A DISSERTATION ON PREVALENCE OF
MICROALBUMINURIA IN THYROID DYSFUNCTION
Dissertation submitted to
THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY CHENNAI
In partial fulfillment of the Regulations for the award of the degree of
M.D.(General Medicine)-Branch I
GOVERNMENT KILPAUK MEDICAL COLLEGE &
HOSPITAL.
CHENNAI, TAMIL NADU
April 2017
BONAFIDE CERTIFICATE
This is to certify that this dissertation titled
“MICROALBUMINURIA IN THYROID DYSFUNCTION”
submitted by Dr.SOWMYA SRIDHARAN to the Tamil Nadu Dr.M.G.R. Medical University Chennai, in partial fulfillment of the requirement of the award of M.D. Degree Branch I (GENERAL MEDICINE) is a bonafide research work carried out by her under our direct supervision and guidance.
Prof.Dr.T.RAVINDRAN,MD,DNB.,Dip.Diabetology., Professor & Unit Chief, Department of General Medicine, Govt.Kilpauk Medical College, Chennai.
Prof. Dr.USHA LAKSHMI,M.D,FMMC.,
Head of the Department, Department of General Medicine, Govt. Kilpauk Medical College, Chennai.
Prof.Dr.R.NARAYANA BABU, M.D, D.C.H.,
The Dean, Kilpauk Medical College, Chennai – 600 010.
DECLARATION
I, Dr.Sowmya Sridharan solemnly declare that the dissertation titled
“PREVALENCE OF MICROALBUMNURIA IN PATIENTS WITH THYROID DYSFUNCTION” has been prepared by me. This dissertation is submitted to The Tamilnadu Dr.M.G.R.Medical University, Chennai, towards the partial fulfillment of the requirement for the award of M.D. Degree Examination, Branch-I (General Medicine) to be held in APRIL 2017.
Place: Chennai.
Date: (Dr.SOWMYA SRIDHARAN)
AKNOWLEGEMENT
At the outset, I would like to thank our beloved Dean, Dr.R.NARAYANA BABU M.D, DCH., for permitting me to do this study on MICROALBUMNURIA AND THYROID DYSFUCNTION utilizing the resources at government Kilpauk Medical College Hospital.
I express my respect and gratitude to Dr.S.USHALAKSHMI MD,FMMC., Professor & HOD, Department of Medicine, Kilpauk Medical College, Chennai for the support and encouragement she offered in completion of this study.
My sincere thanks to my unit chief and guide Dr.T.RAVINDRAN MD, DNB, Dip.Diabetology., who was pivotal in helping me throughout the study. He was instrumental in guiding me throughout my postgraduate course.
I would also like to thank my Professors Dr.MUTHUSELVAN MD., Dr.C.HARIHARAN MD., and the Assistant Professors of General Medicine Department for permitting me to take up cases from their out patient departments. I sincerely thank the Professor of Biochemistry and staff of Biochemistry department for helping carry out the study in the Government Kilpauk Medical College Biochemistry laboratory.
I wish to extend my heartfelt thanks to the Assistant Professor of my unit Dr.G.PANEERSELVAM MD, Dr.BOOPATHY RAJAN MD DTCD, and Dr.DEVIKA MD., for their timely guidance and valuable suggestions.
I thank my patients for cooperating with me for conducting this study. I appreciate their enthusiasm and patience they extended in participating in the study. I express my love and gratitude to family and friends who were a pillar of support during times of need.
CONTENTS
S.NO TOPIC PAGE NO.
1 INTRODUCTION 1
2 AIM OF THE STUDY 4
3 REVIEW OF LITERATURE 5
4 MATERIALS AND METHODS 30
5 RESULTS 34
6 DISCUSSION 72
7 CONCLUSION 74
8 LIST OF ABBREVIATIONS 75
9 BIBLIOGRAPHY 77
10 ANNEXURES
i. Proforma 82
ii. Master Chart with key 83
iii. Patient Consent Form 86
iv. Ethical Committee Approval
Certificate 88
v. Turnitin originality Certificate 89
LIST OF TABLES
S.NO TITLE PAGE NO.
1 Characteristics of the study population 35
2 Age Wise Distribution 36
3 Sex Wise Distribution 38
4 BMI and Age Distribution 39
5 BMI Distribution of Study Subjects 41
6 Sex Wise Distribution of BMI in Study Subjects 42 7 Sex Wise Distribution of Glycemic Status in
Study Subjects 43
8 Sex Wise Distribution of UACR in Study
Subjects 44
9 Serum Cholesterol levels in the study population 46 10 Serum Triglyceride Levels of the Study
Population. 48
11 Sex distribution of Blood Urea Nitrogen in the
study population 49
12 Sex distribution of Dyslipidemia in the study
population 49
13 Sex distribution of Serum Albumin in the study
population 50
14 Sex distribution of Total Proteins in the study
population 50
15 Serum Creatinine levels in the study subjects. 50 16 Sex distribution of thyroid dysfunction in study
subjects 51
S.NO TITLE PAGE NO.
17 Age distribution of thyroid dysfunction in study
subjects 53
18 BMI distribution of thyroid dysfunction in study
subjects 55
19 Sexwise distribution of Dyslipidemia in patients
with thyroid dysfunction 57
20 Sexwise distribution of IGT in patients with
thyroid dysfunction 59
21 UACR distribution in patients with thyroid
dysfunction 60
22 FT3 range in subjects with microalbuminuria. 62 23 FT4 range in subjects with microalbuminuria. 63 24 TSH range in subjects with microalbuminuria. 64
LIST OF FIGURES
S.NO TITLE PAGE NO.
1 Anatomy of Thyroid gland 3
2 Regulation of Thyroid Hormone Secretion 7 3 Prevalence of Thyroid Function Abnormalities. 11
4 Causes of Hypothyroidism 14
5 Signs and Symptoms of Hypothyroidism. 16
6 Prevalence of Hypothyroidism 18
7 Hypothalamo-pituitary-Thyroid axis. 20
8 Graves Opthalmopathy 22
9 Thyroid Cancer Subtypes 25
10 Cellular Origin of Thyroid Malignancy. 27
11 Metabolic Syndrome. 28
12 Stages of Kidney Involvement according to urine
albumin levels 29
13 Distribution of FT3 in the Study Population. 65 14 Distribution of FT4 in the Study Population. 66 15 Distribution of TSH in the Study Population. 67 16 Correlation of FT4 with urine albumin creatinine
ratio. 68
17 Correlation of TSH with urine albumin creatinine
ratio. 68
18 Correlation of FT3 with urine albumin creatinine
ratio. 69
1
INTRODUCTION
Diseases of the thyroid gland are common across the world.
