THYROTOXICOSIS: A RETROSPECTIVE STUDY OF CASES SEEN

AT NUCLEAR MEDICINE UNIT (NEMROCK)

Thesis

Submitted for the fulfillment of master degree

In nuclear medicine

By

Amira Hodhod Elsayed

M.B.B.CH

Under Supervision of

Professor Dr. Shawky Ibrahim El.Haddad

Professor of Radiotherapy and Nuclear Medicine

Faculty of medicine –Cairo University

Dr. Gehan Ahmed Yuonis

Lecturer of Nuclear Medicine

Faculty of medicine –Cairo University

Faculty of medicine

Cairo University

2013

Acknowledgments

First, I would like to thank all my professors who allowed me to quote

their work.

I particularly grateful to professor Dr/ Shawky El.hadad for his

encouragement and generosity in dealing with science and Dr/ Gehan

Younis, this study would be much poorer without her help.

I am grateful to everyone in Nuclear Medicine department, Cairo

University.

A special thanks to Dr/ Ahmed Sabrey who helped me in the statistical

part of the study.

I am deeply indebted to my dear husband Dr/ Hisham Aboelnasr, who

was encouraging and supportive throughout.

This list would not be completed without mentioning the role of my

great mother in supporting me.

And last but not least, to my family and my friends for patiently

persevering with me.

Index

List of figures……………………………………………….…….…………………I

List of tables………………………………………………………………………….III

List of abbreviations………………………………………..………………..….V

Introduction and aim of the study………………………..…………….…1

Review of literature……………………………………….………..……………5

Material, methods and data collection…………………………….….49

Results………………………………………………………………………………..52

Discussion……………………………………………………………………….….69

Conclusion…………………………………………………………………..……..78

References……………………………………………….…………..……..…….81

Arabic summary…………………………………………..………..…………….1

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I

List of Figures

Figure (1) iodine -123 thyroid scan in patient with Graves'

disease …………………............................................................…….19

Figure (2) iodine-123 scan in patient with a toxic multinodular

goiter ……………………………………………………………………..….…………20

Figure (3) iodine-123 scan in a patient with a toxic

adenoma.……..………………………………………………………………….…..20

Figure (4) Tc 99m

thyroid scan of toxic adenoma …….……………..22

Figure (5) Tc 99m

thyroid scan of Graves' disease …….…………….22

Figure (6) Tc 99m

thyroid scan of toxic multi nodular goiter ……23

Figure (7) color flow ultrasonogram in a patient with Graves'

disease ………………………………………………………………..…………….…25

Figure (8) Comparison between age group and percentage of

cases of each type of thyrotoxicosis………………….…………………..54

Figure (9) Figure showing sex and percentage of cases of each

type of thyrotoxicosis …………………………………………..………………55

Figure (10) Treatment frequency according to the type of

thyrotoxicosis and percentage of cases received medical

treatment ….…………………………………………….…………….……….…..56

Figure (11) Thyrotoxicosis and percentage of cases with

previous surgery …………………………………………………….……………57

II

Figure (12) Relationship between response of primary type and

dose value of radio-active iodine……………………..……………………63

Figure (13) Secondary type response and dose value of radio-

active iodine……………………………………………………..…………………..65

Figure (14) Percent of cases received one or more dose of

radio-active iodine …………………………………………………..…………...66

Figure (15) Relationship between onset of hypothyroidism and

dose value of radio-active iodine.………………………………..………..68

III

List of tables

Table (1) lists clinical manifestation of hyperthyroidism ….....14

Equation (1) calculation of I131 dose based on goiter size and

radioactive iodine uptake …………………………………………………....32

Table (2) Relationship between the different age group in each

type of thyrotoxicosis…………………………………………………………53

Table (3) Relationship between sex and percentage of cases of

each type of thyrotoxicosis…………………………………………………55

Table (4) Frequency table of those received medical treatment

in the two groups of patients.………………………………………………56

Table (5) Cases with previous surgery ……………………………………57

Table (6) The predominant symptoms in each type of

thyrotoxicos…………………………………………………………………………..58

Table (7) Relation between TSH levels and type of

thyrotoxicosis……………………………………………………………………….59

Table (8) Relation between T3 levels and type of

thyrotoxicosis…………………………………………………………………….…60

Table (9) Relation between T4 levels and type of

thyrotoxicosis……………………………………………………………………….60

Table (10) The relation between the percent of thyroid gland

uptake and the response to radio-active iodine treatment….61

IV

Table (11) Relationship between response of primary type to

different dose values of radio-active iodine during 2 years of

follow up. ………………………………………………………………………….….62

Table (12) Response of secondary type thyrotoxicosis and

different dose values of radio-active iodine……………………….64

Table (13) Percentage of cases received one or more than one

dose of radio-active iodine…………………………………………………65

Table (14) Relationship between the dose value of radio-active

iodine and the onset of hypothyroidism……………………………..67

V

List of abbreviations

B

Bpm: beat per minute.

C

CI: THE CURIE (symbol CI) is a non-SI unit of radioactivity, named after

Marie and Pierre Curie. One curie is roughly the activity of 1 gram of

Radium isotope Ra226 a substance studied by Curies. 1 Ci =3.7x 1010

Bq=37 GBq.

E

EUGOGO: European Group on Graves' orbitopathy

F

FSH: follicle- stimulating hormone.

FT3: free triiodothyronine

FT4: free thyroxine

G

GnRH: Gonadotropin- Releasing Hormone

Graves' disease: primary diffuse toxic goiter

GY : gray is the unit of the International System of Units(SI) of absorbed

radiation dose , defined as transfer of 1 joul of energy per kilogram of

absorbing material (1 J/Kg); 1 gray equal 100 rads.

VI

H

HCG: Human Chorionic Gonadotropin.

I

I123

: Radioactive Iodine isotope 123.

I 131

: Radioactive Iodine isotope 131.

L

LH: luteinizing hormone.

N

NEMROCK: Kasr- El.Aini- Center of Radiotherapy and Nuclear Medicine.

M

MBq: The Becquerel is the International System of Units(SI) derived

unit of radioactivity . One Bq is defined as the activity of a quantity of

radioactive material in which one nucleus decays per second.

mg: milligram

mIU/L: milli International Unit per Liter

mm: micro meter

R

Rad: The rad is deprecated unit of absorberd radiation dose, defined as

1 rad = 0.01 Gy = 0.01 J/kg.

RAIU%: Radioactive Iodine Uptake percent.

VII

Rem: Is deprecated unit used to measure the biological effect of

ionizing radiaton . The rem is defined as equal to 0.01 sievert.

rhTSH: Recombinant Human thyroid -Stimulating Hormone.

S

SV: The Sievert (symbol: SV) is the International System of Units (SI)

derived unit of equivalent radiation dose, effective dose, committed

dose.

T

TAO: Thyroid-associated orbitopathy.

T3: Triiodothyroxine.

T4: Thyroxine.

Tc 99m

: Technetium Pertechnetate.

TMNG: Toxic multinodular goiter.

TRAb: Thyroid – Stimulating Hormone receptor antibodies.

TSAb: Thyroid Stimulating Antibodies.

TSbAB: Thyroid Stimulating blocking Antibodies.

TSH: Thyroid Stimulating Hormone.

TSI: Thyroid Stimulating Immunoglobulin.

U

uci=1x10-6

ci

VIII

U.K: United Kingdom.

U.S: United States.

1

Introduction & aim of the study

Thyrotoxicosis is the hypermetabolic condition associated

with elevated levels of thyroxin (FT4) and free triiodothyronine

(FT3). (Lee and Ananthakrishnan,2009).

Graves’ disease: Graves’ disease is the most common cause of

hyperthyroidism. It accounts for 60% to 80% of the total reported cases

of hyperthyroidism in the U.S. (Weetman, 2000).

Patients younger than 40 years are the highest risk for the

development of Graves’ disease. (Davies and Larsen, 2003).

Women have a higher reported incidence of Graves’ disease than

men, with a female to male incidence ratio of approximately 7:1 to

10:1. (Nayak and Hodak, 2007).

Graves’ disease is an autoimmune disorder where antibodies

mistakenly attack the thyroid gland, particularly the TSH receptor sites.

