Study of Thyroid Dysfunction in Adults

with Newly Detected Type 2 Diabetes

Mellitus Attending Sir Salimullah
Medical College Mitford Hospital

Dr. Md. Mahabub Hossain Khan

FCPS (Medicine) Part – II student
Examinee – July 2020

Assistant Registrar, Department of Medicine

Sir Salimullah Medical College Mitford Hospital, Dhaka

Date of submission of dissertation manuscript

30th September 2020
Contact No: 01755589274

i
 DECLARATION

This primary data-based dissertation is submitted in partial fulfillment of the

requirements for the Fellowship of the College of Physicians & Surgeon (FCPS)
Medicine Part–II Examinations of Bangladesh College of Physicians & Surgeons
(BCPS). The research work was done during May, 2019 to October, 2019 in the
Department of Medicine, Sir Salimullah Medical College Mitford Hospital, Dhaka.

No portion of the work referred to in this dissertation has been submitted in support of
an application for another degree or qualification of this or any other institute of learning.
It is not published in any journal.

Date: Dr. Md. Mahabub Hossain Khan

FCPS (Medicine) Final Part Examinee
Department of Medicine
Sir Salimullah Medical College Mitford Hospital
Mob: 01755589274

ii
 FORWARDING

This is to be certified that Dr. Md. Mahabub Hossain Khan carried out his research
work titled “Study of Thyroid Dysfunction in Adults with Newly Detected Type 2
Diabetes Mellitus Attending Sir Salimullah Medical College Mitford Hospital” and
prepared this dissertation under my direct supervision. I have found the work and the
dissertation satisfactory for partial fulfillment of the requirements of the Fellowship of the
College of Physicians & Surgeons (FCPS) Medicine Part –II Examinations of
Bangladesh College of Physicians & Surgeons (BCPS).

Dr. Ranajit Sen Chowdhury

MBBS, FCPS (Medicine), FCCP, FACP (USA)
Associate Professor, Department of Medicine
Sir Salimullah Medical College & Mitford Hospital, Dhaka

iii
 ACCEPTANCE PAGE I

This is to be certified that this dissertation titled “Study of Thyroid Dysfunction in

Adults with Newly Detected Type 2 Diabetes Mellitus Attending Sir Salimullah
Medical College Mitford Hospital” submitted by Dr. Md. Mahabub Hossain Khan
has been examined by me and found to be satisfactory for partial fulfillment of the
requirements of the Fellowship of the College of Physicians and Surgeons (FCPS)
Medicine Part – II Examinations of Bangladesh College of Physicians and Surgeons
(BCPS).

……………………………….
(Signature of the examiner)

……………………………….
(Name)

………………………………
(Designation)

iv
 ACCEPTANCE PAGE II

This is to be certified that this dissertation titled “Study of Thyroid Dysfunction in

Adults with Newly Detected Type 2 Diabetes Mellitus Attending Sir Salimullah
Medical College Mitford Hospital” submitted by Dr. Md. Mahabub Hossain Khan
has been examined by me and found to be satisfactory for partial fulfillment of the
requirements of the Fellowship of the College of Physicians and Surgeons (FCPS)
Medicine Part – II Examinations of Bangladesh College of Physicians and Surgeons
(BCPS).

……………………………….
(Signature of the examiner)

……………………………….
(Name)

………………………………
(Designation)

v
 DEDICATED TO

Dedicated to my honorable mentor, supervisor and role model – My teacher

Dr. Ranajit Sen Chowdhury

vi
 ABSTRACT

Diabetes mellitus and thyroid disorders are the endocrine abnormalities that have been
shown to influence each other in regard to pathogenesis and clinical course. Studies
suggest that both insulin and thyroid hormones are involved in cellular metabolism and
dysfunction of one hormone can result in derangement of the other with consequent
clinical complications. The goal of this study is to ascertain the frequency of thyroid
dysfunction in newly detected type 2 diabetes mellitus patients, considering the uprising
trend of both of these conditions worldwide. Objective: The objective of this study was
to observe the frequency of thyroid dysfunction in adult patients with newly detected
type 2 diabetes mellitus attending OPD of Sir Salimullah Medical college. Study
Design: This is a cross sectional descriptive study conducted in the Outpatient
Department of Medicine, Sir Salimullah Medical College & Mitford Hospital, Dhaka from
May 2019 to October 2019 on 102 cases of adult patients. Result: This study
encompassing 102 patients with newly diagnosed cases of type-2 DM, intended to see
the frequency of thyroid dysfunction. FT4, TSH along with anti-TPO antibody were
done in all 102 study patients. Thyroid functional status among the study patients
showed 14 (13.7%) patients had thyroid dysfunction. Most of them had subclinical
hypothyroidism 8 (7.8%) followed by overt hypothyroidism 4 (3.9%), subclinical
thyrotoxicosis 1 (1.0%) and hyperthyroidism 1 (1%). Only 3 (11.5%) of the patients with
thyroid dysfunction had family history of thyroid disorder and 13 (12.7%) patients were
anti-thyroid antibody (Anti-TPO) positive. Among different subgroups, most of the overt
hypothyroidism (75%) and subclinical hypothyroidism (75%) were positive for anti-
thyroid antibody. The comparison of Anti-TPO with different thyroid function status
showed that it was statistically significant. Considering the status of anti-thyroid antibody
in light of different level of TSH, highest frequency for positive anti-thyroid antibody
(80%, 4/5) was observed in group having TSH ≥10 µIU/mL followed by 71.4% (5/7) in
the group having TSH (5-10) µ IU/mL, while only 4.4% (4/90) in the group having TSH
<5 µIU/mL (p<0.001). Comparison of clinical parameters showed that there was
significant difference of mean BMI among various subgroups of thyroid functional status

vii
(p=0.034). Association among glucose profile with thyroid function and anti-thyroid
antibody (Anti-TPO) status showed that there was no significant correlations. Logistic
regression analysis for predictive values over thyroid dysfunction in diabetes revealed
that Anti-TPO antibody is independently related to thyroid dysfunction in patients with
diabetes mellitus (p<0.001). Conclusion: The results of the present study suggest that
the thyroid dysfunction is not uncommon in patients with newly diagnosed type-2
diabetes mellitus. Thyroid autoimmunity is one of the predictors for increased risk of
thyroid dysfunction in them. Screening for thyroid dysfunction should be done in newly
diagnosed type-2 DM.

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TABLE OF CONTENTS

Chapter 1
1.1 Title I
1.2 Declaration II
1.3 Forwarding III
1.4 Acceptance pages IV
1.5 Dedication VI
1.6 Abstract VII
1.7 Table of contents IX
1.8 List of tables XI
1.9 List of figures XII
1.10 Acknowledgement XIII
1.11 Abbreviations XIV
Chapter 2
2.1 INTRODUCTION 1
2.1a Background 2
2.1b Rationale of the study 6
2.1c Research question 7
2.1d Objectives of the study 8
2.1e Literature review 9
2.2 MATERIALS & METHODS 26
2.2a Study design 27
2.2b Place of study 27
2.2c Study period 27
2.2d Sampling method 27
2.2e Study population 27
2.2f Sample size and statistical basis of it 28
2.2g Selection criteria 29

ix
2.2h Operational definitions 30
2.2i Equipment 31
2.2j Data collection procedure 31
2.2k Variables 32
2.2l Study Procedure 32
2.2m Analytic Method 33
2.2n Statistical analysis 36
2.20 Ethical Consideration 36
2.3 OBSERVATION & RESULTS 38
2.4 DISCUSSION 56
2.5 CONCLUSION 60
2.6 LIMITATION 61
2.7 RECOMMENDATION 61
Chapter 3
3.1 REFERANCES 62
3.2 APPENDICES I

Appendix-1: Questionnaire II
Appendix-2: Consent Form IV
Appendix-3: FCPS Part-I Congratulation Letter VII
Appendix-4: Protocol Acceptance Letter VIII
Appendix-5: Ethical Committee Clearance Certificate IX
Appendix-6: Accepted Protocol X

x
LIST OF TABLES

I Characteristics of the study population 40

II Thyroid functional status among study population 43

III Subgroups of Thyroid Dysfunction among Study Population 44

IV Comparison of family history of thyroid dysfunction with thyroid functional status

among study population 45

V Frequency of anti-thyroid antibody among study population 47

VI Comparison of anti-thyroid antibody status with thyroid function among study

population 48

VII Comparison between anti-thyroid antibody status with different levels of TSH

among study population 49

VIII Comparison of clinical characteristics of the study population among different

thyroid functional status 51

IX Comparison of glycemic parameters of the study population among different

thyroid functional status 52

X Correlation among glucose profile with thyroid function and antithyroid antibody

status 54

XI Logistic regression analysis showing predictors of thyroid dysfunction 55

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LIST OF FIGURES

i. Effect of thyroid hormones on glucose metabolism in patients with

euthyreosis hyperthyroidism and hypothyroidism 13

ii. Hyperthyroidism and Glucose Homeostosis 16

iii. Hypothyroidism and Glucose Intolerance 18

xii
 ACKNOWLEDGEMENT

With all prostration to the Omnipotent, I express my profound gratitude to my respected

teacher and guide Associate Professor Dr. Ranajit Sen Chowdhury, MBBS, FCPS
(Medicine), Department of Medicine, Sir Salimullah Medical College & Mitford Hospital,
Dhaka, for his vigilant guidance, active cooperation, valuable suggestions and constant
supervision in preparing this dissertation.

I also express my gratitude to my teacher and mentor Professor Dr. Anup Kumar Saha,
Department Head of Medicine, Sir Salimullah Medical College & Mitford Hospital,
Dhaka; Associate Professor A F M Helal Uddin, Department of Medicine, Sir Salimullah
Medical College & Mitford Hospital, Dhaka for their valuable guidance and advice.

I also am deeply indebted to my loving wife Dr. Nusrat Zarin and my son Nusayr Ibn
Mahabub for their kind and patience support all through my work.

I also acknowledge the co-operation of my colleagues, interns and all other staffs of
Medicine Department, Sir Salimullah Medical College and Mitford Hospital, who helped
me during my dissertation work.

I am deeply indebted to all those patients and their guardians whose participation has
made this study possible.

Finally, I am grateful to Almighty Allah again who made me able to complete this
dissertation work properly.

Dr. Md Mahabub Hossain Khan

Mobile: 01755589274

xiii
 ABBREVIATIONS

ADA American Diabetes Association

ANOVA Analysis of Variance

Anti-TPO Anti-thyroid peroxidase antibody

BMI Body Mass Index

CV Coefficient of Variance

CI Confidence Interval

DM Diabetes mellitus

DBP Diastolic blood pressure

FFA Free fatty acid

FPG Fasting plasma glucose

FT3 Free tri-idothyronine

FT4 Free thyroxine

GLUT Glucose Transporter

HbA1c Glycosylated hemoglobin

IDF Internal Diabetes Federation

NHANES National Health and Nutrition Examination Survey

OGTT Oral Glucose Tolerance Test

SBP Systolic blood pressure

SPSS Statistical Package for Social Sciences

SD Standard Deviation

xiv
S.E Stander Error

TSH Thyroid stimulating hormone

WHO World Health Organization

WC Waist Circumference

xv
 CHAPTER 2

2.1 INTRODUCTION

1
2.1a Background

Thyroid diseases and diabetes mellitus are the two most common endocrine disorders
encountered in clinical practice. Diabetes and thyroid disorders have been shown to
influence each other and an association between both conditions has been reported in
literature1. The strong link between diabetes and thyroid diseases encouraged the
American Diabetes Association (ADA) to propose that people with diabetes must be
checked periodically for thyroid dysfunction2. Studies have shown that diabetes and
thyroid dysfunction can be found to exist together where thyroid disease can affect
glucose metabolism and the untreated thyroid dysfunction can affect the management
of diabetes as well3.