According to various studies it is estimated that around 42 million people in India suffer from thyroid diseases with Goiter, Hypothyroidism, Hyperthyroidism, Hashimoto’s disease and carcinoma of the thyroid being the most entities affecting the thyroid[18].
Microalbuminuria defined as urine albumin to creatinine ratio of 30 to 300mg/g is a valuable marker that predicts endothelial dysfunction[32].
Hence microalbuminuria has been linked to Diabetes Mellitus and Chronic Kidney Disease where there is generalized endothelial dysfunction.[13,14] Also previous studies confirming the association of microalbuminuria to cardiovascular disease and mortality has been well established[29,27]. There is however insufficient data relating thyroid disorders with microalbuminuria.
Subclinical Hypothyroidism is a disorder where there is elevated serum Thyroid Stimulating Hormone (TSH) with Free T3, Free T4 (FT3, FT4) in the normal range [11]. Studies done on subclinical hypothyroidism show that there is higher prevalence among women as compared to men with a peak of 21% in women and 16% in men over 74 years of age[18]. Subclinical Hypothyroidism is also associated with
2
coronary artery disease and independent of serum cholesterol levels have been proved to be linked to aortic atherosclerosis and myocardial infarction in elderly women [30,34]. In the presence of concomitant thyroiditis, due to inflammation and autoimmunity endothelial dysfunction occurs [16].
Albuminuria is closely associated with metabolic syndrome comprising of syndrome of insulin resistance, hypertension, obesity and dyslipidemia[15,17]. Also thyroid disorders are know to alter the metabolism of lipids and tend to have an adverse effect on the lipid profile[33,34]. Added to this hyperthyroidism maybe attributed as an underlying cause for acquired hypercholesterolemia. From the above statements it is likely that there may be a relationship between microalbuminuria and thyroid disorders.
Thus microalbuminuria as an indicator of vascular damage secondary to endothelial dysfunction is well known.[30,37] However studies relating thyroid hormones to microalbuminuria is lacking.
3
Figure 1: Anatomy of Thyroid Gland
4
AIM OF THE STUDY
To study the prevalence of microalbuminuria in patients with thyroid dysfunction in a South Indian population.
5
REVIEW OF LITERATURE
ANATOMY OF THE THYROID GLAND:
The Thyroid gland has two lobes connected by the isthmus in the centre. The gland is highly vascular and soft in consistency [22]. At each pole, posteriorly the parathyroid gland is situated [1,2,8].
This gland develops from the floor of the primitive pharynx at the third week of embryonic life. It migrates along the thyroglossal duct to reach the neck. Sometimes failure of migration can lead to the gland being situated at the base of the tongue and is called lingual thyroid [4,5].
The process of hormone synthesis begins at 11th week of gestation.
The medullary C-cells of the thyroid gland arise from the neural crest cells of the ultimobranchial body. These produce calcitonin [1,8].
The thyroid transcription factor 1 and 2(TTF 1 & 2) and the paired homebox -8 (PAX-8) are among the several transcription factors which play a role in the development of this gland [1]. Mutations in these factors cause thyroid agenesis or dyshormonogenesis.
6
REGULATION OF HORMONE PRODUCTION [1,8]:
The release of Thryoid hormone from the thyroid gland is primarily under the control of the pituitary. The thyrotropic cells of the anterior pituitary secrete TSH. TSH consists of α and β subunits. The α subunit being shared by other glycoprotein hormones and the β subunit being unique to the thyroid gland [1,3].
The feedback loop to the Hypothalamus is via TSH. This causes a reduced production of Thyroid Releasing Hormone (TRH) via negative feed back mechanism [1,4,8].
Dopamine, glucocorticoids and somatostatin depresses the TSH.
Although like other pituitary hormones TSH is produced in a pulsatile manner, with a diurnal rhythm the TSH variations are quite modest as compared to other hormones. Hence a single TSH level assessment may be considered adequate for calculating the TSH levels in the serum. TSH is measured via the immuno-radiometric assays [2].
7
Figure 2: Regulation Thyroid Hormone Secretion.
8
THYROID HORMONE SYNTHESIS [1,8]:
Iodine uptake is the most important and first step in thyroid hormone synthesis.
The sodium iodide symporter (NIS) transports iodine into the thyroid gland.
NIS is located in the basolateral side of the follicular cells.
Pendrin is another transporter located on the apical surface of the thyroid cells. It causes iodine efflux into the lumen. Penred Syndrome occurs due to mutation in this gene. There is defective organification of iodine and sensorineural hearing loss with goiter [4].
Iodine is trapped and transported to the apical membrane of the thyroid follicular cells. Oxidation and Organification involving the thyroid peroxidase (TPO) and hydrogen peroxide occurs.
The iodotyrosine residues in the thyroglobulin molecule are coupled through ether linkages.
Based on the number of iodine residues present in the thyroglobulin molecules tri-iodothyronine (T3) and Thyroxine (T4) is formed.
The uncoupled mono-iodothyronine (MIT) and di- iodothyronine (DIT) are deiodinated by dehalogenase.
9
THYROID METABOLISM AND TRANSPORT [1,2,8]:
T4 and T3 are bound to plasma proteins such as Thyroxine binding globulin (TBG), Transthyretin (TTR), Thyroxine binding pre-albumin (TBPA) and albumin.
Around 80% of the hormone is transported in TBG due to high affinity.
T3 is less tightly bound as compared to T4. Also it is produced in smaller amounts and cleared rapidly than T4. The unbound hormone is biologically active form.
The deiodinase inactivate T4 and T3. Thus reverse T3 is produced (rT3).
ACTIONS OF THE THYROID HORMONE [2,8]:
Thyroid hormone has intranuclear Thyroid receptor (TR) α and β. Α is present in brain, gonad, kidney and heart. β is present in liver and pituitary.
Specific DNA sequences called Thyroid response element (TRE) are present in the nuclear DNA. The TR and retinoid-X- receptor (RXR) form hetero-dimers to bind via TRE.
This causes activation of the receptor which in turn is located in the promoter region of the gene.
10
Hormone binding causes recruitment of coactivation factors and thus results in transcription.