The attack stimulates the gland to synthesize and overproduce thyroid

hormone. (Werner, et al, 2000).

Toxic Multinodular Goiter and Toxic Adenomas: Toxic multinodular

goiter (TMNG), also known as Plummer’s disease, is a condition in

which the thyroid gland contains multiple nodules or lumps that are

hyper functional, causing an overproduction of thyroid hormones.

(Werner, et al, 2000).

TMNG usually occurs in patients who are more than 40 years old and

accounts for 5% of the total cases of hyperthyroidism in the U.S. The

incidence of TMNG is increased in iodine-deficient regions. (Werner, et

al, 2000).

2

Toxic adenomas are independently functioning thyroid nodules that

produce excessive amounts of thyroid hormones. Toxic adenomas are

most commonly found in younger patients who live in iodine-deficient

regions. (Slatosky, et al, 2000).

Thyroiditis: Thyroiditis is a condition where the thyroid gland becomes

inflammed. Inflammation of thyroid causes excess thyroid hormone

stored in the gland to leak into the systemic circulation. (Slatosky, et al,

2000).

Other causes of thyrotoxicosis:-

Iodide -induced hyperthyroidism is classified in two different types.

Type 1 Iodide -induced hyperthyroidism manifested with a low level of

TSH and high levels of T3 and T4. It is caused by uncontrolled excessive

production of T3 and T4 by the solitarily functioning thyroid in response

to iodine (Jod-Basedow phenomenon). (Baskin, et al, 2002).

Type 2 Iodide -induced hyperthyroidism is the destructive

inflammation of the thyroid (thyroiditis). (Baskin, et al, 2002).

Some of the tumors that can lead to a thyrotoxic state is struma

ovarii, Human Chorionic Gonadotropin (HCG)-producing and TSH

receptor-activating trophoblastic tumors, and TSH-secreting

adenomas. (Tierny, et al, 2005).

Laboratory investigations:

Serum Hormonal Level is diagnostic findings show that 95% of

patients with hyperthyroidism have a combination of suppressed serum

TSH levels of <0.05 mIU/L and an elevated serum free T4 level. (Dabon-

Almirante, et al, 1998 and Ladenson, 2005).

The levels of T3 and T4 should subsequently be assessed. (Braverman,

et al, 2005).

3

Imaging Tests:

In addition to clinical evaluation and blood tests, imaging techniques

are used to confirm diagnosis of hyperthyroidism.

The thyroid radioactive iodine uptake test with scanning is a key

diagnostic tool in the evaluation of hyperthyroidism.The average 6-hour

radioiodine uptake reference range is 5% to 15%, whereas the normal

24-hour uptake ranges from 5% to 25 %. (Intenzo and dePapp, 2003

and Meier and Kaplan, 2001).

Thyroid scintigraphy usually performed with technetium-99m

pertechnetate or radioiodine. (Meller and Becker, 2002; Summaria, et

al, 1999 and Smith and Oates, 2004).

Advantages of technetium-99m pertechnetate Lower radiation dose, better image quality, less waiting time after

administration, wider availability, lower cost and images can be

obtained while the patient is taking anti-thyroid medications. (Meller

and Becker, 2002; Summaria, et al, 1999 and Smith and Oates, 2004).

Treatment of thyrotoxicosis includes:

Symptoms relief by Beta-blocker therapy, Anti-thyroid drugs

(e.g.Propylthiouracil,Methimazole) leading to gradual reduction of

thyroid hormone level over 2-8 weeks or longer. (Cooper, 2005)

Radioactive Iodine: The desired outcomes are not seen immediately in

radioactive iodine therapy, endocrinologists often require patients to

continue anti-thyroid drug treatment until positive results are

established. Often patients start to manifest signs and symptoms of

euthyroidism within 2 to 3 months of ablative radioactive iodine

therapy. If complete ablation is not achieved 6 months after the

4

radioactive iodine therapy, repeated treatment is recommended

(Burman, 2006).

Surgical Intervention: Thyroidectomy is reserved for special

circumstances such as intolerance to anti-thyroid drugs or patient

refusal to undergo radioactive iodine therapy. Other candidates for

thyroidectomy are pregnant women with hyperactive thyroid who

cannot tolerate anti-thyroid drugs. (Wilson, et al, 1998).

Aim of the study:-

Review of cases of thyrotoxicosis: presentation, types (Graves’

disease, toxic nodular goiter, subacute thyroiditis and toxic adenoma),

laboratory findings, imaging picture, treatment, follow up and the

differences in between.

5

Hyperthyroidism

Introduction

Thyrotoxicosis is the hyper metabolic condition associated with

elevated levels of free thyroxine (FT4) and/or free triiodo -thyronine

(FT3) caused by excess synthesis and secretion of thyroid hormone by

the thyroid not associated with exogenous thyroid hormone intake .

(Lee and Ananthakrishnan, 2009)

The most common cause of thyrotoxicosis is Graves’ disease. Other

common causes are toxic multinodular goiter (TMNG), solitary toxic

adenoma, and thyroiditis. (Larsen, et al , 2002).

Rare causes of thyrotoxicosis include thyroid-stimulating hormone

(TSH)–secreting pituitary adenoma, struma ovarii, metastatic

functioning differentiated thyroid cancer, and metastatic tumors

within the thyroid gland causing destruction -induced thyrotoxicosis.

(Larsen, et al , 2002).

Specific thyrotoxic state

Graves’ disease:-

The most common cause of thyrotoxicosis is Graves’ disease (50-60%).

(Lee and Ananthakrishnan, 2010).

Graves’ disease is an autoimmune disease caused by an activating

autoantibody that targets the TSH receptor. (Larsen, et al, 2002).

Patients younger than age 40 years are the highest risk for the

development of Graves’ disease. (Davies , Larsen, 2003).

6

Graves’ disease is more common in women, with a female to- male

incidence ratio of approximately 7 to 10:1 (Larsen, et al, 2002).

Thyroid-stimulating antibodies (TSAb) bind to the TSH receptor,

activating adenylate cyclase, causing increased production of thyroid

hormone as well as increased thyroid growth and vascularity. Patients

with hyperthyroidism attributable to Graves’ disease may have (TSAb)

and thyroid stimulation-blocking antibodies (TSBAb) simultaneously.

(Takasu, et al, 1990).

Physical examination findings of Graves’ disease present in various

organ systems. The patient with Grave’s disease can have thyroid gland

findings of goiter and bruit. Ophthalmic findings can include proptosis,

ophthalmoplegia, and conjunctival irritation. (Bahn, 2000).

The proptosis and ophthalmoplegia seen in Graves’ disease are

attributable to infiltrative orbitopathy. Thyroid-stimulating hormone

receptor antibodies (TRAb) are thought to target the retro-orbital

tissues by binding to a TSH receptor antigen, which initiates a

subsequent T-cell inflammatory infiltrate. Fibroblasts stimulated by

cytokines produce glycosaminoglycans causing ophthalmopathy as a

result of mass effect in 20% to 40% of patients who have Grave’s

disease. (Bahn, 2000).

Graves’ disease may also present with multiple dermatologic findings.

Localized dermal myxedema can occur in 0.5% to 4.3% of patients with

Graves’ disease. (Fatourechi. 2005).

Because myxedema of Graves’ disease usually occurs in the anterior

leg, it has been called ‘‘pretibial myxedema’’. (Fatourechi, 2005).

7

Subacute thyroiditis

Subacute thyroiditis is the inflammation of the thyroid gland following

a viral infection of the upper respiratory tract. It is a self-limiting

inflammation of the thyroid characterized by an abrupt inception of

thyrotoxic signs and symptoms that are usually resolved within 8

months. (Slatosky, et al, 2000).

The inflammation of subacute thyroiditis is characterized by an

infiltration of mononuclear cells in affected regions of the thyroid

gland. Histopathologic examination can reveal the classic finding of a

central core of colloid surrounded by multi -nucleated giant cells, which

can progress to form a granuloma. (Farwell, 2005).

Subacute thyroiditis is the next most common cause of thyrotoxicosis

is (approximately 15-20%), due to a destructive release of preformed

thyroid hormone. (Lee and Ananthakrishnan, 2011).