In 2017, the International Diabetes Federation estimated that 425 million people around
the world had diabetes and by 2045 this number is expected to rise at 529 million 4.
Diabetes together with other major non-communicable diseases account for over 80%
of all premature deaths in 20155. In 2017 the number of deaths due to diabetes (20-79
years) was 4.0 million and total healthcare expenditures was USD 727 billion which will
be projected to 776 billion USD in the year 2045.

The North America and Caribbean region (NAC) had the highest diabetes prevalence
(20-79 years) in the world in 2017 which was 11.0%. The South East Asia ranked 3rd in
the list and was home to one fifth of the total number of people with diabetes.
Bangladesh ranked 2nd in South East Asia with estimated 7,349,526 diabetic patients
where every 1 in 15 persons had it. The national prevalence of diabetes was 6.8% (age
adjusted prevalence 8.3%) with diabetes related death 108530. In 2045 Bangladesh will
rank ninth in top 10 countries with estimated 13.7 million patients4.

The National Health and Nutrition Examination Survey (NHANES III) (1988-1994)
measured serum TSH, total T4, anti-thyroperoxidase and anti-thyroglobulin antibodies
from a sample of 17,353 people aged >12 years representing the geographic and ethnic
distribution of the U.S population. Hypothyroidism was found in 4.6% and

2
hyperthyroidism in 1.3% of the U.S population 6. NHANES (1999–2002) revealed
hypothyroidism prevalence in the general population was 3.7%, and hyperthyroidism
prevalence was 0.5%7.

The WHICKHAM Survey documented the prevalence of thyroid disorders in a randomly

selected sample of 2779 adults which matched the population of Great Britain in age,
sex and social class. It revealed the prevalence of overt hyperthyroidism was 19-
27/1000 females, compared with 1.6–2.3/1000 males. The prevalence of overt
hypothyroidism was 14-19/1000 female compared with less than 1/1000 males. TSH
levels above 6 mIU/L showed a strong association with thyroid antibodies in both sexes,
independent of age8. In 20 years follow up of WHICKHAM survey the mean incidence of
spontaneous hypothyroidism in women was raised from 3.5 to 4.1/1000 survivors/ year
and in men was 0.6/1000 survivors/year9. Another study in 25,862 people, attending a
state fair in Colorado found that 9.5% had TSH values greater than 5.1 mIU/L and 2.2%
had TSH less than 0.3 mIU/L10.

There are several studies documenting a higher than normal prevalence of thyroid
function abnormalities in patients with diabetes mellitus. Prevalence of thyroid
dysfunction among Greek Type 2 diabetic patients was 12.3% as documented by
Papazafiropoulou et el. In the group with thyroid dysfunction there was an excess of
women in comparison with the group without it11. In one study of young type 2 diabetic
patients Mukherjee found subclinical hypothyroidism in 43.33% of cases followed by
9.2% of patients with overt hypothyroidism, 8.3% with subclinical hyperthyroidism and
5% of patients showed features of clinical hyperthyroidism 12. In another study of
prevalence of thyroid dysfunction in newly diagnosed type 2 diabetic patients,
Vithiavathi et al. found most prevalent thyroid dysfunction was subclinical
hypothyroidism (21%) followed by overt hypothyroidism (7%) with prevalence of
dysfunction being more common in females13. In Rio de Janeiro, Palma et al. found the
prevalence of thyroid dysfunction was 14.7%; the most frequent was subclinical
hypothyroidism found in 13% of patients with Type 1 DM and in 12% of patients with
Type 2 DM. The prevalence of anti-TPO antibodies was 10.8%14. Elebrashy et al. in a

3
case control study of Egyptian females found hypothyroidism in 45.2% patients with
type 2 diabetes against 11.1% controls. Anti-TPO Ab was found in 75.8% diabetic cases
and in 7.4% controls15. Khurana et al. in a study of 200 type 2 diabetic patients aged
between 40-70 years found 16% prevalence of thyroid dysfunction in which most
common was subclinical hypothyroidism with prevalence of 7.5%. Incidence of
subclinical hypothyroidism was more common in females, elderly patients and patients
with uncontrolled diabetes16.

Insulin resistance and β cell function are inversely correlated with thyroid stimulating
hormone which may be explained by insulin-antagonistic effects of thyroid hormones
along with an increase in TSH17. Insulin resistance also leads to impaired lipid
metabolism according to recent findings18. Thyroid disorders not only worsen the
metabolic control but also affect the management of diabetes 19. It is worth considering
that insulin resistance has been a proven condition in both hyper and hypothyroidism18.
5' adenosine monophosphate-activated protein kinase (AMPK) is a central target for
modulation of insulin sensitivity and feedback of thyroid hormones associated with
appetite and energy expenditure20. In thyrotoxicosis, increased glucose output from liver
is the pivotal reason for the induction of hyperinsulinaemia, glucose intolerance and
development of peripheral insulin resistance21. Glucose intolerance in thyrotoxicosis is
caused by elevated hepatic glucose output along with up-regulated glycogenolysis22.
This phenomenon is responsible for worsening of diabetes and exaggeration of
hyperglycaemia in T2 DM. Thyrotoxicosis may also lead to ketoacidosis due to elevated
lipolytic actions and increased hepatic 𝛽 oxidation23, 24. Reduced glucose absorption
from gastrointestinal tract accompanied by prolonged peripheral glucose accumulation,
gluconeogenesis, diminished hepatic glucose output and reduced disposal of glucose
are hallmarks of hypothyroidism25. In overt or subclinical hypothyroidism insulin
resistance leads to glucose-stimulated insulin secretion22. Moreover, due to reduced
renal clearance of insulin in hypothyroid conditions, physiological requirements of insulin
are diminished26. Diabetes mellitus appears to influence thyroid function at two sites,
one at the level of hypothalamic control of thyroid stimulating hormone (TSH) release
and the other at the conversion of thyroxin (T4) to 3,5,3’- triiodothyronine (T3) in the
peripheral tissue. Marked hyperglycemia causes low serum concentrations of T3,

4
elevated levels of reverse T3 and low, normal or high levels of T4. The values return to
normal after correction of hyperglycemia27. Thyroid hormones have a significant effect
on glucose metabolism and the development of insulin resistance28. In hyperthyroidism,
impaired glucose tolerance is the result of mainly hepatic insulin resistance, whereas in
hypothyroidism the available data suggests that the insulin resistance of peripheral
tissue prevails29.

Type 2 diabetes mellitus is one of the fastest growing non-communicable diseases in

Bangladesh. Begum et el. in a case control study found that serum levels of thyroid
stimulating hormone (TSH) and free T3 (FT3) were significantly lower in T2 DM patients
than that of control patients without any significant difference in levels of free T4 (FT4).
FBG and HbA1c were abnormally high and FT3 was abnormally low in T2 DM patients
whereas levels of TSH, FT4, anti-thyroglobulin (TG) and anti-thyroid peroxidase
antibody (Anti-TPO Ab) all were almost within the normal range30. In a cross sectional
study involving 232 patients with T2 DM Moslem et al. found the prevalence of thyroid
dysfunction was 10% with higher rate of thyroid dysfunction in females (78.3%)31. In
another study Afrin et el. found serum TSH was significantly higher and serum TT4,
FT4, FT3 levels were significantly lower in type 2 diabetic patients 32. In the context of
our country few data are available regarding the frequency of thyroid dysfunction among
patients with newly detected type 2 diabetic patients where in Bangladesh and
worldwide the prevalence of type 2 diabetes mellitus is increasing. This study
demonstrates the importance of early recognition of the mutual relationship between
thyroid dysfunction among newly detected type 2 diabetic patients who visited
endocrine and medicine OPD in a tertiary care hospital which will guide clinicians on the
optimal screening and management of both conditions.

5
2.1b Rationale of the study

Diabetes mellitus and thyroid dysfunction both have profound effect on the metabolism
of our body. Identifying these disorders initially can change the outcome of both
conditions and have huge impact on mortality and quality of life. Studies have showed
the deleterious effect of each condition on another if left undiagnosed or untreated. Very
few studies have reported the relationship of thyroid dysfunction in newly detected type
2 diabetic patients. Detecting thyroid abnormalities in the eraly stage of diabetes may
help improve metabolic, renal and cardiovascular outcome in type 2 diabetics. We know
that hyperthyroidism worsen subclinical diabetes and exaggerates hyperglycemia,
ketoacidosis in type 2 diabetic patients with consequent increased demand of
exogenous insulin. Hypothyroid diabetic patients also have underlying insulin resistance
demanding meticulous control of both conditions. Currently there is scarcity of data in
Bangladesh where association of both these endocrine disorders were scientifically
evaluated. This study intends to find that relationship, collecting data from endocrine
and medicine outdoors at Sir Salimullah Medical College & Mitford Hospital.

6
2.1c Research question

What is the frequency of thyroid dysfunction in adult patients with newly detected type-2
diabetes mellitus in Bangladesh?

7
2.1d Aims & Objectives

General Objective:

To observe the frequency of thyroid dysfunction in adult patients with newly detected
type- 2 diabetes mellitus.

Specific:
 To observe the type of thyroid dysfunction (Euthyroid, Hypothyroid or
Hyperthyroid) among type 2 diabetic patients.
 To observe the thyroid antibody status (anti-TPO Ab) in the selected groups.
 To see the correlation between glycemic and thyroid status in the study patients.
 To observe the socio-demographic and anthropometric pattern in the study
groups.

8
2.1e Literature Review

For the purpose of literature review relevant articles were searched from internet using
the search engine Google. Similar articles from last 20 years were searched through
this search engine. During searching articles global to country specific information and
data were reviewed. Guidelines were reviewed from the websites of relevant authority.

Diabetes mellitus is a long term condition that occurs when there are raised levels of
glucose in the blood because the body cannot produce any or enough of the hormone
insulin or use insulin effectively due to resistance 33. Diabetes is a global issue. It is a
common threat that does not respect borders or social classes. No country is immune
from diabetes and the epidemic is expected to continue. Diabetes is one of the largest
global health emergencies of the 21st century. It is among the top 10 causes of death
globally and together with the other three major non-communicable diseases (NCDs)
(cardiovascular disease, cancer and respiratory disease) account for over 80% of all
premature NCD deaths. In 2015, 39.5 million of the 56.4 million deaths globally were
due to NCDs5. A major contributor to tackle the challenge of diabetes is that 80% of
people are undiagnosed34. In high income countries, approximately 87% to 91% of all
people with diabetes are estimated to have type 2 diabetes35, 36.