HYPOTHYROIDISM:
The terms overt and subclinical hypothyroidism can be made only in the absence of severe ongoing illness, when the TSH values have been stable for weeks and when the hypothalamo-pituitary axis is not altered [1,3,6].
EPIDEMIOLOGY:
Congenital Hypothyroidism is the most important entity in the causes of hypothyroidism with around one in 2640 neonates being affected according to a study done in Mumbai. In children however thyroid dysgenesis, dyshormonogenesis and thyroiditis play a major role. Among the adult population according to a study conducted in Cochin the prevalence 9.4% with a higher ratio of prevalence in women than men. In the same study it was noted that the prevalence of subclinical and overt hypothyroidism was 1.6% and 1.3% respectively [18].
Among 130 countries, according to data collected by WHO around 30.6%
people have inadequate iodine consumption. According to the Framingham study around 5.9% women and 2.4%men more than 60years of age are hypothyroid. The National health and Nutrition Examination
11
Survey(NHANES 1999-2002) done in 4392 patients in United States of America(USA), says that 3.7% of the population is hypothyroid and prevalence of the same was higher in whites(5.1%) and least in African- Americans(1.7%)[39].
Figure 3: Prevalence of Thyroid Function Abnormalities.
12
ETIOLOGY [3,6]:
Causes of hypothyroidism may be primary, secondary or tertiary.
Worldwide iodine deficiency remains the predominant cause for primary hypothyroidism but in developed countries such as USA, where iodine is sufficient, chronic autoimmune thyroid disease (AITD) remains the predominant cause and is noted more commonly in women more than men. AITD is diagnosed based on the elevated anti-thyroid antibodies titer which includes anti-thyroglobulin antibody (Tg-Ab), anti- microsomal/anti-thyroid peroxidase antibodies (anti-TPO Ab) and anti- TSH receptor (anti-TSHR Ab)[1,2,4].
Hypothyroidism may sometimes be iatrogenic (drug induced) too.
Secondary Hypothyroidism occurs when the thyroid gland is normal, but due to low thyrotropin the stimulation of the gland gets reduced.
In tertiary hypothyroidism there is inadequate TRH which causes inadequate thyroid stimulation due to reduced TSH.
TYPES OF HYPOTHYROIDISM [1]:
1. Primary Hypothyroidism:
Autoimmune thyroiditis.
Iatrogenic hypothyroidism(Drug-induced)
13
Infiltrative disorders-sarcoidosis, hemochromatosis, etc.,
2. Secondary Hypothyroidism:
Hypopituitarism
Bexarotene
Hypothalamic disease
3. Transient Hypothyroidism:
Post-partum thyroiditis
Sub-acute thyroiditis.
After radiation and subtotal thyroidectomy.
AUTOIMMUNE THYROIDITIS:
In Hashimoto thyroiditis there is progressive lymphocytic infiltration of the thyroid gland and hence destruction of the gland. Anti-TPO Ab is a hallmark of this disorder [1].
POST-PARTUM THYROIDITIS:
Two to twelve months after delivery, this condition occurs. A short thyrotoxic state may precede this illness [4].
14
Figure 4: Causes of Hypothyroidism SUBACUTE GRANULOMATOUS THYROIDITIS:
De-Quervain disease is a disease of middle age women. Usually self limiting and maybe associated with a transient period of hyperthyroidism followed by hypothyroidism [8].
DRUG INDUCED HYPOTHYROIDISM:
Drugs such as amiodarone, INF-alfa, thalidomide, Lithium, Rifampin, Phenytoin, Carbamazepine cause Hypothyroidism. Radioactive iodine causes permanent hypothyroidism. Thyroidectomy causes hypothyroidism [1].
15
GENETICS:
Worldwide studies suggest that single nucleotide polymorphism near the FOXE1 gene is strongly associated with hypothyroidism. About 10% of the patients with hypothyroidism have mutation in the TPO gene which causes an error in the thyroid hormone synthesis. PAX8 and TSHR mutation have been associated with congenital hypothyroidism. Penred syndrome occurs due to SLC26A4 gene mutation [1,5].
CENTRAL HYPOTHYROIDISM:
Central hypothyroidism can occur due to pituitary adenoma, lymphocytic hypophysisitis, Sheehan syndrome and TRH resistance.
SIGNS AND SYMPTOMS OF HYPOTHYROIDISM:
Cold sensitivity, fatigue, voice change, constipation, cold skin and muscle cramps are the frequent complaints of hypothyroid patients. A few present with carpel tunnel, sleep apnea and pituitary hyperplasia.
Proximal myopathy and gynecomastia may be present [4,5].
16
Figure 5: Signs and Symptoms of Hypothyroidism MEASUREMENT OF THYROID HORMONES:
Most of the T4 is protein bound and hence the factors that alter the protein binding affect the thyroid status of a person irrespective of thyroid disease. Hence assays for measuring free T4 have been devised. In pregnancy measurement of serum total T4 is recommended over direct
17
immunoassay of serum FT4. Like T4, most of T3 is also protein bound.
Assays for measuring FT3 are also available now- a- days [6,7].
TREATMENT OF HYPOTHYROIDISM [6,7]:
Serum TSH more than 10mIU/L in a patient with primary hypothyroidism should be treated. Based on a substantial amount of studies done worldwide, popular consensus is that TSH between 2.5 and 4.5 mIU/L benefit greatly with treatment. Keeping in mind the dyslipidemia and atherosclerosis in such patients L-Thyroxine monotherapy has now-a-days become the mainstay of treatment. The dosage is dependant on age, sex and body size at a dose of 1.6micrograms/kg (µg/kg). L-Thyroxine must be stored at 20-25 ºC and protected from light and moisture. In cases of central hypothyroidism, 1.6µg/kg L-Thyroxine must be given everyday and modification in the treatment must be based on free T4 and not TSH.
CLINICAL HYPOTHYROIDISM:
In the absence of any residual function of thyroid a dose of 1.6µg/kg/body weight, calculating to around 100-150 µg would suffice.
In patients who have a low level of autonomous functioning gland, lower replacement doses would be enough.
18
In patients less than 60 years without evidence of cardiac disease a full replacement dose may be given. One has to wait for atleast 3 to 6 months to experience complete relief of symptoms. Once the TSH levels become stable, physician visits can be scheduled every year [1].
SUBCLINICAL HYPOTHYROIDISM [33]:
Routine treatment for hypothyroidism may not be necessary if the TSH levels are less than 10mIU/L. If the patient is positive for TPO Ab or has a high TSH titer >10mIU/L treatment is recommended.