Subacute thyroiditis has a peak incidence in the fourth and fifth

decades of life. It is rare in the first decade and relatively infrequent in

people older than 50 years, although it has been reported in extreme

age groups. (Ogawa, et al, 2003).

Anterior localized neck pain with or without fever is the hallmark of

the clinical presentation of subacute thyroiditis. The pain may also

radiate to the jaw or ear. Patients may report having hoarseness or

dysphagia. (Pearce, et al, 2003).

Thyrotoxic symptoms, including palpitations, nervousness, and

emotional liability, may also occur in up to 50% of patients (Pearce, et

al, 2003).

8

Physical examination findings include a tender thyroid gland, with

pain frequently localized to one side of the gland more than to the

other side. (Pearce, et al, 2003).

Laboratory evaluation of subacute thyroiditis demonstrates

suppressed TSH, elevated T4 and T3, elevation of the erythrocyte

sedimentation rate, leukocytosis, and an elevated thyroglobulin level.

(Pearce, et al, 2003).

In the initial phase of thyroiditis, inflammation destroys thyroid

tissue, which releases stored thyroid hormone and causes

thyrotoxicosis. This leads to suppression of TSH and a decrease of new

hormone synthesis, causing low uptake on radioactive iodine uptake

scanning. During the recovery phase of thyroiditis, the thyroid gland

can enter a ‘‘rebound’’ phase during which thyroid hormone

production is increased, with evidence of increased radioactive iodine

uptake (Intenzo and dePapp, 2003).

Toxic multinodular goiter Toxic multinodular goiter (TMNG), also known as Plummer’s disease,

is a condition in which the thyroid gland contains multiple nodules or

lumps that are hyperfunctional, causing an overproduction of thyroid

hormones. (Werner, et al. 2000).

TMNG accounts for 5% of the total cases of hyperthyroidism in the

U.S. The incidence of TMNG is increased in iodine-deficient regions.

(Werner, et al, 2000).

TMNG usually presents in individuals older than 50 years of age who

have had a long previous history of multinodular goiter. (Larsen, et al,

2002).

9

Toxic nodular goiter occurs more commonly in women than men. In

women and men older than 40 years the prevalence rate of palpable

nodule is 5-7 % and 1-2 % respectively. (Basaria and Salvatori, 2004).

The clinical presentation of the thyrotoxicosis is usually mild. Because

of the presentation in older age groups, however, TMNG often presents

with cardiovascular manifestations of thyrotoxicosis, such as

palpitations, tachycardia, and atrial fibrillation. (Larsen, et al, 2002).

Diagnosis of TMNG is made through laboratory evaluation that

demonstrates suppressed TSH and elevated levels of thyroxine (T4) and

triiodothyronine (T3). (Larsen, et al. 2002).

Radioactive iodine uptake and scanning reveals normal to increased

uptake and a heterogeneous pattern, with focal areas of increased

uptake corresponding to the hyperfunctioning nodules. (Larsen, et al,

2002).

Toxic adenoma

Toxic adenoma is caused by a single hyper functioning follicular

thyroid adenoma. Patients with a toxic thyroid adenoma comprise

approximately 3-5% of patients who are thyrotoxic. (Larsen, et al,

2002).

Like toxic multinodular goiter (TMNG), the pathogenesis is thought

to be attributable to a mutation in the TSH receptor gene, causing

constitutive receptor activation. The course of the disease, like TMNG,

generally evolves slowly; with frank nodule autonomy occurring only

after the nodule has been present for many years. (Larsen, et al, 2002).

Unlike TMNG, which occurs in older patients, the clinical presentation

of solitary toxic nodules usually occurs in the third and fourth decades.

(Larsen, et al, 2002).

10

Laboratory evaluation of a toxic adenoma demonstrates suppressed

TSH and elevation of T4 and T3. (Larsen, et al, 2002).

Solitary toxic adenoma is one of the most frequent causes of isolated

T3 toxicosis, however. In this situation, T4 may be normal with isolated

elevation of T3. (Larsen, et al, 2002).

Imaging with ultrasound should reveal a nodule. Radioactive iodine

uptake and scanning should demonstrate increased uptake over the

nodule, with evidence of suppressed uptake throughout the remainder

of the gland. (Larsen, et al, 2002).

Other causes of thyrotoxicosis

Iodide -induced hyperthyroidism is classified in two different types.

Type 1 Iodide -induced hyperthyroidism is similar to iodine-induced

hyperthyroidism and is manifested with a low level of TSH and high

levels of T3 and T4. It is caused by uncontrolled excessive production of

T3 and T4 by the solitarily functioning thyroid in response to iodine (Jod-

Basedow phenomenon). (Baskin, et al, 2002).

Type 2 Iodide -induced hyperthyroidism is the destructive

inflammation of the thyroid (thyroiditis). (Baskin, et al, 2002).

An excess of iodine in the diet can also have a devastating effect on

human health, as it can cause excessive production of thyroid

hormones leading to hyperthyroidism, especially in older patients with

pre-existing multinodular goiter. (Fitzgerald, 2005).

Other iodine-related contributing factors include medications and

radiographic contrast media exposure. (Fitzgerald, 2005).

Tumors are one of the rare causes of hyperthyroidism. Some of the

tumors that can lead to a thyrotoxic state are struma ovarii (tumor of

the ovary where predominantly or entirely existing thyroid cells in the

ovary produce thyroid hormones), Human Chorionic Gonadotropin

11

(HCG)-producing and TSH receptor-activating trophoblastic tumors, and

TSH-secreting adenomas. (Tierny, et al, 2005).

Factitious hyperthyroidism is characterized by higher than normal

thyroid hormone levels brought about by taking too many thyroid

hormone medications for hypothyroidism. (Reid, et al, 2005).

Another cause of factitious hyperthyroidism is intentional intake of

thyroid hormone preparation for weight loss. (Reid, et al, 2005).

12

Clinical presentation of thyrotoxicosis:-

Thyrotoxicosis causes a hypermetabolic state resulting in an

imbalance of energy metabolism in which energy production exceeds

energy expenditure. This may cause increased heat production,

resulting in perspiration, heat intolerance, and even fever. (Dabon-

Almirante, et al, 1998).

The signs and symptoms of hyperthyroidism are dependent on age,

duration of illness, extent of the overproduction of thyroid hormones,

and existence of a disease condition not related to hyperthyroidism.

(Reid and Wheeler, 2005).

Tri iodothyronine (FT3) exerts its effects directly on the heart. The

manifestations of these changes include increased heart rate, cardiac

contractility,and cardiac output. (Klein and Ojama, 2001) .

Tachycardia is the most common cardiovascular sign of

thyrotoxicosis. Thyrotoxic patients may also experience palpitations

attributable to increased force of cardiac contraction. (Larsen, et al,

2002).

Thyroid hormone decreases systemic vascular resistance through a

direct vasodilator action on the smooth muscle, which is mediated by

endothelial release of nitric oxide and other endothelial-derived

vasodilators. (Ojamaa, et al, 1996).

Physical findings in thyrotoxicosis can include a strong apical

impulse, increased pulse pressure, and a hyperdynamic precordium.

Heart sounds can include the ‘‘Means-Lerman scratch’’ heard at the

apex, which is thought to be attributable to the hyperdynamic

precordium rubbing against the pleura. (Larsen, et al, 2002 and Dabon-

Almirante, et al, 1998).

13

Thyrotoxic patients can experience chest pain that may mimic

ischaemic angina pectoris. (Dabon-Almirante, et al, 1998).

Older individuals may present with atypical clinical manifestations of

thyrotoxicosis. ‘‘Apathetic hyperthyroidism’’ is a common presentation

in the elderly and is characterized by weight loss, weakness,

palpitations, dizziness, or memory loss and physical findings of sinus

tachycardia or atrial fibrillation. (Dabon-Almirante, et al, 1998).

Thyrotoxicosis causes neuropsychiatric changes resulting in

restlessness, agitation, anxiety, emotional liability. (Wartofsky,2005).

Gastrointestinal manifestations of thyrotoxicosis include increased

frequency of bowel movements caused by increased motor contraction

of the small bowel, resulting in more rapid transit of intestinal contents.

(Dabon-Almirante, et al, 1998).