Some 425 million people worldwide, or 8.8% of adults ranging 20-79 years, were
estimated to have diabetes in 2017, according to IDF. About 79% of them live in low
and middle income countries. If these trend continue, by 2045, around 629 million
people will have diabetes. The prevalence of diabetes among women of 20-79 years is
estimated to be 8.4% which is slightly lower than men (9.1%). There are about 17.1
million more men than women with diabetes (221.0 million men vs 203.9 million
women). The diabetes prevalence in women is expected to increase to 9.7% in women
and to 10.0% in men by 2045.

The North America and Caribbean region (NAC) has the highest age adjusted
comparative prevalence of diabetes in 20-79 years age group in 2017 and 2045 (11.0%

9
and 11.1%). The Africa region has the lowest prevalence in 2017 and 2045 (4.2% and
4.1% respectively).The North America and Caribbean region (NAC) had the highest
diabetes prevalence in the world in 2017 which was 11.0%. The South East Asia ranked
3rd in the list and was home to one fifth of the total number of people with diabetes.
Almost 84 million people who have diabetes here – this region had the second highest
number of deaths (around 1.3 million in 2017) attributable to diabetes out of any of the
seven IDF regions. The largest numbers of people with diabetes from age 20-79 years
were in China, India and the United States in 20174.

Bangladesh ranked 2nd in South East Asia with estimated 7,349,526 (18-99 years)
diabetic patients, where every 1 in 15 persons had it. The national prevalence of
diabetes was 6.9% (age adjusted prevalence 8.4%, 18-99 years) with diabetes related
death was 108,530 (18-99 years). In 2045 Bangladesh will rank ninth in top 10 countries
with estimated 13.7 million patients37.

The National Health and Nutrition Examination Survey (NHANES III)(1988-1994)

measured serum TSH, total serum T4, anti-thyroperoxidase (Anti-TPO Ab), and anti-
thyroglobulin (Anti-Tg Ab) antibodies from a sample of 17,353 people aged >12 years,
representing the geographic and ethnic distribution of the U.S. population.
Hypothyroidism was found in 4.6% of the U.S. population (0.3% clinical and 4.3%
subclinical) and hyperthyroidism in 1.3% (0.5% clinical and 0.7% subclinical). TSH and
the prevalence of antithyroid antibodies were greater in females, increase with age, and
were greater in whites and Mexican Americans than in blacks. Anti-Tg Ab alone in the
absence of Anti-TPO Ab is not significantly associated with thyroid disease6. National
Health and Nutrition Examination Survey (NHANES 1999–2002) revealed
Hypothyroidism prevalence (TSH > 4.5 mIU/L) in the general population was 3.7%, and
hyperthyroidism prevalence (TSH < 0.1 mIU/L) was 0.5%. Among women of
reproductive age (12–49 years), hypothyroidism prevalence was 3.1%. Individuals aged
80 years and older had five times greater odds for hypothyroidism compared to 12 to 49
year-olds7.

10
The WHICKHAM Survey documented the prevalence of thyroid disorders in a randomly
selected sample of 2779 adults which matched the population of Great Britain in age,
sex and social class. It revealed the prevalence of overt hyperthyroidism was 19-
27/1000 females, compared with 1.6–2.3/1000 males. The prevalence of overt
hypothyroidism was 14-19/1000 female compared with less than 1/1000 males. TSH
levels did not vary with age in males but increased markedly in females after the age of
45 years. TSH levels above 6 mu/l showed a strong association with thyroid antibodies
in both sexes, independent of age8. In 20 year follow up of WHICKHAM survey the
mean incidence of spontaneous hypothyroidism in women was raised from 3.5 to
4.1/1000 survivors/ year and in men was 0.6/1000 survivors/ year. The mean incidence
of hyperthyroidism in women was 0.8/1000 survivors/year and was negligible in men 9.

A study of 25,862 people, attending a state fair in Colorado found that 9.5% had TSH
values greater than 5.1 mIU/l and 2.2% had TSH less than 0.3 mIU/l. The high
prevalence of elevated serum TSH and antithyroid antibodies in the United States,
especially in women and the elderly, suggests that thyroid disease should be
considered during routine evaluation of this susceptible population and should be
followed by appropriate detection and treatment10.

Thyroid diseases and diabetes mellitus are the two most common endocrine disorders
encountered in clinical practice. Diabetes and thyroid disorders have been shown to
mutually influence each other and associations between both conditions have long been
reported. On one hand, thyroid hormones contribute to the regulation of carbohydrate
metabolism and pancreatic function, and on the other hand, diabetes affects thyroid
function tests to variable extents.

Effects of Thyroid Hormones on Glucose Homeostasis

It has long been recognised that thyroid hormones have marked effects on glucose
homeostasis. Glucose intolerance is associated with hyperthyroidism and it was shown
that hypothyroidism is characterised by insulin resistance. Thyroid hormones exert

11
profound effects in the regulation of glucose homeostasis. These effects include
modifications of circulating insulin levels and counter-regulatory hormones, intestinal
absorption, hepatic production and peripheral tissues (fat and muscle) uptake of
glucose. It has long been known that thyroid hormones act differentially in liver, skeletal
muscle and adipose tissue – the main targets of insulin action (figure 1).

Hyperthyroidism and Glucose Homeostasis

Several mechanisms have been implicated in the pathogenesis of impaired glucose

tolerance in thyroid dysfunction. There is high incidence of abnormal glucose
metabolism in thyrotoxic patients reflecting the fact that hypethyroidism promote
hyperglycemia38. In a study by Dimitriadis et el. conducted on 10 normal volunteers,
who were iatrogenically converted thyrotoxic by administration of tri-iodothyronine (T3)
orally showed, hyperthyroidism promotes insulin resistance at a post-binding site in both
hepatic and peripheral tissues accompanied by increased insulin clearance39. Insulin
secretion rates not only increased in basal condition but also in response to meal in
hyperthyroid patients. It occurs as a result of reduced half-life of insulin which is most
likely secondary to increased rate of degradation and an enhanced release of
biologically inactive insulin precursors40.

There is an increase in glucose absorption from gut in thyrotoxicosis which is mediated

by excess thyroid hormones. This effect is exerted in three ways:
(1) By a direct effect of the hormone on the absorbing cells;
(2) By the effect of the hormone on gastric emptying, intestinal motility, blood flow and
other functions during the actual period when absorption is being studied;
(3) By indirect effects on the epithelial cells secondary to changes in gastric emptying,
motility, blood flow, etc. caused by the hormone.

Hyperthyroidism causes increase in the weight of intestine reflecting upward projection

in cell numbers, greater uptake of glucose from the mucosal fluid, and increased rate of
metabolism41. C-peptide and proinsulin levels were studied in hyper and hypothyroidism

12
13
both pre and post-treatment and in comparison to matched normals. Fasting C-peptide
was reduced but fasting proinsulin level was elevated in untreated hyperthyroidism
suggesting there may be a defect of proinsulin processing in hyperthyroidism. All these
abnormalities got back to normal after treatment. A similar pattern was also observed
after an oral glucose load42.

In hyperthyroidism, endogenous insulin production has been reported to be increased

by several mechanisms. It leads to an enhanced demand for glucose, which is primarily
provided in the fasting state by increased rates of hepatic glucose production and
output. This occurs as a result of increased gluconeogenesis and increased activity of
cori cycle in both the postprandial and fasting state. In hyperthyroid state, the glycogen
synthesis rate under insulin stimulation in skeletal muscles are decreased, whereas
there is a preferential increase in the rates of lactate formation in comparison to glucose
oxidation, leading to increased cori cycle activity which promotes further hepatic
gluconeogenesis43. There is an up-regulation of hepatocyte plasma membrane glucose
transporter namely GLUT2, which is the principal glucose transporter in liver. As a result
an up-regulation of GLUT-2 transporter contributes to the increased hepatic glucose
output, hyperglycemia and abnormal glucose metabolism. Increased gluconeogenesis
and excessive efflux of glucose from hepatocytes are thought to contribute to impaired
glucose tolerance44. It is well known that diabetic patients with hyperthyroidism
experience worsening of their glycemic control and untreated thyrotoxicosis has been
shown to precipitate ketoacidosis in patients with diabetes. This is as because with
thyrotoxicosis there is enhancement of basal hepatic glucose production and reduced
suppressibility by insulin. Other mechanisms include increased peripheral insulin
resistance and insulin clearance. Though previously assumed otherwise, insulin
resistance in thyrotoxicosis may be a consequence of increased hepatic glucose output
rather than a post-receptor defect because euglycemic insulin clamp studies suggest
insulin responsiveness, clearance and basal insulin delivery rate increase in
thyrotoxicosis. This observation contradicts findings of Dimitriadis et el. Thus, insulin
secretion, hepatic glucose output, its suppressibility by insulin, peripheral tissue insulin
responsiveness and insulin degradation may all be compromised in thyrotoxicosis, but

14
probably to a different extent in different individuals thus precipitating ketoacidosis 45,46.
Another mechanism involved, increased lipolysis which is observed in hyperthyroidism
resulting in an increase in free fatty acids (FFA) that stimulates hepatic
gluconeogenesis. The increased release of FFA could partially be explained by an
enhanced catecholamine-stimulated lipolysis induced by the excess thyroid hormones47.
Several literatures published on the topic of complex interaction between thyroid and
other anabolic hormones48.There is an increase in Growth hormone, glucagon and
catecholamine levels associated with hyperthyroidism that further contributes to the
altered glucose tolerance49, 50. The interaction between hyperthyroidism and glucose
metabolism is displayed in figure 2.

Hypothyroidism and Glucose Intolerance

Several in vivo and in vitro studies have demonstrated that, glucose utilization under
insulin stimulation, in peripheral tissues is impaired in hypothyroidism51. There is
decrease in blood flow in adipose tissue and muscle which may be considered as part
of the pathogenetic mechanism of insulin resistance explaining most of the metabolic
defects in these tissues52. Moreover, in hypothyroidism the targets of insulin action are
not uniformly impaired. The glucose uptake and proteolysis are resistant to insulin, but
lipolysis is not53.
Another study also showed similar findings of insulin action in hypothyroidism:
1) Glucose uptake in muscle and adipose tissue is resistant to insulin;
2) The suppression of lipolysis by insulin is not impaired54.

A reduced rate of glucose production from liver is observed in hypothyroidism. There is

inhibition of gluconeogensis that leads to suppression of both glucose production and
glycogenesis in the liver55. This is the reason for the decrease in insulin requirement in
hypothyroid diabetic patients. This phenomenon is also evident from the observation of
recurrent hypoglycemic episodes that manifested not only as initial presenting sign in
hypothyroid patients43 but in a case control study also, where this was a frequent
feature in subclinically hypothyroid patients46.

15
16
Impact of thyroid hormone deficiency on glucose, lipid and insulin metabolism is not fully
understood. Thyroid hormones play a role in lipid synthesis, metabolism and
mobilization. Metabolic syndrome is a status where most features of hypothyroidism can
be seen. In a case control study, Erdogan et al. found an increased frequency of
metabolic syndrome in subclinical and overt hypothyroidism compared to healthy
controls58. The complex interplay between hypothyroidism and glucose intolerance is
showed in figure 3. Therefore, it seems prudent to consider hypothyroidism in patients
with newly diagnosed metabolic syndrome. This raises the issue whether routine
screening for thyroid disease in all patients newly diagnosed with metabolic syndrome
will be cost effective.