Figure 6: Prevalence of Hypothyroidism.
19
HYPOTHYROIDISM IN SPECIAL SITUATIONS:
Women who plan conception must become euthyroid prior to pregnancy as maternal hypothyroidism affects fetal neural development.
Thyroid functions have to been done in each trimester of pregnancy.
Elderly patient require lesser doses compared to younger patients.
Patients with Coronary Artery Disease (CAD) have to be started on L-Thyroxine cautiously
TREATMENT OF MYXEDEMA COMA:
It is a medical emergency. Levothyroxine is given as an IV bolus of 500µg as loading dose followed by 50-100 µg IV per day.
As there is impaired conversion of T4 to T3, studies recommend Liothyronine IV or through Nasogastric tube, 10-25 µg every 8-12 hours.
Combination of Levothyroxine and Liothyronine is also another modality of treatment.
IV antibiotics have to be started. Electrolyte imbalance and Hypoglycemia must be corrected appropriately.
20
HYPERTHYROIDISM:
Hyperthyroidism involves overproduction of thyroid hormones leading to an elevation in FT3, FT4 and thus to a state of hyper metabolic state of Thyrotoxicosis [21].
EPIDEMIOLOGY:
The prevalence of subclinical and overt hyperthyroidism based on an epidemiological study conducted at Cochin was found to be 1.6% and 1.3% respectively. More than one-third of the patients of the community detected hyperthyroidism had anti-TPO Ab positive [18].
PATHOPHYSIOLOGY:
HYPOTHALAMUS
TRH (+) (-) dopamine/somatostatin PITUITARY GLAND
TSH (+)
T3,T4 THYROID GLAND T3,T4 peripheral tissues.
Figure 7: Hypothalamo-Pituitary- Thyroid Axis [2]
21
ETIOLOGY:
1. Primary Hyperthyroidism
2. Thyrotoxicosis with hyperthyroidism 3. Secondary Hyperthyroidism.
Autoimmune Thyroid disease is a major contributor to Thyrotoxicosis.
Syndrome associations of Hyperthyroidism are many. A mutation in TSHR gene is associated with Familial Gestational Hyperthyroidism, Congenital non-goiterous Thyrotoxicosis, and Toxic thyroid adenoma with somatic mutation. Type 2 autoimmune polyendocrine syndrome comprises of type-1 diabetes mellitus, adrenal insufficiency with hyper or hypothyroidism. Graves disease is HLA associated. A few studies suggest that is relation between single nucleotide polymorphism in TSHR gene and development of toxic multinodular goiter [23].
IODINE INTAKE:
When patients living in areas of chronic iodine deficiency with nodular goiter move to areas of sufficient iodine, they develop thyrotoxicosis.
GRAVES DISEASE:
This is the most common cause of thyrotoxicosis characterized by anti- TPO antibodies. The TSI is also an important autoantibody. Clinical
22
features specific to graves disease include thyroid opthalmopathy and thyroid dermopathy [23].
Figure 8: Graves Opthalmopathy.
SUBACUTE THYROIDITIS:
There is a destructive release of preformed thyroid hormones. In the thyrotoxic phase of the disease, there is no radio-active iodine uptake [1,2].
TOXIC MULTINODULAR GOITRE:
Also called Plummer disease, toxic multinodular goiter is more common in the elderly. Symptoms are mild as only a slight elevation of thyroid hormones is present [1].
23
TOXIC ADENOMA:
This condition occurs due to a single hyper functioning follicular adenoma. The excess hormone produced by this tumor suppresses TSH.
OTHER CAUSES:
Struma Ovarii, Jod-Basedow syndrome, Choriocarcinoma and metastatic follicular carcinoma are amongst the other causes for thyrotoxicosis[1].
MANAGEMENT [6,7]:
There are four modalities of treatment available for thyrotoxicosis which includes symptomatic relief, anti-thyroid medications, radioactive iodine- 131 and thyroidectomy.
SYMPTOMATIC THERAPY:
1. Beta-Blockers.
2. Saline drops and sun-glasses for mild opthalmopathy.
3. For vision threatening opthalmopathy, high dose glucocorticoids with orbital decompression surgery.
ANTI-THROID DRUGS:
Carbimazole, Methimazole and Propylthiouracil (PTU).
24
Methimazole is more potent than Propylthiouracil.
In adult men and non-pregnant women, mostly methimazole is used before definite therapy.
Propylthiouracil is used for thyroid storm, in first trimester of pregnancy and methimazole allergy or intolerance.
RADIOACTIVE IODINE TREATMENT:
A single dose either in capsule or liquid form is administered causing fibrosis and destruction of thyroid over weeks to months. Pregnancy, Breast feeding, Lactation and children below 5 years are contraindications.
THYROIDECTOMY:
Indication for thyroidectomy is under special circumstances such as people with large goiter, severe opthalmopathy, pregnant women intolerant to drugs and severe hyperthyroidism in children.
25
THYROID CANCER [1,16,23]:
Carcinoma of the thyroid gland is of four types.
1. Papillary Thyroid Cancer.
2. Follicular Thyroid Cancer.
3. Medullary Thyroid Cancer.
4. Anaplastic Thyroid Cancer.
Figure 9: Thyroid Cancer Subtypes.
26
PAPILLARY THYROID CANCER (PTC):
This is the commonest subtype of thyroid cancer.
The lesions of PTC are very small.
Histologically the psammoma bodies and orphan annie eye appearance of the cells are characteristic.
PTC is multifocal mostly and tends to be locally invasive.
Lymph node spread is common.
FOLLICULAR CANCER (FTC):
More common in iodine deficient regions.
Hematogenous spread is most common.
Histologically Hurtle cells are characteristic.
Has a poorer prognosis compared to PTC.
MEDULLARY THYROID CANCER (MTC):
It accounts only for 5% of the total thyroid cancers.
Three familial forms of MTC are noted- MEN 2A, MEN 2B and familial MTC.
ANAPLASTIC THYROID CANCER (ATC):
It is a poorly differentiated cancer.
More aggressive compared to other subtypes.
27
Has a very poor prognosis.
Most people survive only until 6 months after diagnosis of the cancer.
Figure 10: Cellular Origin of Thyroid Malignancy.
