHAN ROSE T. T. YEUNG High-Density Lipoprotein Cholesterol, Hepatic Lipase and Lipoprotein Lipase Activities in Thyroid Dysfunction - Effects of Treatment QJM (1986) 59 (2): 513-521. art24)
Hypothyroidism was separated into either overt or subclinical disease and that diagnosis was determined on the basis of the TSH laboratory blood tests. Hypothyroidism is characterized by low T3 and T4 values with raised TSH levels. Decreased levels of T4 and T3 due to iodine deficiency during the first trimester could result in abnormal foetal development. Neurological cretinism is associated with increased levels of TSH and is characterized by poor cognitive ability, deaf mutism, speech defects and proximal neuromotor rigidity. 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. (REF??????)
Hypothyroidism is associated with abnormal lipid metabolism, cardiac dysfunction, diastolic hypertension conferring the elevated risk of artherosclerosis and if ignored, as in most of the undiagnosed cases, could result in ischaemic heart disease and myocardial infarction. (Morris MS, Bostom AG, Jacques PF, Selhub J, Rosenberg IH. Hyper-homocystinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Study. Atherosclerosis 2001;155:195-200)
Our study showed significant lower levels of T4 and T3 with raised TSH levels (20.5 ± 11.4 mU/L). Other studies reveal that most sensitive indicator for hypothyroidism was TSH, more than10mU/l, along with reduced levels of T421. (. J J Abrams and S M Grundy; Cholesterol metabolism in hypothyroidism and hyperthyroidism in man. J. Lipid Res. 1981 22:(2) 323-338. art23). In hypothyroidism, there is 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 .Rosenman, R. H., S. 0. Byers, and M. Friedman. 1952. The mechanism responsible for the altered blood cholesterol content in deranged thyroid states. J. ClinEndocrinol. Metab. 12: 1287- 1299.art25. In our study, there was significant increase in the mean concentration of total cholesterol (279.31 ± 34.65mg/dl) and triglycerides (168.43 ± 45.02mg/dl) in cases of hypothyroidism. In a similar study done by Texeira at al in 2008 showed that hypothyroidism could significantly increase the levels of most of lipids, most importantly that of cholesterol and LDL. In contrast hyperthyroidism was not associated with plasma lipid variation23. art27 Teixeira PDE F, Reuters VS, Ferreira MM, Almeida CP, Reis F. A, Buescu A, et al. Lipid profile in different degrees of hypothyroidism and effects of levothyroxine replacement in mild thyroid failure. J. Transl Res. 2008; 151:224-31. The mean and SD of cholesterol in hypothyroid subjects was 283 ± 53 mg/dl which were quite similar to our values.25 Risal P, Maharjan BR, Koju R, Makaju RK, Gautam M Variation of total serum cholesterol among the patient with thyroid dysfunction Kathmandu University Medical Journal (2010), Vol. 8, No. 2, Issue 30, 265-268 art27 . In another study, triglycerides levels were significantly high in hypothyroid patients when compared with the controls. Torun AN, Kulaksizoglu S, Kulaksizoglu M, Pamuk BO, Isbilen E, Tutuncu NB. Serum total antioxidant status and lipid peroxidation marker malondialdehyde levels in overt and subclinical hypothyroidism. Clin Endocrinol (Oxf) 2008;34:45-52. art28
The post-heparin plasma hepatic lipase and lipoprotein lipase activity are reduced which leads to increase in serum total cholesterol and triglyceride in cases of overt hypothyroidism. KAREN S. L. LAM, MAN KAM CHAN ROSE T. T. YEUNG High-Density Lipoprotein Cholesterol, Hepatic Lipase and Lipoprotein Lipase Activities in Thyroid Dysfunction - Effects of Treatment QJM (1986) 59 (2): 513-521. art24 Unlike increased serum cholesterol levels, triglyceride metabolism is not grossly deranged in hypothyroidism28. Abrams J J and Grundy S M. Metabolism of plasma triglycerides in hypothyroidism and hyperthyroidism in man. The Journal of Lipid Research 1981; 22: 307-322.
In cases of subclinical hyperthyroidism, fT4 (1.15 ± 0.21 pg/ml) levels were in reference range and TSH levels (10.04 ± 1.46 mU/L) were moderately raised. These values were quite close to values found in other studies i.e TSH (11.43 ± 5.50 mU/L) and fT4 (1.05 ± 0.21 pg/ml).25 . Risal P, Maharjan BR, Koju R, Makaju RK, Gautam M ; Variation of total serum cholesterol among the patients with thyroid dysfunction: Kathmandu University Medical Journal (2010), Vol. 8, No. 2, Issue 30, 265-268.
Our results showed that the levels of total cholesterol was increased (257.88 ± 22.29mg/dl) while triglyceride levels were near the upper limit of the reference range (152.35 ± 53.55mg/dl). The serum total cholesterol was increased while serum triglyceride levels, activity of post-heparin plasma hepatic lipase and lipoprotein lipase were normal in cases of subclinical hypothyroidism KAREN S. L. LAM, MAN KAM CHAN ROSE T. T. YEUNG High-Density Lipoprotein Cholesterol, Hepatic Lipase and Lipoprotein Lipase Activities in Thyroid Dysfunction - Effects of Treatment QJM (1986) 59 (2): 513-521. In other studies, total cholesterol and TG levels were 237.50+1.01mg/dl and 168.53+0.89mg/dl respectively in cases of subclinical hypothyroidism , somewhat similar to above mentioned results26. Ibrahim M Madani, EL amin Ammar M, Mahmoud Niamat O, EL Sanosi Mai M,EL Bagir Nabiela M. Effect on subclinical hypothyroidism on important serum lipid values of Sudanese women. Journal of Chinese Clinical Medicine 2010; 7; Vol.5,no.7
Similar results obtained from other studies show that serum levels of total cholesterol and LDL were increased in patients of subclinical hypothyroidism in comparison to the normal controls (euthyroid) 27. Bauer D C,Ettinger B,Browner WS,Thyroid functions and serum lipids in older women; A population based study ,AMJ Med, 1998,104(6):546-551.
Thus, it is seen that patients with thyroid dysfunction had significant reversible alterations in levels of serum total cholesterol and triglycerides.
Conclusion
Thyroid dysfunction is very common both in elderly and younger age groups so regular screening shall be there to minimize the problem of undiagnosed cases particularly the patients having the artherogenic profile.
Future Directions of the Study Multi-centered randomized and population based studies is needed to get the association between hypothyroidism and cardiovascular disorders. The maximum randomized, placebo-controlled trials of iodine supplementation should be started such as salt iodization. Regular checkups of women >50 years old to avoid confusion as the symptoms of menopause and hypothyroidism are similar. Early screening is inexpensive and would prevent progression to hypothyroidism. The 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.