Type 2 diabetic patients with subclinical hypothyroidism are associated with an

increased risk of nephropathy and cardiovascular events, but not with retinopathy. Chen
et el. suggested that the higher cardiovascular events in subclinical hypothyroidism with
type 2 diabetes may be mediated by nephropathy59. This phenomenon can be
explained by the decrease in cardiac output and increase in peripheral vascular
resistance seen with hypothyroidism and the resulting decrease in renal flow and
glomerular filtration rate60. Renal function is profoundly influenced by thyroid status.
However, this has not been studied thoroughly in human patients. In 2005, Hollander et
al. reported that treating hypothyroidism improved renal function in diabetic patients.
Renal function improved significantly during treatment of hypothyroidism and decreased
during treatment of hyperthyroidism61. As for retinopathy, Yang et al. demonstrated
recently that diabetic patients with subclinical hypothyroidism have more severe
proliferative retinopathy than euthyroid patients62. The increased risk of retinopathy and
nephropathy observed in diabetic patients with subclinical hypothyroidism provides
evidence in favor of screening patients with type 2 diabetes for thyroid dysfunction and
treating when present. Reduced glucose absorption from gastrointestinal tract
accompanied by prolonged peripheral glucose accumulation, gluconeogenesis,
diminished hepatic glucose output and reduced disposal of glucose are hallmarks of
hypothyroidism20.

17
18
Thyroid hormones may influence carbohydrate metabolisms via its interaction with
adipocytokines and gut hormones. Adiponectin, the most abundant adipocytokines has
important insulin sensitizing properties. Low levels of adiponectin have been shown to
confer a higher risk for development of type 2 diabetes. Adiponectin and thyroid
hormones share some biological properties including reduction in body fat by increasing
thermogenesis and lipid oxidation63. The relationship between thyroid hormones and
adiponectin are not clarified as some studies found that adiponectin are increased in
hyperthyroidism64, 65, whereas other studies reported unchanged levels in states of
excess thyroid hormones66, 67. In hypothyroidism, reduced levels of adiponectin have
been shown by Dimitriadis et al.51, and comparable levels of adiponectin were observed
in hypothyroid patients and controls in a study by Nagasaki et al. 68. Leptin is another
hormone produced by adipocytes that regulates energy expenditure and body weight.
A correlation between leptin and thyroid hormones has been demonstrated in several
studies. However, results have also been discordant. Nevertheless, the complex
interplay between thyroid hormones and leptin and its possible influence on
carbohydrate metabolism remains to be clarified by further studies 69.

Besides all of the aforementioned mechanisms, thyroid hormones can indirectly affect
glucose metabolism through modulation of energy homeostasis. Although the
underlying mechanisms have not yet been clearly defined, thyroid hormones have been
shown to alter the expression of uncoupling proteins in brown adipose tissue involved in
effective thermoregulation. Thyroid hormones could indirectly alter glucose metabolism
via their interaction with various hypothalamic signals. However, the exact mechanisms
behind this complex interaction remains to be elucidated70.

Effects of Diabetes Mellitus on Thyroid Hormones and Thyroid Diseases

It has been shown that thyroid functions happen to be altered in patients with diabetes
especially those with poor glycemic control. Diabetes mellitus appears to influence
thyroid function in at least two sites, one at the level of hypothalamic control of

19
thyrotropin-releasing hormone (TRH) release and the other at the conversion of
thyroxine (T4) to 3,5,3'- tri-iodothyronine (T3) in the peripheral tissue. Study showed, the
nocturnal TSH peak is blunted or abolished, and the serum baseline TSH secretion in
the morning may be normal, low or high and the serum TSH response to TRH may be
normal or blunted in patients with diabetes mellitus71, 72. Reduced T3 levels have been
observed in uncontrolled diabetic patients which is characteristically known as “Low T3
Syndrome”. Marked hyperglycemia decreases the activity and concentration of hepatic
T4-5' deiodinase. The characteristic findings include low serum concentrations of T3,
elevated levels of reverse T3 (rT3) and low, normal or high levels of T4. The values
return to normal after correction of hyperglycemia. There is an impairment in peripheral
conversion of T4 to T3 that normalizes with improvement in glycemic control which can
explain this low T3 state73. However, in a study conducted by Coiro and his team
involving type 1 diabetic patients, an improvement in glycemic control did not restore the
normal nocturnal TSH peak. It suggests that a permanent alteration in the central
control of TSH might have occurred by long standing uncontrolled glycemic exposure 74.
Metabolic syndrome associated with insulin resistance have higher prevalence of
increased thyroid volume and nodule75. Increased levels of circulating insulin as a
consequence of insulin resistance have shown a proliferative effect on thyroid tissue
resulting in larger thyroid size76. A higher prevalence of type 1 diabetes is observed in
patients with Graves’ ophthalmopathy than in the normal population. Furthermore, the
microvascular changes associated with diabetes renders the optic nerve more
susceptible to the pressure exerted by the enlarged extraocular muscles. Consequently,
a higher incidence of optic neuropathy is observed in diabetic patients with Graves’
ophthalmopathy compared to nondiabetic77. When hyperthyroidism is also present in a
patient with poorly controlled diabetes, the total and even free T4 and T3 concentrations
may be inappropriately normal, in which case the diagnosis can be difficult. A
suppressed serum basal TSH or absolutely flat response to TRH would support the
diagnosis. In this situation, serum thyroid hormones rose to hyperthyroid levels with
treatment of the diabetes, and the diagnosis becomes clear78.

20
A case control study was carried out by Uppal et el. incorporating North Indian
population to correlate serum insulin and glycosylated haemoglobin with the level of
thyroid hormones. 120 patients of type 2 diabetes were included in this study among
them 17% had hypothyroidism and 7.5% had hyperthyroidism. There was higher
prevalence of thyroid disorders in type 2 diabetics and it was more common in females.
The most common thyroid disorder was hypothyroidism. The association of thyroid
disorder with diabetes was more frequent who have deranged metabolic control.
Thyroid dysfunction also influences the glycosylated haemoglobin levels. The author
concluded the justification of biochemical screening for thyroid disorder in diabetic
patients79.

A cross sectional study was carried out in the National Hospital of Sri Lanka to evaluate
the prevalence of thyroid dysfunction and to identify risk factors which are associated. It
showed that thyroid dysfunction was identified in 83 out of 393 type 2 diabetic patients.
The prevalence of thyroid dysfunction among study patients was 21.1%. The most
common thyroid dysfunction categories were subclinical hypothyroidism (9.4%) and
overt hypothyroidism (6.1%). Subclinical hyperthyroidism and overt hyperthyroidism
were detected only in 5.1% and 0.5% of cases respectively. The presence of thyroid
dysfunction was strongly associated with female sex (p<0.01)80.

Another cross-sectional retrospective randomized hospital-based study comprising 411

Type 2 diabetic Saudi patients, was conducted by Al-Geffari et al. to observe the
prevalence of different types of thyroid dysfunction and their risk factors. The
prevalence of thyroid dysfunction was 28.5%, of which 25.3% had hypothyroidism,
where 15.3%, 9.5%, and 0.5% were clinical (hypothyroid patient on treatment),
subclinical, and overt hypothyroidism, respectively. The prevalence of hyperthyroidism
is 3.2%, of which subclinical cases accounted for 2.7% and overt hyperthyroidism
accounted for 0.5%. Risk factors for thyroid dysfunction among Saudi Type 2 diabetic
patients were family history of thyroid disease, female gender, and duration of diabetes
of >10 years81.

21
Another case-control study conducted by Vagasiya et el. where 100 patients (50
case/diabetic and 50 control/non-diabetic) were enrolled. Their thyroid profile (free T3,
T4 and thyroid stimulating hormone) was done by chemiluminescence assay method.
Prevalence of thyroid dysfunction was found significantly high in diabetic patients. In this
study out of 50 diabetic patients 14 (28%) patients had thyroid dysfunction. Among them
1 (3%) had hypothyroidism, 8 (16%) had subclinical hypothyroidism and
hyperthyroidism was noted in 5 (10%) patients. In that study, prevalence of thyroid
dysfunction was high and 80% among the cases had diabetes for more than 10 years.
The authors concluded increased duration of diabetes had significant relation with the
increase in thyroid dysfunction in this study82. In another led by Telwani et el. in Jammu
and Kashmir on 100 diabetics and 100 controls, all the participants were evaluated for
thyroid dysfunctions and the correlation of prevalence of thyroid disorder with age and
gender distribution, BMI, duration of diabetes and HbA1C was done. Result showed the
prevalence of thyroid dysfunctions were high in diabetic patients compared to controls
(29% versus 9%, P value <0.001). Most common thyroid disorder in diabetic patients
was subclinical hypothyroidism (16%) while least common was hyperthyroidism (1%).
Prevalence of thyroid disorders in diabetics were significantly more in patients with age
≥ 50 years, in females, in patients with BMI ≥ 30 and duration of diabetes ≥ 5 years. The
association of prevalence of thyroid disorders with HbA1C was not significant83.

Another study was done on 150 patients with known type 2 diabetes mellitus or newly
detected type 2 diabetes mellitus without known thyroid disorders. 3rd generation TSH
assay was utilised to screen the status of thyroid profile. Among 150 cases of Type 2
diabetes, 43 (28.67%) had abnormal thyroid functions. Of these 23 (15.34%) had
subclinical hypothyroidism, 16 (10.66%) had overt hypothyroidism and 2 (1.33%) each
had subclinical and overt hypothyroidism. Thyroid disorders were noted more commonly
among those having diabetes over a period of 5 years. There was a significant
correlation between abnormal thyroid profile and family history of diabetes, BMI and
serum lipid profile84. In an attempt to find out the prevalence of hypothyroidism and
hyperthyroidism in Indonesian diabetics, a cross-sectional study was conducted on 303 diabetic
patients by Subektiet el. Out of 303 patients 273 (90.1%) were euthyroid, 7 (2.31%) were

22
hyperthyroid, and 23 (7.59%) were hypothyroid. Majority of the patients had subclinical
hypothyroidism85.

Another study, consisted of 161 patients, had defined thyroid function status of diabetics
in Calabar, Nigeria, probably the first of such work in Africa. Out of 161 diabetic patients
studied this study had shown a high incidence (46.5%) of abnormal thyroid hormone
levels among the diabetics in Nigeria (hypothyroidism 26.6%, hyperthyroidism, 19.9%).
The prevalence of hypothyroidism was higher in women (16.8%), while hyperthyroidism
was higher in males (11%) than in females (8%)86. To compare the prevalence of
thyroid dysfunction and autoimmunity in type 2 diabetic patients, Ardekani et el.
recruited 2797 type 2 diabetic patients who were compared with 4844 non-diabetic, age
and sex matched control patients. Findings showed that the levels of thyroid hormone
were not significantly different from levels in non-diabetic controls (P < 0.05). Positive
anti-TPO antibody was found in 1032 type 2 diabetic patients (36.9%) versus 1802
(37.2%) in control group (P = 0.8). Positive both thyroid antibodies, TPO antibody and
TG antibody were found in 314 diabetic patients; (11.2%) versus 516 (10.8%) in
controls (P = 0.54)87.