28
MICROALBUMINURIA IN A NUT SHELL:
Albumin excretion in urine has been recognized as one of the earliest sign of vascular damage in both kidney and heart [28]. Microalbuminuria helps us to identify those at risk for cardiovascular events [35]. Also a positive link exists between high blood pressure and microalbuminuria [15]. Microalbuminuria occurs when there is abnormally high permeability for albumin in the kidney. It is also an independent risk factor for stroke, myocardial infarction and congestive cardiac failure [24]. Few studies suggest that it is also a risk factor for venous thromboembolism.
Figure 11: Metabolic Syndrome.
29
It has also been recommended as a reliable marker for early detection of Balkan nephropathy. Thus it is important to identify microalbuminuria in patients with family history of nephropathy, poor glycemic control and increased GFR [32,37]. In addition there is positive relation between microalbuminuria and metabolic syndrome. Metabolic Syndrome comprises of obesity, hypertension, dyslipidemia and insulin resistance [29]. Low thyroid function according to various studies is also implicated in increased insulin resistance which might be a mediator of microalbuminuria [25].
Figure 12: Stages of Kidney involvement according to the urinary albumin level.
30
MATERIALS AND METHODS
STUDY SUBJECTS:
Patients attending the General Medicine Outpatient Department, Government Kilpauk Medical College, Chennai.
STUDY DESIGN:
Cross Sectional Study.
STUDY AREA:
Government Kilpauk Medical College.
PERIOD OF STUDY:
6 months
SAMPLE SIZE:
100
ETHICAL COMMITTEE APPROVAL:
Obtained.
INFORMED CONSENT:
Obtained.
31
FINANCIAL SUPPORT:
Nil.
CONFLICT OF INTEREST:
Nil.
SELECTION OF STUDY SUBJECTS:
Inclusion Criteria
Patients in the age group of 18-65 attending the General Medicine Out- patient Department at Kilpauk Medical College Hospital are selected and screened using a thyroid profile after obtaining due consent. Patients with abnormal values are taken into the study.
Thyroid Function Test:
Serum Free T3: 2.4-4.2pg/ml Serum Free T4:0.7-1.24ng/dl TSH:0.34-4.25µIU/ml
Exclusion Criteria
1. Patients who are on treatment for hypo or hyperthyroidism.
2. Patients with history of thyroidectomy.
3. Patients taking drugs that alter thyroid function such as amiodarone, lithium, anti-epileptics etc.
32
4. Patient with overt proteinuria.
5. Patients who are known cases of diabetes mellitus, systemic hypertension, coronary artery disease and chronic kidney disease.
METHOD OF STUDY:
Patients attending the general medicine out patient department are randomly selected.
A written informed consent is obtained.
They are evaluated for thyroid dysfunction using a thyroid profile test.
Patients meeting any one of the exclusion criteria are excluded from the study.
Patients who test positive for any form of thyroid dysfunction are selected.
All participants are advised to refrain from heavy exercise the day before.
A single void first morning urine sample is obtained for urinary albumin-creatinine ratio measurement.
Patients are grouped according to various parameters in the proforma and evaluated for microalbuminuria.
The results are analyzed.
33
LIMITATIONS OF THE STUDY:
The patients were sampled randomly based on a one time contact at the OP department. A recent illness may alter the thyroid profile.
But this is subjective as the patient may not have sought medical advice and would still be in the recovery phase. Hence they might have tested positive for microalbuminuria.
Over the counter drug intake is common in India. Patients continue taking medications prescribed long ago, without any follow up with the Medical Practioner who prescribed it. These may alter the testing of Thyroid profile and microalbuminuria.
The sample size is a very small representation of the entire South Indian population.
The relationship between microalbuminuria and thyroid
dysfunction in pregnancy is a gray area which has not been dealt with in my study.
Patients with Metabolic syndrome have not been excluded in the study, which may alter the outcome of my study.
34
RESULTS
STATISTICAL TOOLS:
The data was entered in excel and double checked for missing data.
Statistical Analysis was done by SPSS version 23 (demo version).
Data cleaning was done.
Outliers were identified.
Continuous variables were expressed as Mean with Standard deviation.
Categorical variables were expressed in numbers and percentages.
Chi square test with or without Yates correction and Fischers test was used for univariate analysis.
Factors significant by univariate analysis were taken for Multivariate analysis.
P value of less than 0.05 is considered statistically significant for rejecting null hypothesis.
35
TABLE 1: CHARACTERISTICS OF THE STUDY POPULATION
S.NO. VARIABLES
MEAN ± STANDARD DEVIATION
95%
CONFIDENCE INTERVAL OF THE MEAN 1. Age of the Subject in years 47.67 ± 13.77 44.94 to 50.4 2. Body Mass Index 25.15 ± 4.81 24.2 to 26.11 3. Fasting Blood Sugar ( FBS ) 80.42 ± 17.03 77.04 to 83.8 4. Post Prandial Blood Sugar
( PPBS ) 126.09 ± 12.86 123.54 to 128.64 5. Blood Urea Nitrogen ( BUN ) 15.31 ± 3.27 14.66 to 15.96
6. Total Protein 7.24 ± 0.63 7.12 to 7.37
7. Serum Albumin 4.19 ± 0.51 4.09 to 4.29
8. Serum Creatinine 0.892 ± 0.282 0.836 to 0.948
9. Free T3 3.07 ± 1.43 2.79 to 3.36
10. Free T4 1.27 ± 1.09 1.05 to 1.49
11. Thyroid Stimulating Hormone
( TSH ) 6.61 ± 4.20 5.77 to 7.44 12. Total Cholesterol 206.99 ± 52.36 196.6 to 217.38 13. Triglycerides 110.96 ± 36.83 103.65 to 118.27 14. Urine Albumin Creatinine Ratio 64.07 ± 76.02 48.99 to 79.15
36
TABLE 2: AGE DISTRIBUTION
AGE MALE FEMALE TOTAL
16-25 0 6 (100%) 6
26-35 2 (16.7%) 10 (83.3%) 12
36-45 3 (13%) 20 (87%) 23
46-55 3 (9.1%) 30 (90.9%) 33
56-65 3 (20%) 12 (80%) 15
66 and Above 1 (9.1%) 10 (90.9%) 11
37
Among the 100 patients in the study, maximum 33% were in the age group of 46-55 years.
Nu m be r
Age
AGE DISTRIBUTION
38
TABLE 3: SEX DISTRIBUTION
SEX NUMBER (PERCENTAGE)
MALE 12 (12%)
FEMALE 88 (88%)
Of the 100 subjects taken into the study 88 were females and 12 were males.
39
TABLE 4: BMI AND AGEWISE DISTRIBUTION.