Thyrotoxicosis can affect the menstrual cycle in women, resulting in

oligomenorrhea or amenorrhea. The etiology of the menstrual

irregularity is unclear but may be attributable to the effects of thyroid

hormone on gonadotropin-releasing hormone (GnRH) causing

disruption of normal luteinizing hormone (LH)/follicle-stimulating

hormone (FSH) pulsatility. (Larsen, et al, 2002).

Approximately 10% of male patients with hyperthyroidism may

experience symptoms of decreased libido or gynecomastia and

development of spiderangiomas. (Dabon-Almirante, et al, 1998).

14

TABLE 1 lists clinical manifestations of hyperthyroidism. (Reid and

Wheeler,2005 and Baskin, et al, 2002).

15

Diagnosis of hyperthyroidism:-

(A) Laboratory diagnosis:-

T3 ,T4 and TSH level A suppressed TSH level (<0.05 mU/mL) in combination with an

elevated serum free T4 level occurs in 95% of patients with clinically

evident thyrotoxicosis. (Dabon-Almirante, et al,1998 and Ladenson.

2005).

Although a TSH assessment alone may be appropriate for routine

screening in an asymptomatic patient, the suspicion of thyrotoxicosis

warrants the additional assessment of T4 and T3. In cases in which

subclinical hyperthyroidism is suspected, TSH measurement may be

used as a first diagnostic step, with subsequent T4 and T3 assessment if

TSH is suppressed.

(Dabon-Almirante, et al,1998 and Ladenson. 2005).

Free hormone concentrations are preferable in the diagnosis of

thyrotoxicosis because of the possible interference of protein binding

with total thyroid hormone levels. (Baloch, et al, 2003).

Thyroid-stimulating hormone receptor antibodies

The measurement of Thyroid-stimulating hormone receptor

antibodies (TRAb) may occasionally be helpful in the diagnosis and

management of Grave’s disease. A second generation of this assay

using recombinant TSH receptor has been developed and has a

reported sensitivity of 98.6%. (Costagliola, et al, 1999).

TRAb measurements are particularly useful in the prediction of

postpartum Grave’s thyrotoxicosis and neonatal thyrotoxicosis.

(Hidaka, et al, 1994).

16

Thyroxine/triiodothyronine ratio

The ratio of T4 to T3 frequently has a characteristic pattern in different

thyrotoxic states. Evaluation of the T4/T3 ratio may be a useful tool in

the initial diagnosis of thyrotoxicosis when radio -active iodine uptake

testing is not readily available or is contra -indicated. (Ladenson,

2005).

Grave’s disease and toxic nodular goiter typically present with

increased T3 production, with a T3/T4 ratio greater than 20.

(Yanagisawa, et al, 2005).

With thyrotoxicosis caused by thyroiditis, iodine exposure, or

exogenous levothyroxine intake T4 is the predominant hormone and

the T3/T4 ratio is usually less than 20.

(Ladenson. 2005).

Other laboratory findings

Thyrotoxicosis may also cause hyperglycemia, hypercalcemia,

elevated alkaline phosphatase, leukocytosis, and elevated liver

enzymes. (Wartofsky, et al, 2005 and Pimental, Hansen, 2005 ).

17

(B) Imaging:-

Multiple imaging modalities may assist in the determination of the

etiology of thyrotoxicosis. These include thyroid nuclear imaging

studies and anatomic studies like thyroid ultrasound.

Nuclear imaging studies:-

A key diagnostic tool in the evaluation of thyrotoxicosis is radioactive

iodine uptake and scanning. Radioactive iodine uptake and scanning

uses a radioactive isotope of iodine, typically I123

or I131

. (Meier and

Kaplan, 2001).

After ingestion of the tracer, the normal values for the24-hour

radioiodine uptake range between 5% and 25%, and the average6-hour

uptake reference range is between 5% and 15% (Meier and Kaplan,

2001).

The differential diagnosis of thyrotoxicosis may be divided into

categories based on whether increased or decreased uptake of

radiotracer is observed during thyroid scanning.

Increased nuclear tracer uptake

May be seen in toxic multi-nodular goiter, toxic solitary nodule, or

Grave’s disease. (Cakir, 2005).

Graves’disease generally demonstrates homogeneous uptake

throughout the gland. With markedly increased thyroid hormone

synthesis and turn over in Graves’ disease, there can be a paradoxical

finding of elevated uptake at 4 or 6 hours after radioiodine dosing but a

normal uptake at 24 hours as a result of accelerated clearance of the

radioactive iodine. (Cavalieri, 1991).

18

TMNG generally has a heterogeneous pattern of uptake with

hyperfunctioning nodules that demonstrate increased radionuclide

uptake on scan. These nodules appear on a background of partially or

completely suppressed uptake in the uninvolved areas of the thyroid

gland. (Cavalieri, 1991).

Solitary toxic nodules have a radioactive iodine scan pattern

demonstrating increased uptake in the hyperfunctioning nodule and

decreased uptake in the remainder of the gland. When the uptake in

the uninvolved parts of the thyroid is completely suppressed, such a

nodule is frequently referred to as an autonomous or ‘‘hot’’ nodule. If

the uninvolved parts of the thyroid are not completely suppressed, the

nodule is frequently referred to as a ‘‘warm’’ nodule to differentiate

this type of radiographic pattern. (Cavalieri, 1991).

Paradoxically, increased radioactive iodine uptake may also be found

in Hashimoto’s thyroiditis. This finding usually occurs with early or

relatively mild disease. (Meier and Kaplan, 2001).

Decreased nuclear tracer uptake

Thyrotoxic conditions typically associated with decreased radioactive

iodine uptake include exogenous thyroid hormone intake, thyroiditis,

and iodine intoxication. The main cause of the decreased isotope

uptake in all these conditions is suppression of TSH. (Intenzo and

dePapp , 2003).

In the initial phase of thyroiditis, inflammation destroys thyroid

tissue, which releases stored thyroid hormone and causes

thyrotoxicosis. This leads to suppression of TSH and a decrease of new

hormone synthesis, causing low uptake on radioactive iodine uptake

scanning. (Intenzo and dePapp, 2003).

During the recovery phase of thyroiditis, the thyroid gland can enter

a ‘‘rebound’’ phase during which thyroid hormone production is

19

increased, with evidence of increased radioactive iodine uptake

(Intenzo and dePapp, 2003).

Iodine-rich agents, such as amiodarone, radiographic contrast

agents, or increased oral iodine intake are a frequent cause of iodine

intoxication. Iodine intoxication decreases radioiodine uptake. (Intenzo

and dePapp, 2003 and Cavalieri, 1991).

Figure (1) Iodine-123 thyroid scan in a patient with Grave’s disease: Tracer

uptake is uniform throughout the gland. The 5-hour iodine uptake was high at

53%. (Piga , et al, 2008).

20

Figure (2) Iodine-123 scan in a patient with a toxic, multinodular goiter: The 5-

hour iodine uptake was elevated at 28%. Note the multiple foci of variably

increased tracer uptake. (Piga , et al, 2008).

Figure (3) Iodine-123 scan in a patient with a palpable nodule in the right neck,

a low serum level for thyrotropin, and a slightly elevated serum level of free

triiodothyronine. The autonomously functioning nodule only partially

suppresses uptake in the remainder of the gland. The 5-hour iodine uptake was

mildly elevated at 22 %.(Piga , et al, 2008).

21

Technetium-99m pertechnetate imaging

Thyroid scintigraphy usually performed with technetium-99m

pertechnetate or radioiodine. (Meller and Becker, 2002 ; Summaria, et

al, 1999 and Smith and Oates, 2004).

:m pertechnetate99-vantages of technetiumAd

• Lower radiation dose

• Better image quality

• Less waiting time after administration

• Wider availability

• Lower cost

• Images can be obtained while the patient is taking anti-thyroid

medications.

(Meller and Becker, 2002 ; Summaria, et al, 1999 and Smith and

Oates, 2004).

: active iodine-Advantages of radio

• Has lower levels of vascular background activity which is useful when

assessing retrosternal masses.

• Has some advantages in the evaluation of thyroid nodules, although

these are rarely of clinical significance

• Oral administration

(Intenzo, et al, 2003; Naik and Bury, 1998 and Smith and Oates, 2004)

Scintigraphy is particularly useful for distinguishing Graves' disease

from conditions such as subacute, silent and post -partum thyroiditis

and factitious hyperthyroidism. (Meier and Kaplan, 2001).