In Bangladesh probably the largest cross-sectional study across the country was
conducted by Hasan et el. on 1056 T2 DM patients with unknown thyroid function
status. The observed frequency of thyroid dysfunction in that study was 21.9%
(subclinical hypothyroid 14.1%, primary hypothyroid 4%, subclinical hyperthyroid 1.9%,
overt hyperthyroid 1%, and secondary hypothyroid 0.9%). 32.9% of the participants
were positive for thyroid autoantibodies. The patients with thyroid dysfunction had a
higher body mass index (BMI) and higher thyroid autoantibody titer than euthyroid ones.
Thyroid dysfunction was more common in females and autoantibody‑positive
individuals. TSH had an inverse negative correlation with FT4 in both euthyroid and
thyroid dysfunction groups and had a positive correlation with age in the euthyroid group
only. FT4 had an inverse correlation with age and duration of diabetes in both groups
and with BMI in euthyroid diabetic patients. They concluded thyroid dysfunction and
autoimmunity are common in Bangladeshi T2DM patients88.

23
In another comparative study led by Islam et el. in BIRDEM, Dhaka 52 diabetic patients
were consecutively selected from OPD against 50 healthy patients. They found patients
with type 2 diabetes had significantly lower serum FT3 levels (p=0.000) compared to the
control groups. There were no significant differences observed in serum FT4 (p=0.339)
and TSH (p=0.216) levels between the control and study patients. All the diabetic
patients had high fasting blood glucose levels (12.15±2.12). The researchers concluded
that FT3 levels were altered in these study patients with uncontrolled diabetes 89.

Alam et el. performed another case-control study taking 140 diabetic patients against
similar number of healthy non-diabetic patients. Out of 140 diabetic patients studied,
70% had euthyroidism, 18.6% had hypothyroidism, and 11.4% had hyperthyroidism.
Serum T3, T4 and FT3 levels were low, TSH and FT4 levels were high in diabetic
patients whereas, in non-diabetic patients all these levels were normal. All the diabetic
patients had high fasting blood sugar levels (10.82 ± 2.72). Statistically no significant
differences were observed in serum FT4 (p = 0.791) and BMI (p = 0.477) levels
between non-diabetic and diabetic groups. Fasting blood sugar significantly correlated
with TSH, FT3. In this study, 30% diabetic patients were found to have abnormal thyroid
hormone levels. The prevalence of thyroid disorder was higher in women (17.1%) than
in men (12.9%), while hyperthyroidism were higher in males (13.3%) than in females
(10%) and hypothyroidism was higher in females (20%) than in males (16.7%)90.

The magnitude of hypothyroidism at community level in Bangladesh is unknown except

some clinic-based studies. In a study Sayeed et el. tried to find out the Prevalence of
hypothyroidism in different occupational groups of Bangladeshi population. His team
selected three occupational groups (house-wives, college students, rickshaw-pullers) of
native Bangladeshi population. Overall, 626 (M/F=123 / 503) participants with a mean
age of 35.9 years volunteered. The mean values of all participant for TSH and FT4 were
2.08 μiu/ml and 13.04 pmol/L respectively. The prevalence of hypothyroidism in both
sexes was 7.0% (M/F=4.1/8.3%). Occupational groups, sex, increasing age, obesity,
blood pressure, and lipids showed no association with hypothyroidism. Hyperglycemia
was proved to be a significant risk for hypothyroidism (prevalence in diabetic vs. non-

24
diabetic was 12.9% vs. 5.5%, p = 0.04; FBG was correlated with TSH, r = 0.138, p
<0.001)91.

Thyroid hormonal status in newly diagnosed Type 2 diabetes mellitus was evaluated by
Mamun et el. A total of 98 newly diagnosed type 2 diabetic patients (Group I) and 98
healthy individuals (Group II) were enrolled in this study purposively. Mean TSH, FT3
and FT4 were 2.37 ± 3.86 mIU/L, 6.35 ± 2.41 pmol/L and 15.79 ± 5.41 pmol/L
respectively in group I whereas 2.28 ± 2.67 mIU/L, 6.59 ± 1.83 pmol/L and 16.25 ± 3.46
pmol/L respectively in group II. But there was no statistically significant difference
between group I and group II. In group I, sixteen patients had thyroid disorder (seven
had hyperthyroidism and nine had hypothyroidism). In group II, five patients had thyroid
disorder (two had hyperthyroidism and three had hypothyroidism). The difference was
statistically significant. Fasting blood sugar positively correlated with TSH, FT3 and FT4
and similarly HbA1c correlated with TSH and FT4 but not with FT3 in group I 92.

There are scarcities of data regarding frequency of thyroid dysfunction among patients
with newly detected type-2 DM at Old Dhaka and adjoining area of Mitford in Dhaka.
The pathophysiology of thyroid dysfunction and diabetes mellitus are closely intertwined
and the co-occurrence of these common endocrine conditions have impacts on clinical
presentation and long term complications. As the incidence of occurring both these
conditions is rising sharply, I have decided to conduct the study to ascertain the
frequency of thyroid dysfunction in newly detected patients with type-2 DM.

25
2.2 MATERIALS & METHODS

26
2.2a Study Design

This is a cross sectional descriptive study.

2.2b Place of Study

Outpatient Department of Medicine and Endocrinology, Sir Salimullah Medical College

& Mitford Hospital, Dhaka.

2.2c Study Period

May 2019 to October 2019.

2.2d Sampling Method

Purposive sampling method.

2.2e Study Population

Adult patients (above 20 years) with newly diagnosed type 2 diabetes mellitus attending
the Endocrinology and Medicine OPD of Sir Salimullah Medical College &Mitford
Hospital.

27
2.2f Sample Size & Statistical Basis of It

For this study, sample size calculation will be done by following statistical formula,

n = P (1-P) Z2 / (error)2

The study will be conducted with 95% confidence interval of and 5% error.

Here,

P, prevalence = 16%16.

For 95% confidence level Z = 1.96 and

for 5% error = .05

 n = P(1-P)Z2/(error)2

 n = .16(1-.16)1.962/(.05)2

 n = 207

For time and financial constraint, the study will be conducted on a sample comprising of
102 patients.

28
2.2g Selection Criteria

Inclusion Criteria

 Adults aged 20 years or above.

 Newly detected patients with type -2 diabetes mellitus, irrespective of sex.

 Willing to participate.

Exclusion Criteria

 Patients with thyroid disorder or on treatment.

 Patients with acute illness (Sepsis, Acute MI, Severe heart failure, recent
admission in intensive care unit).

 Patients with established hepatic dysfunction or with acute or chronic renal

failure.

 Patients with drug induced hyperglycemia (high dose steroids, pentamidine,

diazoxide etc).

 Gestational diabetes mellitus and other specific types of diabetes.

 Unwilling to participate in the study.

 Patients with type-1 diabetes mellitus.

29
2.2h Operational Definitions

a) Thyroid dysfunction:

Hyperthyroidism: Biochemical evidence of elevated serum FT4 level (>25.6 fmol/mL)

and low TSH level (<0.3 µIU/mL).

Hypothyroidism: Biochemical evidence of low serum FT4 level (< 8.56 fmol/mL) and
elevated TSH level (>5.0µIU/mL).

Subclinical Hyperthyroidism: Biochemical evidence of normal serum FT4 level (8.56-

25.6 fmol/mL) and low TSH level (<0.3µIU/mL).

Subclinical Hypothyroidism: Biochemical evidence of normal serum FT4 level (8.56-

25.6 fmol/mL) and high TSH level (>5.0µIU/mL).

Anti-TPO Ab: Antibody against thyroid peroxidase (anti-TPO Ab) is polyclonal and
appear as secondary response to thyroid injury. This antibody may contribute to disease
mechanisms and correlates well with thyroid damage and lymphocyte infiltration. It will
be analyzed by using the chemiluminescent microparticle immunoassay (CMIA) with the
ARCHITECT system. Normal cut off value for this antibody is <5.61 IU/mL.

b) Criteria for the diagnosis of DM: According to ADA, 2018 criteria for non-pregnant
adults, DM includes any one of the following values:
 Fasting plasma glucose ≥ 7.0 mmol/L or
 2-hour plasma glucose ≥ 11.1 mmol/L during an OGTT or

 HbA1c ≥ 6.5% or

 In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a

random plasma glucose ≥ 11.1 mmol/L.

c) Anthropometric measurements:

BMI (kg/m2): BMI of the patients were calculated using standard formula, BMI=Weight
(kg) / [Height (m)]2

30
Waist circumference: Waist circumference is the area midpoint between the lower
border of rib cage and the iliac crest. Normal value of Waist circumference according to
International Diabetes Federation (IDF) criteria: Men :< 90cm, Women :< 80cm in South
Asian population.

2.2i Equipments:

 Automated analyzer: ABBOTT Architect System Chemiluminescence

Microparticle Immuno Assay (CMIA)/ ELISA (Germany).

 RA-50 analyzer (Dade Behring, Germany)

 Centrifuge Machine (table top centrifuge, Digisystem Laboratory Instruments

Inc.) for plasma separation

 Vacutainer tube (both plain and fluorinated), syringe, pipette, calibrated bathroom
scale for weight, calibrated sphygmomanometer for BP measurement, mounted
measuring tape for height measurement, eppendorf tube for serum storage,
plastic rack for storage and transport of sample, microtiter plate reader.

2.2j Data Collection Procedure

1. Written Informed consent will be obtained from the patients.

2. Face to face interview will be conducted by using a semi-structured questionnaire

containing socio-demographic data and clinical information.

3. 5 ml of venous blood will be drawn from each eligible patients and to be sent to
the laboratory for the estimation of OGTT, serum FT4, TSH and anti-TPO Ab.

4. Prevalence and correlation will be done according to the objectives.

31
2.2k Variables

 Socio-demographic characters : Age, socioeconomic status, area of residence

 Clinical variables: Height, Weight, BMI, Waist Circumference, Pulse and Blood
Pressure.

 Biochemical variables: Serum FT4

Serum TSH
Anti-TPO antibody
FPG
2 Hr after 75g oral glucose load

2.2l Study Procedure

The study was carried out during May, 2019 to October, 2019 at the outpatient
department of Medicine and Endocrinology of Sir Salimullah Medical College Mitford
Hospital. Patients attending with newly diagnosed type-2 DM awaiting were given an
appointment after matching inclusion and exclusion criteria. Written consent was
taken from each eligible patients after properly explaining the steps and purpose of
the study. A data collection sheet containing general information on demographic
characteristics, family history of thyroid disease ,diabetes mellitus, history of
smoking, presence of any co morbidities like hypertension, ischemic heart disease,
dyslipidaemia etc. were filled up for each patient on the first day. Clinical evaluation
was also done including estimation of height (cm), weight (kg), BMI (kg/m 2) and BP
(mmHg), waist circumference (cm). Then 5 ml of venous blood was drawn from each
eligible patient. Serum was separated and transported to the Institute of Nuclear
Medicine and Allied Sciences, Sir Salimullah Medical College Mitford Hospital.
Assay of serum FT4, TSH, anti-TPO, and FPG and 2 Hr after 75g oral glucose load
from collected samples were done at nuclear medicine lab without causing any harm
to quality using ABBOTT Architect System Chemiluminescence Microparticle

32
 Immuno Assay (CMIA)/ ELISA (Germany) and RA-50 analyzer (Dade Behring,
Germany). Reports were collected and preserved in raw data sheet.