AGE IN YEARS
BODY MASS INDEX OF THE STUDY POPULATION
<18.5 18.5-24.9 25-29.9 30-34.9 35-39.9 >=40
16-25 1 (11.1%) 1 (2.5%) 2 (5.4%) 2 (16.7%) 0 0
26-35 0 5 (12.5%) 7 (18.9%) 0 0 0
36-45 1 (11.1%) 10 (25%) 8 (21.6%) 4 (33.3%) 0 0 46-55 3 (33.3%) 12 (30%) 11 (29.7%) 5 (41.7%) 1 (100%) 1 (100%)
56-65 1 (11.1%) 6 (15%) 7 (18.9%) 1 (8.3%) 0 0 66 and
above
3 (33.3%) 6 (15%) 2 (5.4%) 0 0 0
TOTAL 9 40 37 12 1 1
40
BODY MASS INDEX OF THE STUDY POPULATION
41
TABLE 5: BMI DISTRIBUTION OF STUDY SUBJECTS
BMI NUMBER
UNDERWEIGHT
<18.5
9 (9%)
HEALTHY 18.5-24.9
40 (40%)
OVERWEIGHT 25-29.9
37(37%)
OBESITY CLASS 1 30.0-34.9
12(12%)
OBESITY CLASS 2 35.0-34.9
1(1%)
OBESITY CLASS 3
>= 40
1(1%)
42
TABLE 6: SEXWISE DISTRIBUTION OF THE BMI IN STUDY SUBJECTS
BMI MALE FEMALE TOTAL
UNDERWEIGHT 1 (11.1%) 8 (88.9%) 9
HEALTHY 6 (15%) 34 (85%) 40
OVERWEIGHT 3 (8.1%) 34 (99.9%) 37
OBESITY CLASS 1 2 (16.7%) 10 (83.3%) 12
OBESITY CLASS 2 0 1 (100%) 1
OBESITY CLASS 3 0 1 (100%) 1
43
TABLE 7: DISTRIBUTION OF THE GLYCEMIC STATUS IN STUDY SUBJECTS
GLYCEMIC STATUS OF THE
SUBJECTS
SEXWISE DISTRIBUTION
NUMBER MALE FEMALE
NORMAL 11 (12.5% ) 77 (87.5%) 88
IGT 1 (8.3%) 11 (91.7%) 12
DM 0 0 0
88% of the study subjects had a normal glycemic status. The rest had impaired glucose tolerance.
GLYCEMIC STATUS
44
TABLE 8: SEXWISE DISTRIBUTION OF THE UACR IN STUDY SUBJECTS
URINE ALBUMIN CREATITINE RATIO
SEXWISE
DISTRIBUTION TOTAL MALE FEMALE
NORMAL
<30mg/g
5 50 57
MICROALBUMINURIA 30-300mg/g
7 36 43
OVERT PROTEINURIA
>300mg/g
0 0 0
45
Of the 100 subjects in the study 57 were in normal range of Albuminuria and 43 had microalbuminuria out of which 36 were females and 7 were males.
MALE FEMALE
URINE ALBUMIN CREATININE RATIO
46
TABLE 9: SERUM CHOLESTEROL LEVELS OF THE STUDY POPULATION.
SERUM CHOLESTEROL
SEXWISE DISTRIBUTION
TOTAL MALE FEMALE
NORMAL
<200
7 (15.6%) 38 (84.4%) 45
BORDERLINE 201 – 240
2 (11.8%) 15 (88.2%) 17
HIGH
>300mg/g
3 (7.9%) 35 (92.1%) 38
47
Around 45 patients had normal cholesterol levels and the rest 55 patients had borderline to high cholesterol levels.
SERUM CHOLESTEROL
48
TABLE 10: SERUM TRIGLYCERIDES OF THE STUDY POPULATION.
SERUM TRIGLYCERIDES
SEXWISE DISTRIBUTION
TOTAL MALE FEMALE
LOW 0 0 0
NORMAL 11 (11.7%) 83 (88.3%) 94
HIGH 1 (16.7%) 5 (83.3%) 6
Majority of the study subjects had normal triglyceride levels.
Only 6% of the total had elevated triglyceride levels.
SEXWISE DISTRIBUTION OF SERUM TRIGLYCERIDE LEVELS
49
TABLE 11: BLOOD UREA NITROGEN LEVELS OF THE STUDY POPULATION
BLOOD UREA NITROGEN
SEXWISE DISTRIBUTION
TOTAL MALE FEMALE
LOW 0 0 0
NORMAL
10 (10.4% ) 86 (89.6%) 96
HIGH 2 (50%) 2 (50%) 4
TABLE 12: SEXWISE DISTRIBUTION OF DYSLIPIDEMIA IN STUDY SUBJECTS
DYSLIPIDEMIA
SEXWISE DISTRIBUTION
TOTAL MALE FEMALE
PRESENT 3 35 38
ABSENT 9 53 62
38 % of the total study population had dyslipidemia out of which 35 were females and 3 were males.
50
TABLE 13: SEXWISE DISTRIBUTION OF SERUM ALBUMIN IN STUDY SUBJECTS
SERUM ALBUMIN
SEXWISE DISTRIBUTION
TOTAL MALE FEMALE
LOW 0 3 (100%) 3
NORMAL 12 (12.4%) 85 (87.6%) 97
HIGH 0 0 0
TABLE 14: SEX DISTRIBUTION OF TOTAL PROTEINS IN STUDY SUBJECTS
TOTAL PROTEIN
SEXWISE DISTRIBUTION
TOTAL MALE FEMALE
LOW 0 7 (100%) 7
NORMAL 12 (13%) 80 (87%) 92
HIGH 0 1 (100%) 1
TABLE 15: SERUM CREATININE LEVELS IN STUDY SUBJECTS
SERUM CREATININE NUMBER
LOW 10
NORMAL 78
HIGH 12
51
TABLE 16: SEXWISE DISTRIBUTION OF THYROID DYSFUNCTION IN STUDY SUBJECTS.
SEX
THYROID DYSFUNCTION STATUS
OVERT HYPOTHYROID
SUBCLINICAL HYPOTHYROID
OVERT HYPERTHYROID
SUBCLINICAL HYPERTHYROID
MALE 8 3 1 0
FEMALE 25 42 18 3
TOTAL 33 45 19 3
52
Among the 100 subjects in the study 78% were hypothyroid with 33% of the subjects having overt hypothyroidism and the rest having subclinical hypothyroidism.