Scintigraphy is also useful for demonstrating toxic adenomas.

(Intenzo, et al , 2003).

22

Figure (4) Tc99m

thyroid scan of Toxic adenoma in a patient seen at Nuclear

Medicine Unit (NEMROCK) presented with a palpable nodule in the left neck

show an autonomous functioning nodule with complete suppressed uptake in

the remainder of the gland.

Figure (5) Tc

99m thyroid scan of Grave’s disease in a patient seen at Nuclear

Medicine Unit (NEMROCK) presented with thyrotoxic manifestation show

diffusely enlarged gland with homogenous radio tracer uptake all over the gland

and decreased background activity to such an extent that the submandibular

salivary glands (arrowhead) are barely visualized. pyramidal lobe is seen (large

arrow). The round photopenic area (small arrow) represents the 2-cm lead

marker placed at the suprasternal notch.

23

Figure (6) Tc99m

thyroid scan of Toxic multinodular goiter in a patient seen at

Nuclear Medicine Unit (NEMROCK) presented with neck lump show

heterogeneous tracer uptake with multiple foci of variably increased tracer

uptake.

24

Thyroid ultrasonography in the evaluation of

hyperthyroidism

Thyroid sonography may be useful in the diagnostic evaluation of

thyrotoxicosis. Sonographic assessment can identify thyroid nodules

and goiter that may not be readily apparent on examination. (Kurita, et

al, 2005).

Additionally, sonographic Doppler flow assessment may provide

particularly useful information about several thyrotoxic states.

Kurita and colleagues used an index measurement of thyroid blood

flow per unit area to distinguish between Graves’ disease and

thyrotoxicosis caused by non hypermetabolic destructive thyroiditis.

(Kurita, et al, 2005).

Using a thyroid blood flow area of 8% or greater had a sensitivity of

95% and a specificity of 90% for the prediction of Graves’ disease.

(Kurita, et al, 2005).

Ultrasound can detect the presence of nodules and goiter that may

favor the diagnosis of type I Iodide –Induced thyrotoxicosis. (Bogazzi, et

al, 1997).

Color flow Dopppler sonography can also aid in the differentiation of

type I Iodide –Induced thyrotoxicosis and type II Iodide –Induced

thyrotoxicosis. Type I is attributable to an underlying hypermetabolic

state and typically demonstrates normal to increased blood flow that is

readily apparent with Doppler imaging while Type II is a type of

destructive thyroiditis, generally presents with markedly decreased

blood flow. (Bogazzi, et al, 1997).

25

Figure( 7): Color flow ultrasonogram in a patient with Grave’s disease.

Generalized hypervascularity is visible throughout the gland, which often can be

heard as a hum or bruit with a stethoscope. (Loy, et al, 2007).

26

Differential Diagnosis of Hyperthyroidism

Graves’ disease there is cases where in elevated levels of free thyroid

hormones (T3 and T4) despite a normal-sized thyroid gland. There are

also circumstances wherein patients would only develop T3 toxicosis, as

manifested by sole elevation of triiodothyronine hormone levels.

Sensitive assay testing reveals depressed levels of TSH in Graves’

disease, whereas radioactive scans reveal diffused uptake of radioactive

isotopes and, in some cases, a pyramidal lobe. (Baskin, et al, 2002).

Thyroid adenoma (toxic adenoma) also known as hot nodule is

manifested by suppressed levels of TSH, with or without elevated levels

of free thyroid hormones. Thyroid scanning reveals a normally

functioning thyroid nodule and decreased iodine uptake in the

surrounding extranodular and contralateral thyroid tissue. The same is

true of toxic multinodular goiter where thyroid gland variably enlarged

with multiple nodules. (Baskin, et al, 2002).

Subacute thyroiditis, silent thyroiditis, iodine-induced

thyrotoxicosis, and factitious thyroxine-induced thyrotoxicosis are

characterized by a low radioiodine uptake and poor thyroid gland

imaging in scintigraphic scan. These conditions are often accompanied

by increased levels of thyroid hormones during the hyperactive thyroid

state. (Baskin, et al, 2002).

Classic subacute thyroiditis is a thyroid condition that is manifested

by painful inflammation of the thyroid gland accompanied by fever. It

has a triphasic clinical pathway consisting of: hyperthyroid phase,

hypothyroid phase and resolution phase. (Baskin, et al. 2002).

Silent thyroiditis is an autoimmune disorder characterized by painless

inflammation of the thyroid gland. It has a clinical course similar to that

of classic subacute thyroiditis. It is common in women, especially during

the postpartum period. (Baskin, et al, 2002).

27

Iodine-induced thyrotoxicosis more often affects elderly patients. It

can also be seen in patients with pre-existing autonomously functioning

thyroid nodules. (Baskin, et al, 2002).

Factitious thyrotoxicosis has the same clinical presentation as iodine-

induced thyrotoxicosis. In contrast to all types of thyroiditis, the

thyroglobulin level is very low and sometimes nonexistent. (Baskin, et

al, 2002).

28

Treatment of thyrotoxicosis

Disease’ Treatment of Graves

Antithyroid medications

Those in current use are methimazole (carbimazole in the U.K. and

countries influenced by British medicine) and propylthiour -acil. The

longer half-life of methimazole allows for once-daily intake, which is a

considerable advantage over the dosage schedule for propylthiouracil,

which generally has to be taken 2 or 3 times daily (Cooper, 2005)

Propylthiouracil is preferred during pregnancy to avoid teratogenic

effect of methimazole. (Zweig, et al, 2006).

The main action of these drugs is to interfere with the iodination of

tyrosine within the colloid of the thyroid follicle. The drugs have a

minor immunologic effect that is not entirely attributable to the

normalization of thyroid function. The inhibition of the conversion of T4

to T3 by Propylthiouracil is of minor significance. (Zweig, et al, 2006).

Both medications are introduced in a loading dose for about 4–6

weeks. As the patient’s condition improves symptomatic -cally and

biochemically, the dose can usually be reduced. Daily loading doses of

10–30 mg of methimazole or 100–300 mg of propylthiouracil,

Maintenance doses of 5–10 mg of methimazole or 50–100 mg of

propylthiouracil twice daily keep most patients euthyroid. (Zweig, et al,

2006).

Medication is prescribed for 12–18 months with the hope

that the disease will remit.(Abraham, et al, 2005).

An alternative medical approach is to continue the larger loading dose

for 18 months and to add thyroid hormone (block and-replace therapy).

29

This approach was thought to increase the percentage of patients

whose disease would remit (Abraham, et al, 2005).

Mild complications include maculopapular and urticarial skin rashes,

nausea, dislike of the taste of the medications, and arthoropathy.

(Koornstra, et al, 1999).

More serious complications is agranulocytosis, which occurs most

often within weeks of starting either medication and usually presents

as a sore throat with fever. Patients must be warned to stop the drug

and have an immediate differential white cell count test. (Koornstra, et

al, 1999).

When the granulocyte count is less than 1,500/mm the medication

should not be restarted and an alternative medication should be used.

(Koornstra, et al, 1999).

Anti-thyroid medication has a significant role in rendering patients

euthyroid before treatment with I131

or thyroidectomy (Koornstra, et

al, 1999).

For radioiodine, this process is advised for older patients, very

thyrotoxic patients, and patients with cardiac problems.Patients being

treated by surgery should be euthyroid first. (Imseis, et al, 1998 and

Santos, et al, 2004).

Propylthiouracil is discontinued for 3 days and methimazol is

discontinued for 5 days before testing and therapy. (Razvis, et al, 2004;

Walter, et al,2006 and Weaver and Razvis, 2005).

30

Surgery

Indications for surgery include a coexisting nonfunctioning nodule or a

nodule suggestive of cancer on fine-needle aspiration.

One indication for surgery is a patient who desires to become

pregnant and who is not convinced that it is safe to be treated with I131

before conception or to take anti-thyroid medication during pregnancy

(England, et al, 2006).

The procedure should be a nearly total thyroidectomy with the

expectation for lifelong thyroid hormone replacement. (Gurleyik, et al,

2005).