2.2m Analytic method:

 Measurement of anti-TPO Ab, anti-TG Ab, FT4 and TSH:

Blood samples were analyzed for FT4, TSH and anti-TPO Ab at Institute of Nuclear
Medicine and Allied Sciences, Sir Salimullah Medical College Mitford Hospital.

Methods for measurement of FT4 and TSH:

a) Measurement of FT4 (fmol/mL):

The ARCHITECT Free T4 (FT4) assay is a Chemiluminescent Microparticle

Immunoassay (CMIA) for the quantitative determination of free thyroxine (Free T4) in
human serum and plasma. The ARCHITECT Free T4 assay is a two-step immunoassay
to determine the presence of free thyroxine (Free T4) in human serum and plasma
using Chemiluminescent Microparticle Immunoassay (CMIA) technology with flexible
assay protocols, referred to as Chemiflex. The ARCHITECT Free T4 assay is designed
to have a slope of 1.00 ± 0.20 and a correlation coefficient (r) of ≥ 0.90 when compared
to the AxSYM Free T4 assay.

b) Measurement of TSH (µIU/mL):

The ARCHITECT TSH assay is a Chemiluminescent Microparticle Immunoassay

(CMIA) for the quantitative determination of human thyroid stimulating hormone (TSH)
in human serum and plasma. The ARCHITECT TSH assay is a two-step immunoassay
to determine the presence of thyroid stimulating hormone (TSH) in human serum and
plasma using Chemiluminescent Microparticle Immunoassay (CMIA) technology with
flexible assay protocols, referred to as Chemiflex. The ARCHITECT TSH assay is
designed to have a slope of 1.0 +/- 0.2 and a correlation coefficient (r) of ≥ 0.95 when
compared to the AxSYM Ultrasensitive hTSH II assay.

33
Analytic Methods for anti-TPO:

ARCHITECT Anti-TPO is a Chemiluminescent Microparticle Immunoassay (CMIA) for

the quantitative determination of the IgG class of thyroid peroxidase autoantibodies
(anti-TPO) in human serum and plasma on the ARCHITECT i System. The
ARCHITECT Anti-TPO assay is a two-step immunoassay for the quantitative
determination of anti-TPO in human serum and plasma using CMIA technology with
flexible assay protocols, referred to as Chemiflex. The ARCHITECT Anti-TPO assay is
designed to have an assay precision of < 10% total CV for samples > 5.61 IU/mL.

Incubation cycle: 2×30 minutes.

Volume required: 75 µL for the first ARCHITECT Anti-TPO test plus 25 µL for each
additional ARCHITECT Anti-TPO test from the same sample cup.

Storage: The ARCHITECT Anti-TPO Reagent Kit must be stored at 2-8°C in an upright
position and may be used immediately after removal from 2-8°C storage. Specimens
can be stored up to 30 days frozen at -10°C or colder.

Precaution: Pooling of reagents within a kit or between reagent kits were avoided.
Septa was used to prevent reagent evaporation and contamination and to ensure
reagent integrity. To avoid contamination, clean gloves were worn when placing a
septum on an uncapped reagent bottle.

Procedure: Assays done in an air conditioned room. During the day of assay
eppendorp tube taken from freeze and kept in normal temperature. Sample, taken by
micropipette, kept in test tube and later introduced in ARCHITECT SYSTEM.

Quality Control: The recommended control requirement for the ARCHITECT Anti-TPO
assay is a single sample of each control level be tested once every 24 hours each day
of use. If the quality control procedures in the laboratory were required more frequent
use of controls to verify test results, laboratory-specific procedures were followed. The
ARCHITECT Anti-TPO Control values were within the acceptable ranges specified in
the control package insert. If a control is out of its specified range, the associated test

34
results were considered invalid and it was retested. Recalibration was performed in that
case.

 Assay Procedure for Plasma Glucose:

Plasma glucose was analyzed by using RA-50 analyzer (Dade Behring, Germany). It is
one type of enzymatic colorimetric test (GOD-POD). Here glucose is oxidized by
glucose-oxidase to gluconate and hydrogen peroxide according to the following
equation:

Glucose+O2+H2O ═ H2O2+Gluconate

2H2O2+Phenol+4-AP═ Quininomide+4H2O 18

Reagent -1(TRIS buffer PH 7.5+phenol) and reagent-2 (glucose oxidase, peroxidase, 4-

aminophenazene) are mixed together to form a solution that is stable at 2-8◦C for 1
month. Plasma is added to it and incubated at 370C for 10 minutes to yield a
colorimetric reaction (at 550 nm wave length).

Quality assurance strategy:

Training and Piloting :

Initially 4 – 5 samples were enrolled for training and piloting. Blood samples were
collected under guidance of supervisor. Collected data were cross checked by
supervisor and co supervisor.

Mid–term meeting and evaluation:

Interim meeting with supervisor & co supervisors arranged to evaluate the progress of
the study and to do needful if necessary.

Quality of assay of laboratory:

Blood samples were collected and sent to Institute of Nuclear Medicine and Allied
Sciences, Sir Salimullah Medical College Mitford Hospital in presence of investigator for
assay of serum FT4, TSH, anti-TPO antibody, a small portion of sample was preserved

35
for future analysis & use. It may not be possible to analyze these variables in single-
assay-runs due to technical problems and financial constraints. However, a quality
control sample (QC) and a fixed standard will be used in every assay-run for each of the
variables for assessment over coefficient variance (CV) and precision of the study.

Utilization of study results:

Knowing the actual frequency of thyroid dysfunction among the patients with newly
detected type-2 DM may help clinicians to take appropriate decision in managing
patients with thyroid dysfunction and diabetes mellitus. This study results may also
influence screening, diagnostic and therapeutic strategies as well and help regulatory
authority body to formulate appropriate guideline in management of thyroid dysfunction
and diabetes mellitus.

2.2n Statistical Analysis

After collection of data, it was checked, verified for consistency and then tabulated into
the computer using the SPSS/PC software 23. Data was described in frequencies or
percentages for qualitative values and mean (±SD) for quantitative values. Subgroups
made on the basis of clinical and biochemical findings, was compared by student t-test
or chi-square test as applicable. Pearson correlation was used to see correlation
between different variables. Logistic regression was done to detect different predictors
of thyroid dysfunction. P values less than or equal to 0.05 was considered as significant.

2.2o Ethical Consideration

The informed consent of the patients was taken by describing the objectives and
purpose of the study. They were also given freedom to withdraw themselves from the
study whenever they want and were ensured that the information obtained from them
will be kept confidential. Furthermore, they were clearly informed that participation of the
study had no effect on their treatment and management process and they will not get

36
any kind of financial benefits. Researcher himself did all physical Examination. Patient
were not willing to participate the study were excluded from the study. Consecutive data
was collected within the study duration. Confidentiality of the collected Data was
maintained.

37
2.3 Observation and Results

38
This study encompassing 102 patients with newly diagnosed cases of type-2 DM
attending the outpatient department of Sir Salimullah Medical College Mitford Hospital,
intended to see the frequency of thyroid dysfunction. FT4, TSH along with anti-TPO
antibody were done in all 102 study patients.

Characteristics of the study patients are shown in table 1 where average age was
45.1±7.4 years mean ± SD, BMI was 25.0±3.8 kg/m 2 mean±SD, and mean WC was
98.4±8.6 cm mean ±SD among the study patients. Around 66% patients were male,
majority of them were from urban areas (88%) and nearly half them were businessman
(45%). 45% patients had a family history of diabetes mellitus while 6.0% had a family
history of thyroid disorder. Their blood pressure were within normal limits (mean SBP
=135.5±10.2 mmHg and mean DBP=70.2±7.3 mmHg mean ± SD). 37% patients were
smoker and 30% patients presented with multiple co-morbidities like hypertension,
dyslipidaemia, ischemic heart disease, stroke etc.

39
Table 1: Characteristics of the study population (n=102)

Characteristics Frequency n (%) Mean±SD

Age (year) 45.1±7.4
BMI (kg/m2) 25.0±3.8
SBP (mmHg) 135.5±10.2
DBP (mmHg) 70.2±7.3
WC (cm) 98.4±8.6
Gender
Male 67 (65.69)
Female 35 (34.31)
Area of residence
Urban 90 (88.24)
Rural 12 (11.76)
Occupation
Service 30 (29.4)
Business 46 (45.1)
Housewife 24 (23.5)
Others 2 (2.0)
Smoking status
Smoker 38 (37.2)
Non-smoker 64 (62.8)
F/H of Diabetes Mellitus
Yes 46 (45.1)
No 56 (54.9)

40
F/H of Thyroid Disorder
Yes 6 (5.9)
No 96 (94.1)
Co morbidities
Yes 31 (30.4)
No 71 (69.6)

BMI=Body mass index, WC=Waist circumference, SBP=Systolic blood pressure,

DBP=Diastolic blood pressure, Co morbidities=Hypertension, Dyslipidaemia, Ischemic
Heart Disease, Stroke.

41
Status of the thyroid function among patients with diabetes mellitus and relation
with family history of thyroid disorder

Table 2 describes the thyroid functional status among the study patients showing 14
(13.7%) patients had thyroid dysfunction and table 3 shows the frequency of different
subgroups of thyroid dysfunction among the study patients. Most of them had
subclinical hypothyroidism 8 (7.8%) followed by overt hypothyroidism 4 (3.9%),
subclinical hyperthyroidism 1 (1.0%) and hyperthyroidism 1 (1%).

Table 4 displays comparison of family history of thyroid dysfunction with thyroid

functional status among study population showing only 1 (7.1%) of the patient with
thyroid dysfunction had family history of thyroid disorder whereas a large number of
patients 13 (92.9%) with thyroid dysfunction did not have family history of thyroid
disorder though it was not statistically significant.

42
Table 2: Thyroid functional status among study population (n=102)

Thyroid functional Number (n) Percentage (%)

status

Euthyroid 88 86.3

Thyroid dysfunction 14 13.7

Total 102 100

43
 Table 3: Subgroups of thyroid dysfunction among study population (n=102)

Categories of dysfunction Number of patients Frequency (%) (95% CI)

Hypothyroidism 4 3.9 (0.9-6.1)

Subclinical hypothyroidism 8 7.8 (6.5-8.9)

Hyperthyroidism 1 1.0 (0.2-2.4)

Subclinical thyrotoxicosis 1 1.0 (0.3-2.3)

Total 14 13.7 (8.1-16.8)

95% CI=95% Confidence Interval

44
 Table 4: Comparison of family history of thyroid dysfunction with thyroid
functional status among study population (n=102)

F/H of thyroid Thyroid dysfunction P value

dysfunction

Yes No
n (%) n (%)

Yes 1 (7.1) 5 (5.7)

0.829
No 13 (92.9) 83 (94.3)

Total n (%) 14 (100) 88 (100)

Within parenthesis are percentages over column total. Analysis done by Chi Square test

45
Anti-thyroid antibody; Relation with Thyroid Function and Level of TSH

Table 5 narrates the frequency of anti-thyroid antibody among the functional groups of
thyroid showing 13(12.7%) patients were anti-thyroid antibody (Anti-TPO) positive.
Among different subgroups of thyroid functional status most of the overt hypothyroidism
(75%) and subclinical hypothyroidism (75%) were positive for anti-thyroid antibody
though the number of subject were smaller. On the contrary euthyroid and hyperthyroid
patients were antibody negative (Cent percent).