The rest 22% had hyperthyroidism, 19 having overt hyperthyroidism and 3 having subclinical hyperthyroidism.
SEXWISE DISTRIBUTION OF THYROID DYSFUNCTION IN STUDY SUBJECTS
53
TABLE 17: AGEWISE DISTRIBUTION OF THYROID DYSFUNCTION IN STUDY SUBJECTS.
AGE
THYROID DYSFUNCTION STATUS
OVERT HYPOTHYROID
SUBCLINICAL HYPOTHYROID
OVERT HYPERTHYROID
SUBCLINICAL HYPERTHYROID
16-25 0 4 2 0
26-35 5 6 0 1
36-45 12 6 5 0
46-55 11 16 5 1
56-65 4 8 2 1
66 and above
1 5 5 0
TOTAL 33 45 19 3
54
Among the various age groups, analysis revealed that majority of the patients with hypothyroidism fell in the age group between 46 to 55 years and the lowest prevalence of hypothyroidism was in the age group between 16 to 25 years. The highest prevalence of hyperthyroidism was also in the same range as hypothyroidism.
AGE WISE DISTRIBUTION OF THYROID DYSFUNCTION IN STUDY SUBJECTS
55
TABLE 18: BMI DISTRIBUTION OF THYROID DYSFUNCTION IN STUDY SUBJECTS.
BMI
THYROID DYSFUNCTION STATUS
OVERT HYPOTHYROID
SUBCLINICAL HYPOTHYROID
OVERT HYPERTHYROID
SUBCLINICAL HYPERTHYROID
UNDERWEIGHT 1 1 7 0
HEALTHY 13 12 12 3
OVERWEIGHT 15 22 0 0
OBESITY CLASS 1
4 8 0 0
OBESITY CLASS 2
0 1 0 0
OBESITY CLASS 3
0 1 0 0
TOTAL 33 45 19 3
56
15 patients with overt hypothyroidism and 22 patients with subclinical hypothyroidism were overweight. 4 with overt and 8 with subclinical hypothyroidism had class 1 obesity.
None of the patients with hyperthyroidism were overweight or obese.
BMI DISTRIBUTION IN PATIENTS WITH THYROID DYSFUNCTION
BMI DISTRIBUTION OF THYROID DYSFUNCTION IN STUDY SUBJECTS
57
TABLE 19: SEXWISE DISTRIBUTION OF DYSLIPIDEMIA IN PATIENTS WITH THYROID DYSFUNCTION.
SEX
THYROID DYSFUNCTION STATUS
OVERT HYPOTHYROID
SUBCLINICAL HYPOTHYROID
OVERT HYPERTHYROID
SUBCLINICAL HYPERTHYROID MALES
WITH DYSLIPIDEMIA
1 1 1 0
FEMALES WITH DYSLIPIDEMIA
14 15 5 1
TOTAL 15 16 6 1
58
14 females with dyslipidemia had overt hypothyroidism while 15 had subclinical hypothyroidism. A Total of 7 females with dyslipidemia had hyperthyroidism.
SEXWISE DISTRIBUTION OF DYSLIPIDEMIA
59
TABLE 20: SEXWISE DISTRIBUTION OF IGT IN PATIENTS WITH THYROID DYSFUNCTION
SEX
THYROID DYSFUNCTION STATUS OVERT
HYPOTHYROID
SUBCLINICAL HYPOTHYROID
OVERT HYPERTHYROID
SUBCLINICAL HYPERTHYROID MALES WITH
IGT 1 0 0 0
FEMALES
WITH IGT 2 8 0 1
TOTAL 3 8 0 1
A total of 11 females with hypothyroidism had impaired glucose tolerance and only one with hyperthyroidism had impaired glucose tolerance.
SEXWISE DISTRIBUTION OF IGT
60
TABLE 21: UACR DISTRIBUTION IN PATIENTS WITH THYROID DYSFUNCTION.
UACR
THYROID DYSFUNCTION STATUS
OVERT HYPOTHYROID
SUBCLINICAL HYPOTHYROID
OVERT HYPERTHYROID
SUBCLINICAL HYPERTHYROID
NORMAL 6 31 18 2
MICROALBUM INURIA
27 14 1 1
OVERT PROTEINURIA
0 0 0 0
61
Of the 78 subjects with hypothyroidism 37 fell into the normal Albuminuria range. The rest 41 had microalbuminuria. Among them 27 patients with overt hypothyroidism had microalbuminuria and 14 with subclinical hypothyroidism had microalbuminuria. 20 subjects with hyperthyroidism had normal protein excretion with one each with subclinical and overt hyperthyroidism having microalbuminuria.
UACR DISTRIBUTION IN THE SUBJECTS
62
TABLE 22: FT3 RANGE IN SUBJECTS WITH MICROALBUMINURIA.
FREE T3 RANGE NUMBER OF SUBJECTS WITH MICROALBUMINURIA
0.5-2.50pg/ml 30
2.51-4.50pg/ml 13
4.51-6.50pg/ml 0
6.51-8.50pg/ml 0
On analyzing the FT3 levels in 43 patients with microalbuminuria it was found that 30 had FT3 between the range of 0.5 to 2.5 pg/ml and the rest 13 had FT3 in the range of 2.51 to 4.50pg/ml.
63
TABLE 23: FT4 RANGE IN SUBJECTS WITH MICROALBUMINURIA.
FREE T4 RANGE
NUMBER OF SUBJECTS WITH MICROALBUMINURIA
< 0.7 ng/dl 28
0.7-1.24 ng/dl
14
>1.24 ng/dl 1
On comparing the FT4 ranges in the 43 subjects with microalbuminuria it was found that 28 had levels less than 0.7ng/dl, 14 in between the range 0.7 to 1.24ng/dl and 1 above 1.24ng/dl.
64
TABLE 24: TSH RANGE IN SUBJECTS WITH MICROALBUMINURIA.
TSH RANGE NUMBER OF SUBJECTS WITH MICROALBUMINURIA
< 0.34 mIU/ml 2
0.34-4.25 mIU/ml 0
>4.25 mIU/ml 41
41 patients with microalbuminuria had TSH levels above 4.25mIU/ml and 2 less than 0.34mIU/ml.
65
Figure 13:Distribution of Free T3 in the study Population
66
Figure 14: Distribution of TSH in the study Population
67
Figure 15: Distribution of FT4 in the study Population
68
r = - 0.355, p = 0.01
Figure 16: Correlation of FT4 with urine albumin creatinine ratio.
r = + 0.349, p = 0.01
Figure 17: Correlation of TSH with Urine Albumin Creatinine ratio.