The incidence of recurrence after subtotal thyroidectomy is high and

this almost always should be treated with I131

.Thus, the patient receives

radioiodine treatment which, for one reason or another, was originally

believed to be less desirable complications, such as hypoparathyroidism

and damage to the recurrent and superior laryngeal nerves, should be

uncommon. (Gurleyik, et al, 2005).

Surgery provides a more rapid outcome and should be considered in

a patient who wishes an early conception or is concerned about

radiation(Kang, et al, 2002).

31

CTIVE IODINEA- TREATMENT WITH RADIO

There has never been any debate that the goal of I131

treatment is to

cure the thyrotoxic condition. (Cooper, 1996 and Franklyn, 1994).

Radioactive iodine is the treatment of choice for most patients with

Graves’ disease and toxic nodular goiter. It is inexpensive, highly

effective, easy to administer, and safe.

(American Academy of Clinical Endocrinologists, 2002 and

Harper and Mayeaux, 2003).

The treatment of hyperthyroidism in children remains controversial,

but radioactive iodine is becoming more acceptable in this group.

(Rivkees , 2001) .

HOW IS ADMINISTERED DOSE DETERMINED?

There are 2 common approaches for determining the administered

dose (Kalinyak and McDougall, 2003).

One is to prescribe a fixed dose for all patients. The other is to

calculate a dose based on the size of the thyroid and its percentage

uptake at 24 h. Fixed doses vary but are commonly in the range of 185–

555 MBq (5–15 mCi). (Kalinyak and MC Dougall, 2003).

A variation on the fixed-dose is to add an incremental dose of I131

when the gland is large or when the uptake is relatively low. (Kalinyak

and MC Dougall, 2003).

A gland-specific dosage based on the estimated weight of the gland

and the 24-hour uptake may allow a lower dosage and result in a lower

incidence of hypothyroidism but may have a higher recurrence rate.

(Harper and Mayeaux, 2003).

Higher-dose ablative therapy increases the chance of successful

treatment and allows the early hypothyroidism

32

(Weetman , 2000 and Allahabadia, et al, 2001).

CALCULATING ADMINISTERED DOSE

Many use a formula that is based on gland size and 24 hour

radioactive iodine uptake % for calculating the administered dose.

Generally, large glands require a relatively higher therapeutic dose and

patients with higher %RAIU require a lower dose.

I131

administerated dose =

24 hour % RAIU

Equation (1) calculation of I131

dose based on goiter size and radioactive iodine

uptake. (Burmank, et al, 2006).

Therefore, a 40-g gland with 50% uptake would be treated with 474

MBq (12.8 mCi). This method has a high probability of cure with a single

dose of I131

and less than 10% of patients needing to be retreated

(Alexander and Larsen, 2002).

The administration of a quantity of I131

on the basis of the size of the

thyroid implies that the exact size is known. This size can be

determined with some accuracy by ultrasound. (Alexander and Larsen,

2002).

CALCULATING ABSORBED DOSE

33

Controversies exist with regard to the radiation dose to the thyroid

needed to successfully treat Graves’ disease. A study comparing doses

of 150, 300, and greater than 300 Gy to the thyroid found no significant

difference in the rates of recurrent hyperthyroidism whereas the rates

of hypothyroidism in the 3 groups were significantly correlated with

doses. (Howarth, et al, 2001).

FAILURE OF THERAPY

The need for retreatment indicates that insufficient I131

was

administered. This situation could result because a fixed dose was too

small relative to the size of the gland or because the thyroid was less

able to trap iodine than expected (Erem, et al, 2004) or because the

size of the gland was underestimated when a dose per gram corrected

for uptake was administered. A rapid turnover of iodine must be

considered and can be adjusted for by measuring 24-h uptake rather

than uptake at 4–6 hours (Venulakonda, et al, 1996).

Another rare cause of failure was described: a patient ‘‘spat up’’ the

capsule and also had a high level of serum iodine (Kinuya, et al, 2004).

When a patient is not rendered euthyroid or hypothyroid, a second

treatment is advised. Some authorities advise a second treatment after

3 months, some prefer a delay of 6 months or more because a

proportion of patients respond later. (Kinuya, et al, 2004).

34

TREATMENT OF SINGLE HYPERFUNCTIONING AUTONOMOUS

NODDULE

In few cases necrosis of the center of the nodule result in

euthyroidism however, that remission is not long-lasting. As a result,

the decision to remove the nodule by lobectomy or to ablate it with I131

is generally accepted. Each treatment has benefits and drawbacks.

(Vidal, et al, 2004 and Gurleyik, et al, 2005).

Indications for surgery include a coexisting nonfunctioning nodule or

a nodule suggestive of cancer on fine-needle aspiration. (England, et al,

2006).

One indication for surgery is a patient who desires to become

pregnant and who is not convinced that it is safe to be treated with I131

before conception or to take anti-thyroid medication during pregnancy

(England, et al, 2006).

Lobectomy is undertaken after the patient is rendered euthyroid by

anti-thyroid medications. It produces a speedy cure, there is no

radiation, but it requires surgery, usually under general anesthesia.

(Vidal, et al, 2004 and Gurleyik, et al, 2005).

I131

treatment avoids surgery and anesthesia but requires radiation

safety education and planning. (Vidal, et al, 2004 and Gurleyik, et al,

2005).

35

I131

takes several weeks to have its full effect, and the nodule will not

dissolve completely; therefore, the patient must be advised that

physicians may want to perform follow up examinations. (Vidal, et al,

2004 and Gurleyik, et al, 2005).

Ceccarelli et al 2005. administered 7.4 MBq (200 UCi) of I131

per gram

corrected for uptake had a success rate of 94%, and 60% of their

patients were hypothyroid by 20 years .

The volume can be determined by ultrasound and the uptake can be

determined with a I123

tracer. (Reiners and Schneider, 2002).

A total of 66% of the patients were adequately treated with a single

calculated dose; in comparison, 27% were adequately treated with a

single empiric dose. Thus, calculated doses appear to be preferable to

fixed doses. (Huysmans, et al, 1993).

Finally, the administered dose can be calculated to deliver a specific

dose defined in rads or grays to the nodule. A recent study of 425

treated patients demonstrated that doses of 300–400 Gy delivered to

the nodule were successful in 90%–94% of patients (Reinhardt, et al,

2006).

Other therapeutic options for autonomous hyperfunctioning thyroid

nodules include ultrasound-guided laser thermal ablation and

percutaneous ethanol injection (Pacella, et al. 2004).

Several injections of alcohol are administered to the nodule by use of

ultrasound to localize the appropriate site. Free hormone levels fall,

TSH levels rise, and the volume of the nodule decreases. The

advantages include no surgery or exposure to radiation. The

disadvantages are multiple visits (occasionally more than 10), pain and,

in rare cases, serious local complications, such as necrosis of the larynx

(Mauz, et al, 2004).

36

TOXIC MULTINODULAR GOITERS

The American Thyroid Association and American Association of

Clinical Endocrinologists have released guidelines for the management

of hyperthyroid and other causes of thyrotoxicosis, including the use of

radioactive iodine or surgery to treat toxic multinodular goiter

(TMNG).(Bahn Chair, et al, 2011).

Because the affected patients are usually older, it is important to

render them euthyroid with antithyroid medications before definitive

therapy. (Giovanella, et al, 2000 and Nygaard, et al, 1999).

In the United States and Europe, radioactive iodine is considered the

treatment of choice for TMNG. Except for pregnancy, there are no

absolute contraindications to radioiodine therapy.

( Allahabadia , et al, 2001).

Much debate exists regarding optimal dosing of radioactive iodine.

Patients with TNG tend to have less uptake than patients with Grave’s

disease; therefore, they are generally considered to need higher doses

of I131

. However, studies by Allahabadia and colleagues suggest that

fixed doses of radioiodine do not demonstrate any difference in

response in these 2 groups of patients (patients with Grave’s and

patients with TNG) using a fixed dose of 10 mci. (Allahabadia , et al,

2001).

One approach is to deliver 7.4MBq (200 uCi) per gram, a dose

calculated from the 24-h uptake and the volume determined by

ultrasound. (Duick and Baskin, 2003 and Rubio, et al, 2005).