Table 6 displays the comparison of Anti-TPO with different thyroid functional status
among study population, showing the comparison is statistically significant.

Considering the status of anti-thyroid antibody in light of different level of TSH, highest
frequency for positive anti-thyroid antibody (80%, 4/5) was observed in group having
TSH ≥10 µIU/mL followed by 71.4% (5/7) in the group having TSH (5-10) µ IU/mL, while
only 4.4% (4/90) in the group having TSH <5 µIU/mL (p<0.001) (table 7).

46
Table 5: Frequency of Anti-TPO Antibody among Study Population (n=102)

Thyroid Anti-TPO Antibody Total

functional status
Positive Negative
n (%) n (%)

Euthyroid 4 (4.5) 84 (95.5) 88

Hypothyroidism 3 (75.0) 1(25.0) 4

Subclinical
6 (75.0) 2 (25.0) 8
hypothyroidism

Hyperthyroidism 0 1 (100) 1

Subclinical
0 1 (100) 1
Hyperthyroidism

Total n (%) 13 (12.7) 89 (87.3) 102 (100)

Within parenthesis are percentages over row total.

47
Table 6: Comparison of Anti-TPO Antibody Status with Thyroid Function among
Study Population (n=102)

Thyroid Positive Negative P value

functional
n (%) n (%)
status

Euthyroid 4 (4.5) 84 (95.5)

Hypothyroidism 3 (75) 1 (25)
Subclinical <0.001
6 (75) 2 (25)
hypothyroidism
Hyperthyroidism 0 1 (100)
Subclinical
0 1 (100)
Hyperthyroidism

Within parenthesis are percentages over row total. Analysis done by Chi Square test.

48
Table 7: Comparison between anti-TPO Antibody status with different levels of
TSH among study population (n=102)

TSH Anti-TPO Antibody Total P value

(µIU/mL) n (%)
Positive Negative
n (%) n (%)

<5 4 (4.4) 86 (95.6) 90 (100)

(5-10) 5 (71.4) 2 (28.6) 7 (100) <0.001

>10 4 (80.0) 1 (20.0) 5 (100)

Within parenthesis are percentages over row total. Analysis done by Chi Square test;
Anti-TPO Ab = Anti-thyroid peroxidase antibody, TSH= Thyroid stimulating hormone

49
Clinical characteristics; Relation with thyroid function, Biochemical parameters

Comparison of clinical parameters of the study population among different thyroid

functional status in table 8 shows that there was significant difference of mean BMI
among various subgroups of thyroid functional status (p=0.034). Tukey’s post hoc
analysis showed mean BMI of patient with subclinical and overt hypothyroidism was
significantly higher than that of euthyroid patients (28.9±4.3 vs 26.5±3.0, p= 0.039 and
28.2±5.6 vs 26.5±3.0, p= 0.042 respectively).

As shown in table 9, comparison of glycemic parameters of the study population among

different thyroid functional status shows that there was no significant difference of
glycemic parameters among different thyroid functional status.

50
Table 8: Comparison of Clinical Characteristics of the Study Population among
Different Thyroid Functional Status (n=102)

Variabl Euthyroid Hypothyroidi Subclinical *Thyrotoixco P

es sm hypothyroidi sis value
sm

mean±SD

BMI
26.5±3.0 28.2±5.6 28.9±4.3 22.1±3.2 0.034
(Kg/m2)

WC
98.2±8.5 99.4±6.3 102.8±6.8 90.0±1.5 0.227
(cm)

SBP
134.2±6.9 136.6±7.5 137.2±7.2 128.5±7.6 0.365
(mmH)

DBP
74.8±7.2 73.2±9.4 72.0±8.1 67.2±6.3 0.374
(mmH)

By one way ANOVA. *Thyrotoxicosis=Hyperthyroidism and Subclinical thyrotoxicosis

only for this table. BMI=Body mass index, WC=Waist circumference, SBP=Systolic
blood pressure, DBP=Diastolic blood pressure
Tukey’s post hoc analysis shows mean BMI of patient with subclinical and overt
hypothyroidism was significantly higher than that of euthyroid patients (28.9±4.3 vs
26.5±3.0, p=0.039 and 28.2±5.6 vs 26.5±3.0, p= 0.042 respectively).

51
Table 9 : Comparison of glycemic parameters of the study population among
different thyroid functional status (n=102)

Variable Euthyroid Hypothyroidis Subclinical *Thyrotoixco P

s m hypothyroidis sis value
m

mean±SD

FPG
9.1±1.5 8.5±1.8 9.5±1.7 8.9±1.8 0.754
(mmol/)
2Hr PPG
15.2±3.5 16.1±3.2 16.5±2.9 16.9±3.8 0.652
(mmol/)

By one way ANOVA *Thyrotoxicosis=Hyperthyroidism and Subclinical thyrotoxicosis

only for this table. FPG = Fasting plasma glucose, 2HrPPG = Plasma glucose 2 hour
after 75gram glucose load.

52
Correlation and regression

Table 10, highlighting correlation among glucose profile with thyroid function and anti-
thyroid antibody (Anti-TPO) status among study patients, shows that there was no
significant correlations among glucose profile with thyroid function and anti-thyroid
antibody status (p=Not Significant for all).

Table 11 highlights Logistic regression analysis for predictive values over thyroid
dysfunction in diabetes revealed that Anti-TPO antibody is independently related to
thyroid dysfunction in patients with diabetes mellitus (p<0.001).

53
Table 10: Correlation among glucose profile with thyroid function and antithyroid
antibody status (n=102)

Variables r p

FPG vs FT4 0.014 0.754

FPG vs TSH 0.059 0.521

FPG vs TPO-Ab 0.011 0.356

2Hr75gPPG vs FT4 0.031 0.810

2Hr75gPPG vs TSH 0.065 0.650

2Hr75gPPG vs TPO-Ab 0.023 0.456

Analysis done by Pearson’s correlation coefficient test. FPG= Fasting Plasma Glucose,
2hr 75g PPG=Plasma glucose 2 hours after 75gm glucose load, FT4 = Free T4, TSH =
Thyroid stimulating hormone, TPO-Ab= Anti-thyroid peroxidase antibody.

54
Table 11: Logistic regression analysis showing predictors of thyroid dysfunction
(n=102)

Variables OR S.E P value

Age 0.785 0.048 0.654

F/H of thyroid
0.495 1.025 0.450
disorder

BMI 1.059 0.074 0.537

Anti-TPO Ab 0.021 0.654 <0.001

Anti-TPO Ab= Anti-thyroid peroxidase antibody, BMI=Body mass index, WC=Waist

circumference. OR= Odds ratio, S.E= Standard error

55
2.4 DISCUSSION

56
This study investigated thyroid dysfunction in patients with newly detected diabetes
mellitus in the OPD of a tertiary level hospital. It was observed that about 13.7% of the
newly diagnosed patients with diabetes mellitus have thyroid dysfunction with a higher
frequency for subclinical hypothyroidism followed by overt hypothyroidism, and an equal
proportion of subclinical hyperthyroidism and hyperthyroidism. Anti-thyroid (Anti-TPO)
antibody was also found to be positive in 12.7% patients with highest frequency in
subclinical hypothyroidism and overt hypothyroidism subgroups. However, 4.5% of
euthyroid patients were also positive for anti-TPO antibody. Frequency of positive anti-
TPO antibody was found to be more with the TSH level between 5-10 mIU/L. However,
there was no particular correlations of glucose level with thyroid hormones and anti-
TPO antibody is an independent predictor for thyroid dysfunction. Similar findings were
observed by other investigators like Papazafiropoulou et al. in 2010 11, Norbe et al. in
200893 and Aljabri in 201994, in different populations. As there is an uprising global trend
of occurring diabetes and observing autoimmunity among diabetic population by many
investigators, it may be imperative in future to include testing for thyroid function test
and autoimmunity while diagnosing diabetes.

In the present study, 14 (13.7%) patients had thyroid dysfunction and 88 (86.3%) were
found to be euthyroid. Similar findings were observed by the investigators in Greek 11,
Portuguese93, Saudi Arabian94, Brazillian14 and Indian16, 95 population although the study
population were different in terms of geographic and ethnic origins. It was found that
subclinical hypothyroidism was the commonest dysfunction occurring in 7.8%, followed
by overt hypothyroidism in 3.9%, subclinical hyperthyroidism in 1.0% and
hyperthyroidism in 1.0% study population. These results are in concordance with the
results from studies conducted in Norway (HUNT Study) by Fleiner et el.96, a systematic
review and meta- analysis in China by Han et el.97, in Portugal by Nobre et el.93 and in
India by Khurana et el.16, Sreelatha et el.95. This relationship cannot be explained as
causal to diabetes but needs to keep in consideration while diagnosing any newly
detected diabetic patients in terms of giving the importance of testing for thyroid
dysfunction.

57
In an attempt to find out the status of anti-thyroid antibody in relation with thyroid
functional status, 13 (12.7%) patients were anti-TPO antibody positive and among the
different subgroups most of the overt hypothyroidism (3 out of 4, 75%) and subclinical
hypothyroidism (6 out of 8,75%) were positive for anti-TPO antibody. On the other hand,
most of the euthyroid (95.5%) and all hyperthyroid (100%) patients were antibody
negative. Presence of significantly this higher frequency of anti-TPO antibodies in
patients with type-2 diabetes mellitus indicates important role of autoimmunity in the
development of thyroid dysfunction among type 2 diabetes mellitus patients.
Alternatively, the two diseases are prevailing simultaneously in the same population and
apparently there seems to be an association though practically it may be co-occurrence
in the same person. Thus unless followed for a substantial period of time and
investigated for causal relation between the two diseases, it cannot be clearly
concluded regarding co-occurance of the conditions. Nevertheless, it does not
necessarily mean the presence of one disease in the event of another but warrants for
need of searching the presence of one if the other is detected.