69
r = - 0.494, p = 0.01
Figure 18: Correlation of FT3 with Urine Albumin Creatinine Ratio In univariate analysis of risk factors for Microalbuminuria, only subclinical and overt hypothyroidism had significant association.
Presence of Dyslipidemia, Impaired Glucose Tolerance, BMI, Age and Sex had no significant association with Microalbuminuria. The factors significant by univariate analysis were then taken for Multivariate analysis and results are shown below. Overt Hypothyroidism was a strong and significant predictor of Microalbuminuria compared to Subclinical Hypothyroidism in both univariate and multivariate analysis.
70
SUBCLINICAL HYPOTHYROIDISM AS A PREDICTOR OF MICROALBUMINURIA
Model Odds ratio 95% Confidence
Interval P value
Model 1 2.47 1.08 to 5.63 0.031
Model 2 4.553 0.93 to 22.23 0.061
Model 3 1.614 0.25 to 10.6 0.618
Model 1 - Univariate Analysis (Nagelkerke R2 = 0.063)
Model 2 – Multivariate Analysis with overt hypothyroidism without adjusting for Age, Sex, BMI.
(Nagelkerke R2 = 0.409).
Model 3 - Multivariate Analysis with overt hypothyroidism with adjustment for Age, Sex, BMI.
(Nagelkerke R2 = 0.452).
OVERT HYPOTHYROIDISM AS A PREDICTOR OF MICROALBUMINURIA
Model Odds ratio 95% Confidence
Interval P value
Model 1 14.34 5.03 to 40.9 0.000
Model 2 45.00 8.21 to 246.7 0.000
Model 3 23.045 3.55 to 149.42 0.001
Model 1 - Univariate Analysis (Nagelkerke R2 = 0.365)
71
Model 2 – Multivariate Analysis with subclinical hypothyroidism without adjusting for Age, Sex, BMI.
(Nagelkerke R2 = 0.409)
Model 3 - Multivariate Analysis with subclinical hypothyroidism with adjustment for Age, Sex, BMI.
(Nagelkerke R2 = 0.452)
In univariate analysis, subjects with Subclinical hypothyroidism had 1.08 to 5.63 times higher odds of having microalbuminuria compared to other study subjects.
72
DISCUSSION
Thyroid disorders are a major contributor to morbidity in our country.
Coexistence of other metabolic disorders Diabetes Mellitus, Dyslipidemia and metabolic syndrome complicate the scenario. Presence of Coronary artery disease, cerebrovascular accidents and chronic kidney diseases in such patients add to the disease burden further.
Presence of microalbuminuria in most of the above condition indicates widespread endothelial damage and further helps us to identify patients at risk of development of other conditions. As hypothyroidism coexists with many of the above conditions it necessitates early evaluation of microalbuminuria to identify endothelial dysfunction.
In my study, Of the 100 subjects taken into the study 88 were females and 12 were males. Maximum 33% were in the age group of 46-55 years.
40% were healthy and 37% were overweight. Of the 100 subjects in the study 57 were in normal range of albuminuria and 43 had microalbuminuria out of which 36 were females and 7 were males. Of the 78 subjects with hypothyroidism 37 fell into the normal albuminuria range. The rest 41 had microalbuminuria. Among them 27 patients with overt hypothyroidism had microalbuminuria and 14 with subclinical hypothyroidism had microalbuminuria. 20 subjects with hyperthyroidism
73
had normal protein excretion with one each with subclinical and overt hyperthyroidism having microalbuminuria.
On analyzing the FT3 levels in 43 patients with microalbuminuria it was found that 30 had FT3 between the range of 0.5 to 2.5 pg/ml and the rest 13 had FT3 in the range of 2.51 to 4.50pg/ml.
On comparing the FT4 ranges in the 43 subjects with microalbuminuria it was found that 28 had levels less than 0.7ng/dl, 14 in between the range 0.7 to 1.24ng/dl and 1 above 1.24ng/dl.
41 patients with microalbuminuria had TSH levels above 4.25mIU/ml and 2 less than 0.34mIU/ml.
In univariate analysis of risk factors for Microalbuminuria, only subclinical and overt hypothyroidism had significant association.
Presence of other parameters had no significant association with Microalbuminuria.
Also an inverse relationship between the FT3 and FT4 levels with microalbuminuria was noted.
Overt Hypothyroidism was a strong and significant predictor of Microalbuminuria compared to Subclinical Hypothyroidism in both univariate and multivariate analysis.
74
CONCLUSION
From my study I conclude that there is an increased prevalence of hypothyroidism among females. Also all forms of thyroid dysfunction were more common in the age group of 46 to 55 years. A higher prevalence of overweight individuals was noted in the same age group.
On analyzing the presence of microalbuminuria, from my study I infer that there was a high prevalence of microalbuminuria in the females with both impaired glucose tolerance and dyslipidemia individually. A negative correlation between the FT3 and FT4 levels with microalbuminuria exists. Also a significant association of subclinical and overt hypothyroidism with microalbuminuria is present. There is no significant association between Age, Sex, BMI, IGT and dyslipidemia with microalbuminuria.
Hence we can conclude that microalbuminuria plays an important role in thyroid dysfunction and thus plays an important role in screening of patients with other co-existent illness such as prediabetes, hypertension, coronary artery disease and metabolic syndrome.
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LIST OF ABBREVIATIONS
T3- Tri-iodothyronine T4- Thyroxine
FT3- Free Tri-iodothyronine FT4- Free Thyroxine
TSH- Thyroid Stimulating Hormone TRH- Thyroid Releasing Hormone TBG- Thyroid Binding Globulin TTR- Transthyretin
TBPA- Thyroid Binding Pre-albumin.
rT3- reverse T3
TRE- Thyroid response element HPA- Hypothalamo-pituitary axis.
AITD- Autoimmune Thyroid Disease TSHR- TSH Receptor.
76
TPO Ab- Thyroid Peroxidase Antibody.
Tg Ab- Thyroglobulin Antibody.
Anti TSHR Ab- Anti-TSH Receptor Antibody.
PTU- Propylthiouracil.
PTC- Papillary Thyroid Carcinoma FTC- Follicular Thyroid Carcinoma MTC- Medullary Thyroid Carcinoma ATC- Anaplastic Thyroid Carcinoma.
NIS- Sodium Iodide Symporter.
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