A single dose of radioiodine therapy has a success rate of 85-100% in

patients with TNG. Radioiodine therapy may reduce the size of the

goiter by up to 40%. (Zingrillo, et al, 2007).

37

Failure of initial treatment with radioactive iodine has been

associated with increased goiter size and higher T3 and free T4 levels,

which suggests that these factors may present a need for higher doses

of I131

. ( Albino, et al , 2005 and Duick and Baskin, 2003).

A positive correlation exists between radiation dose to the thyroid

and decrease in thyroid volume. ( Albino, et al , 2005 and Duick and

Baskin, 2003).

In patients with uptake of less than 20%, pretreatment with lithium or

recombinant TSH can increase the effectiveness of iodine uptake and

treatment. ( Albino, et al , 2005 and Duick and Baskin, 2003).

Hypothyroidism occurs in 10-20% of patients; this is similar to the

incidence rate after surgery and is substantially less than in the

treatment of Graves' disease. (Adamali, et al, 2007).

surgery A subtotal thyroidectomy is performed most commonly. This surgery

preserves some of the thyroid tissue and reduces the incidence of

hypothyroidism to 25 percent, but persistent or recurrent

hyperthyroidism occurs in 8 percent of patients. (Alsanea, et al, 2000).

38

Side effects and complications of radio-active iodine I131

treatment and how to overcome:-

Acute radiation thyroiditis

Is very rare after I131

therapy of Graves’ disease. It is painful and

similar to subacute thyroiditis, with referral of the pain to the jaws and

ears. Anti-inflammatory medication or a short course of corticosteroids

is of value. (Kadman, et al, 2001).

Thyroid storm

Can occur several days after therapy and is more common in older

patients and those with severe disease—hence, the recommendation

for the pretreatment of these patients with anti-thyroid drugs.

(Kadman, et al, 2001).

There are rare reports of a thyroid crisis in children (Kadman, et al,

2001).

These data further support the argument for first rendering severely

thyrotoxic patients and those at most risk euthyroid by medical

therapy. (Ron, et al, 1998).

Salivary Gland Dysfunction

Sialoadenitis is a direct result of radiation injury from active iodine

uptake into the gland 20 to 100 times that of plasma. (Mandel, et al,

2003).

The incidence of acute radiation sialoadenitis with swelling and pain is

widely variable, reported in between 12% and 67% of patients after RAI

treatment. (Caglar, et al, 2002).

39

Sialoadenitis can be prevented with lower activities of prescribed I

131,

good hydration, and use of sialogogues. (Van Nostrand , et al, 2009).

Quantitative studies have shown that radiation within the parotid

decreased rapidly after induction of salivary gland secretion with lemon

juice. (Van Nostrand , et al, 2009).

Stomatitis

Occasionally acute stomatitis is seen, which is thought to be the

result of mucosal radiation from the I131

secreted into saliva. many

experts have seen this complication 5 to 7 days after therapy.

Symptoms can be controlled with an elixir mouthwash containing

dexamethasone, viscous lidocaine, diphenhydramine, and aluminum

and magnesium hydroxide. (Mandel, et al, 2003).

Taste Changes

Loss of taste or altered taste is thought to be caused by radiation

destruction of lingual taste buds from the RAI secreted into saliva. (

Mendoza, et al, 2004 and Kita, et al, 2004).

Gastrointestinal Complications

Nausea is the most common gastrointestinal symptom of RAI therapy

but is rarely accompanied by emesis. ( Mendoza, et al, 2004).

Studies have shown that 50% to 67% of patients complain of nausea

starting as early as 2 hours after treatment and lasting up to 2 days

after therapy. (Maenpaa, et al, 2008).

Antiemetics can be given intravenously to patients with severe

symptoms to prevent emesis and allow oral hydration. (Lassmann, et

al, 2010).

40

Gonadal Radiation and Fertility

The gonads receive radiation from the free and iodinated proteins

circulating in blood and from the urinary excretion of the RAI. Gonadal

exposure in the first 3 days after RAI treatment can be reduced with

good hydration and frequent urination. (Hyer, et al, 2002).

The biochemical abnormalities (elevated luteinizing hormone, low

testosterone) usually resolved within 18 months after I131

treatment

with less than 150 mCi, but the risk for persistent gonadal dysfunction

increased after a repeated or high cumulative dose of RAI, male fertility

is not significantly affected by a single lower dose of RAI. (Sawka, et al,

2008).

RAI effects on female fertility have been examined carefully. Transient

amenorrhea or oligomenorrhea has been reported after RAI. (Vini, et

al, 2002).

Additional small clinical observational studies confirm that female

fertility, pregnancies, and babies’ health are not affected by prior high-

dose radioiodine treatment. (Bal, et al, 2005).

Bone Marrow Suppression

Asymptomatic transient drops in white blood cell, red blood cell, and

platelet counts are seen with usual doses of I131

. (Sisson, et al, 2001).

41

LITHIUM AS ADJUVANT TO I131

Lithium reduces the release of thyroid hormones from the thyroid

and has been used alone to treat hyperthyroidism.

Lithium has also been used as an adjuvant to I131

by retaining the

radionuclide within the gland and delivering more radiation with a

smaller administered dose. (Bogazzi, et al, 1999).

RADIATION SAFETY

When a patient is treated with I131

and released, it is important that

members of the public, including the family, are not exposed to

significant radiation.

Family members have confirmed that simple measures, such as

sleeping in a separate bedroom and remaining more than 2 meters

from family members for a few days, ensure that the regulations are

fulfilled (Cappelen, et al, 2006).

In 1 investigation, the maximum exposure to a family member from

the treatment of Grave’s disease was 2.4 mSv (240 mrem); when

detailed instructions were given, this exposure was reduced to 1.9 mSv

(190mrem) (Pant, et al, 2006).

42

SPECIAL SITUATIONS

Children

Most thyrotoxic children have Graves’ disease (Hung and Sarlis,

2004).

Children are less likely to have infiltrative orbitopathy but

there have been reports of eye disease.(Hung and Sarlis, 2004 and

Wiersinga, 2004).

The incidence of side effects from anti-thyroid medications is higher

in children, and they can be serious (Rivkees, et al, 1998; Birrell and

Cheetham, 2004 and Segni and Gorman, 2001).

Children are less consistent in taking the medications, and the

remission rates are lower. (Barrio, et al, 2005).

When high doses of anti-thyroid medications are required for a long

time, remission is unlikely (Barrio, et al, 2005).

Thyroidectomy is technically more difficult in young children, and

few surgeons are trained in this procedure. As a result, there has been

increasing experience in the role and value of I131

treatment in pediatric

patients (Rivkees, 2003).

Several authorities have promoted the administration of I131

earlier in

the management of pediatric patients and even as the primary

treatment. Children as young as 3 years can be treated (Rahman, et al,

2003).

Some children have relatively large goiters, and the size can be

calculated from length, width, and depth measurements obtained by

43

ultrasound. This calculation provides a more exact size for treatment

based on a dose per gram corrected for percentage uptake. (Rahman,

et al, 2003).

Pregnancy

Graves’ disease occurs in young women, and a patient may become

pregnant before, coincidentally with, or after the diagnosis (Chen and

Khoo, 2002 and Perros, 2005).

The maternal thyroid dysfunction, the presence of TSI (thyroid

stimulating immunoglobulin), and the management of the condition

can all affect the fetus. Usually, the treatment consists of anti-thyroid

medications, but maternal allergy to the medications presents a

difficult management problem (Cho and Shon, 2005).

Methimazole administered to the mother has been reported to cause

aplasia cutis (a scar like lesion of the scalp) and recently was linked to

choanal atresia in offspring. (Barbero, et al, 2004 and Foulds, et al,

2005).

Therefore, propylthiouracil is preferred. (Luton, et al, 2005)

It is very important to ensure that the mother does not receive

diagnostic or therapeutic radioiodine when pregnant. There should be a

mechanism to ensure that all women about to be tested with radio

nuclides of iodine are asked about the possibility of pregnancy and that

all women who are to be treated have a negative pregnancy test. (Cho

and Shon, 2005).

After 11 weeks, the fetal thyroid concentrates iodine, and if the fetus

is exposed, it will be born a thyrotic (Cho and Shon, 2005).