In Ghana, a case-control study98 involving 302 type 2 diabetes patients and 310 non-
diabetic controls aged 40–80 years revealed the prevalence of thyroid autoimmunity
was significantly higher among Type 2 diabetic patients (12.2% vs. 3.9%, p = 0.0004)
which has similar prevalence like the current study. Another study in India led by S
Mukherjee12 (2015), it was revealed that 22 patients with diabetes mellitus out of 79 with
thyroid dysfunction were positive for anti-TPO antibodies (27.84% of total thyroid
abnormality) which were much higher than the frequency detected in the present study.
On the other hand, as observed by them, 7 patients without any thyroid dysfunction
showed anti-TPO antibody positivity (17.07%) which were 4.5% found by this study.
Therefore, presence of thyroid dysfunction and positivity of anti-thyroid antibody is
neither obligatory association nor mutually exclusive events. With diabetes that could
better be accomplished by thinking for need of testing for hormonal abnormality and
anti-thyroid antibody status in patients with newly detected diabetes mellitus. Owing to
little number of investigations on thyroid autoimmunity in diabetic patients it is not
prudent to ascertain the relative status of present findings in context to previously
prevailing thyroid functional status in diabetic population. There are few studies on

58
thyroid autoimmunity in our country; but most of them were in general population.
Therefore, assessing status of thyroid dysfunction in diabetic population will need
investigation in mass scale involving larger sample size.

In one study accomplished by Khurana et al. (2015), out of 32 diabetic patients who had
thyroid disorders, 25 (78.12%) had no family history of thyroid disorders and 7 (21.87%)
had family history of thyroid disorder16. Present study also found the prevalence of
thyroid disorder in patients who had no family history of thyroid disorder. These findings
will have huge impact in considering family history of thyroid disorder and diabetes in
terms of new detection of thyroid dysfunction in any diabetic patient. This disparity may
be attributable to relatively small number of the sample size in their study. Unless
observed in larger study sample, no definite conclusion can be obtained in this regard.

Comparing the clinical parameters of the study population among different thyroid
functional status, there was significant difference of mean BMI among various
subgroups of thyroid functional status. This findings were similar to a study done by
Khurana et al. (2015), where out of 32 diabetic patients who had thyroid disorders, 7
(21.87%) had BMI < 25, 6 (18.75%) had BMI between 25 - 30 and 19 (59.37%) had BMI
> 3016. Though apparently it seems that BMI is related to thyroid dysfunction, it can also
be explained by the fact that hypothyroid patients gain weight and conversely
hyperthyroid patients lose weight that ultimately caused significant difference of BMI
among various thyroid functional status.

It is necessary to mention here that, some recent past studies revealed that frequency
of thyroid autoimmunity is relatively more than assumed. This is assumed to be part of
consequence coined by the implementation of universal salt iodinization. The observed
autoimmunity in newly detected diabetic patients is niether part of that phenomenon nor
could be claimed clearly until this diabetic patients would also be investigated for the
iodine related functional hazards of thyroid. The long term impact of this observation
and their consequences need further studies.

In conclusion, present study observed that about 13.7% of newly diagnosed patient with
type-2 DM have thyroid dysfunction with a higher frequency for subclinical
hypothyroidism. However background hazards, if any in the environment related to

59
iodine status or to universal iodinization of salt needs be considered before any clear
inference.

2.5 Conclusion

Thyroid dysfunction and diabetes are closely associated with each other through multi-
directional pathways. The co-occurrence of these common endocrine conditions
impacts clinical presentation and laboratory results, while influencing screening,
diagnostic and therapeutic strategies. A high index of suspicion should be kept for
thyroid dysfunction in diabetes, especially difficult- to treat diabetes, and for diabetes in
thyroid dysfunction, especially difficult-to-manage cases. The results of the present
study suggest that thyroid dysfunction is likely to be more common in newly diagnosed
patients with type-2 DM. This is in accordance with other studies. Furthermore, thyroid
autoimmunity is one of the predictors for increased risk of thyroid dysfunction in this
population group. No correlation appeared to be found between glycemic profile and
thyroid functional status. In addition, patient with subclinical hypothyroidism had higher
BMI than those with normal thyroid function. The treatment of hypothyroidism in diabetic
population helps in better control of other associated conditions. Based on these results,
any patient presenting to an outpatient department with type 2 diabetes mellitus, it is
worthwhile to perform a thyroid function test to evaluate the thyroid status. This study
necessitates a routine screening for thyroid function in all patients with type 2 diabetes
mellitus to detect, treat and prevent diverse range of complications of both these
conditions.

60
2.6 Limitation

The study was done on 102 cases only due to time and resource constraint. Study with
larger sample size is needed.

It was done in only one centre in Dhaka, which may not reflect the wholesome picture of
our country.

Duration of the study was restricted to 6 months; a one year data could provide better
impressions.

2.7 Recommendation

A larger study involving greater sample size can be undertaken.

61
 Chapter 3

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75
3.2 Appendices

I
 Appendix 1
Data Collection Form

Questionnaire

Prevalence of Thyroid Dysfunction in Adults with Newly Detected Type 2 Diabetes

Mellitus Attending Sir Salimullah Medical College Mitford Hospital.

Name of the researcher: Dr. Md.Mahabub Hossain Khan

1. Patient ID:

A. General and demographic information: Date: …………………

Name of patient: _____________________ Mobile No: ___________________

Address: (Rural=1, Urban=2)

2Age: (Completed years)

3. Sex: (Male=1, Female=2)

4. Occupation: (Unemployed=1, Day labor=2, Service=3, Business=4,

Housewife=5, Retired=6, Others =7, Specify: ................)

5. Monthly family income (In thousands):

B. Personal / Family information:

6. Smoking status (Non smoker=1, Previous smoker=2, Current smoker=3)

7. Non smoke tobacco consumption (Never consumed=1, Previous consumed=2,

Current consumer=3)

8. Family history of (Hyperthyroidism=1, Hypothyroidism=2, Autoimmune Thyroid

Disease=3, Goitre=4, None=5)

9. Family history of Diabetes Mellitus (Yes=1, No=2)

10. Co morbidities: (HTN=1, Dyslipidaemia=2, IHD=3, Stroke=4, Vitiligo=6, RA=7,

SLE=8, None=9)

II
C. Anthropometric measurements:

11. Weight of the participant (Kg)

12. Height of the participant (cm)

13. BMI [Kg /m2]

14. Waist circumference (cm)

D. Clinical Examination:

15. Systolic Blood Pressure (SBP) mmHg

16. Diastolic Blood Pressure (DBP) mmHg

17. Pulse (Tachycardia=1, Bradycardia=2, normal=3)

18. Current Thyroid related Diagnosis: (Euthyroid=1 Hypothyroidism=2, Subclinical

Hypothyroidism=3, Thyrotoxicosis=4, Subclinical Thyrotoxicosis=5)

E. Check list of Laboratory reports:

19. Fasting Blood glucose (mmol/l):

20. 2h after 75 gm oral glucose (mmol/l):

21. Serum FT4 (pmol/ml)

22. Serum TSH (µIU/ml)

23. Anti-TPO Antibody (IU/mL)

Interviewer’s Name: ……………………………… Signature: ……………..

Date: …………………..

III
 Appendix 2

Consent form

I am Mr. / Mrs…………………………………………………………hereby giving

well informed consent willingly to participate in this study conducted by
Dr.Md Mahabub Hossain Khan. The aim & objectives of this study titled:
Study of Thyroid Dysfunction In Adults With Newly Detected Type 2 Diabetes
Mellitus Attending Sir Salimullah Medical College Mitford H o s p i t a l , a l o n g
with its procedure, risk & benefits were explained to me in easily
understandable local language & then informed written consent was
taken. I agree to participate in this study voluntarily without any prejudice. I
am fully convinced that during this study I will not suffer from any physical or
psychological problem. I am also informed that this study was carried out in
the developed countries safely. My participation will bring f ruitful result
that will be beneficial for most people in our country. I shall not receive any
financial benefit. I have understood that my personal information, medical
records & investigation records will be kept strictly confidential & will be
used for research purpose only.

Participants / Guardians signature or Left thumb print:

Participant's Name:
Researcher's Name:
Date:

IV
 অবগতিক্রমে সম্মতিপত্র
এই সম্মতিপমত্রর উমেশ্য আপনামে প্রময়াজনীয় িথ্য প্রদান েরা যা আপনামে তসদ্ধান্ত তনমি সাহাযয েরমব আপতন
এই গমবষণা েমেে অংশ্গ্রহণ েরমবন তেনা?

গমবষণাোরীর নােঃ ডাঃ মোঃ োহবুব মহামসন খান।

প্রতিষ্ঠানঃ সযার সতিেুল্লাহ মেতডমেি েমিজ তেটম াডে হাসপািাি।

গমবষণার উমেশ্য ও ববতশ্ষ্ট্যঃ

ডায়ামবতটস এবং থ্াইরময়ড জতনি মরাগ উভয়ই হরমোনজতনি সেসযা,যা সাধারণি এেই সামথ্ মদখা যায় এবং
তিেেি তিতেৎসা না েরমি োরাত্মে জতটিিার সৃ তষ্ট্ েরমি পামর।ইদাতনংোমি তেছু গমবষণায় মদখা মগমছ
ময,ডায়ামবতটস জতনি সেসযায় থ্াইরময়ড মরামগর প্রাদু ভাে ব অমনে মবশ্ী।তেন্তু আোমদর মদমশ্ এই সম্পতেেি িমথ্যর
যমথ্ষ্ঠ ঘাটতি আমছ।িাই এই গমবষণার োধযমে আোমদর মদমশ্র মরাগীমদর ডায়ামবতটস জতনি সেসযায় থ্াইরময়ড
মরামগর প্রাদু ভোব মেেন িা মদখমি িাই।

গমবষণায় অংশ্গ্রহণ েরার সু ি ও ঝুতেঃ

এই গমবষণায় অংশ্গ্রহণ েরমি বা না েরমি বযতিগিভামব মোন সু তবধা পাওয়া সম্ভব নয়,তেন্তু এই গমবষণা হমি
প্রাপ্ত িথ্য হমি তিতেৎসেমদর সতিেভামব মরাগ তনণেয় ও তিতেৎসা প্রদামন সহায়িা েরমি পামর।

বযতিগি মগাপনীয়িাঃ

আপনার োছ মথ্মে সংগৃহীি িথ্যসেূ হ ও আপনার পতরিয় সম্পু নেভামব মগাপন রাখা যামব।আপনার নামের তবপরীমি
মেবিোত্র এেতট সংখযা প্রোশ্ েরা হমব।

V
গমবষণা মথ্মে প্রিযাহামরর স্বাধীনিাঃ

ময মোন সেয় গমবষণা মথ্মে তনমজমে প্রিযাহার েরার পূ ণে স্বাধীনিা আপনার োমছ আমছ-যা আপনার পরবিেী
তিতেৎসায় মোন প্রভাব ম িমব না।

এই গমবষণায় আপনার অংশ্গ্রহমণর সেয়োমি আপনার তিতেৎসা মসবার জনয আতে দাতয়ত্বপ্রাপ্ত থ্ােব।

আপতন এই গমবষণায় অংশ্গ্রহমণর প্রস্তামব রাতজ থ্ােমি ,আপতন নীমি স্বাক্ষর/বৃ দ্ধাঙ্গুতির ছাপ প্রদান েমর সম্মতি
জ্ঞাপন েরমবন।

--------------------------------------- --------------------------------------
---

অংশ্গ্রহণোরীর স্বাক্ষর/বাে বৃ দ্ধাঙ্গুতির ছাপ গমবষণাোরীর স্বাক্ষর

নােঃ --------------------------------------- িাতরখঃ----------------------

VI
Appendix 3

VII
Appendix 4

VIII
Appendix 5

IX