44

Exposure of the fetus also reduces the intelligence quotient by 30

points per gray (100 rads) and introduces a slightly increased cancer

risk. (Mc Dougall, 2006).

When exposure occurs in the first trimester, the risk of neonatal

hypothyroidism is reduced considerably however; every effort should

be made to ensure that such exposure does not occur. (Berlin, 2001).

Thyroid Eye Disease

Eye disease is seen only in patients with autoimmune thyroid disease,

such as Graves’ disease. (Wiersinga, 2005; Bartalena, et al, 2005 and

Wiersinga, 2004).

Correction of both hyperthyroidism and hypothyroidism is important

for the ophthalmopathy. Anti-thyroid drugs and thyroidectomy do not

influence the course of the ophthalmopathy, whereas radioiodine

treatment may exacerbate preexisting ophthalmopathy but can be

prevented by glucocorticoids. In the long term, thyroid ablation may be

beneficial for ophthalmopathy because of the decrease in antigens

shared by the thyroid and the orbit in the autoimmune reactions. In

general, treatment of hyperthyroidism is associated with an

improvement of ophthalmopathy, but hypothyroidism must be avoided

because it worsens ophthalmopathy.( Bartalena, et al, 2004).

For mild-to-moderate ophthalmopathy, local therapeutic measures

(e.g., artificial tears and ointments, sunglasses, eye patches, nocturnal

taping of the eyes, elevating the head at night) can control symptoms

and signs.

45

If the disease is active, the mainstays of therapy are high-dose

glucocorticoids. (Macchia, et al, 2001).

The antioxidant selenium (200 mcg daily) was shown in one study to

help patients with mild Grave's orbitopathy. (Marcocci, et al, 2011).

Systemic steroids are usually reserved for patients with severe

inflammation or compressive optic neuropathy in thyroid-associated

orbitopathy (TAO). The consensus statement of the European Group on

Grave's orbitopathy (EUGOGO) suggests intravenous glucocorticoids for

patients with advanced thyroid-associated orbitopathy. (Bartalena, et

al, 2008).

If no response to therapy occurs in the inflammatory phase, orbital

radiotherapy with or without steroids may be tried. (Wakelkamp, et al,

2004).

Orbital irradiation is sometimes prescribed for moderate to severe

inflammatory symptoms, diplopia, and visual loss in patients with

thyroid-associated orbitopathy (TAO). The radiation (1500-2000 cGy

fractionated over 10 days) is usually administered via lateral fields with

posterior angulation. Radiation is believed to damage orbital fibroblasts

or perhaps lymphocytes. (Gorman, et al, 2001).

The radiation requires several weeks to take effect, and it may

transiently cause increased inflammation. Thus, most patients are

maintained on steroids during the first few weeks of treatment. In

addition, better response to radiation is observed in patients with

active inflammation who are treated within 7 months of the onset of

thyroid-associated orbitopathy. Radiation may be more effective if

combined with steroid treatment. (Gorman, et al, 2001).

46

Orbital radiotherapy does not increase the risk for radiation-induced

tumors, cataract, and retinopathy, except in patients with diabetes with

possible or definite retinopathy. (Wakelkamp, et al, 2004).

Orbital decompression by resecting orbital fat was found to reduce

proptosis in patients with disfiguring Grave's ophthalmopathy.

(Wakelkamp, et al, 2004)

A study by Liao and Huang 2011 evaluated the correlation of retro

bulbar volume change, resected orbital fat volume, and proptosis

reduction after surgical decompression in patients with Grave's

ophthalmopathy.

Orbital irradiation, orbital decompression & glucocorticoids at 40

mg/d (usual dose) may be tried in severe or progressive disease. The

drug should be continued until evidence of improvement and disease

stability is observed. The dosage is then tapered over 4-12 weeks. High-

dose pulse glucocorticoid therapy has also been used with good results.

(Liao, et al, 2011).

Gamma knife surgery has been attempted with success in a limited

number of patients, but further studies are needed to validate this

approach. ( Dickinson, et al, 2004; Wemeau, et al. 2005 and Stan, et

al, 2006).

Surgical management is generally performed in the fibrotic phase,

when the patient is euthyroid. ( Dickinson, et al, 2004; Wemeau, et al.

2005 and Stan, et al, 2006).

Novel treatments such as somatostatin analogs or intravenous

immunoglobulins are under evaluation. Studies with octreotide LAR

(long-acting, repeatable) show conflicting or marginal therapeutic

47

benefit for patients with Grave's ophthalmopathy. ( Dickinson, et al,

2004; Wemeau, et al. 2005 and Stan, et al, 2006).

Infliximab, an anti-tumour necrosis factor alpha (TNF-α) antibody, has

been reported to successfully treat a case of sight-threatening Grave's

ophthalmopathy. (Durrani, et al, 2005).

Chronic Renal Failure and Dialysis Patients

Administered iodine that is not trapped in the thyroid gland is cleared

from the body largely by renal excretion.

Thus, the selection of a dose for I131

therapy can be a challenging

decision in patients with impaired renal function.

Holst et al 2005. reviewed the medical literature and concluded that

the I131

dose does not need to be adjusted in patients who have end-

stage renal disease and who are referred for the therapy of

hyperthyroidism.

However, they recommended I131

administration as soon as possible

after dialysis and a delay in subsequent dialysis until the maximum I131

uptake has occurred in the thyroid. (Holst, et al, 2005).

The radiation dose to the technician in the dialysis unit should be

monitored, and the patient should undergo dialysis in a private room.

(Mello, et al, 1994).

Equipment and fluid disposed from the dialysis unit should be

monitored by radiation safety personnel, but they did not find any

contamination in a patient treated for thyroid cancer (Mello, et al,

1994).

48

Care after radioactive Iodine ablation Follow-up examination at 4- to 6-week intervals is advised for patients

after the completion of radioactive iodine therapy. These checkups

should be continued until patients return to their euthyroid state and

their condition stabilizes. (Wilson, et al, 1998 and Franklyn, 1994).

Since the adverse effect of radioactive iodine therapy is permanent

hypothyroidism, patients may require lifelong thyroid hormone

replacement therapy. (Wilson, et al, 1998 and Franklyn, 1994).

Even though signs and symptoms of hypothyroidism begin to appear

3 months after the initiation of radioactive iodine therapy, thyroid

hormone replacements of levothyroxine should be initiated in the

second month of radioactive iodine therapy. (Wilson, et al, 1998 and

Franklyn, 1994).

The decision to initiate hormonal replacement should be based on

clinical evaluation and laboratory testing. This is because during the

second month of radioactive therapy, the thyroid gland quickly changes

from a euthyroid to a hypothyroid state. At this stage, the TSH level is

not a good tool to use in determining hypothyroidism, as it takes about

2 weeks to several months to recover and increase TSH concentration

in response to hypothyroidism. (Wilson, et al, 1998 and Franklyn,

1994).

During this period, free thyroid hormone estimates are more accurate

than TSH values. Once the patient’s condition stabilizes, the frequency

of clinic visits can be decreased and intervals of examination can be

extended and modified per the physician’s judgment. Usually, the

follow-up consultations are conducted every 3 months, 6 months, and

yearly. (Wilson, et al, 1998 and Franklyn, 1994).

49

PATIENT METHODS& DATA COLLECTION

• Case selection:-

The study population consisted of 200 cases with previous

thyroid gland troubles seen at Nuclear Medicine Unit (NEMROCK),

Cairo University during the period of January 2008 till December

2010.They were 120 female and 80 male.

Inclusion criteria

• Primary and secondary type of thyrotoxicosis.

• Different sex.

• Different age groups.

• Different duration of symptoms.

• Different methods& duration of treatment.

• Different responses to treatment.

-:They all were subjected to

• History taking:

Including age, sex, symptoms, duration of illness, type and

response to treatment.

• Clinical examination:-

Looking for gland size, consistency, nodularity & other neck swellings,

Eye signs examination.

50

• Laboratory investigations:-

Including T3, T4, TSH levels and antibodies.

• Neck ultrasound:-

To detect size, nodularity & other neck swellings.

• Radio –nuclear imaging :-

technetium-99m pertecnetate (Tc 99m

) thyroid scan to detect

size ,nodules , gland uptake & Radio-active iodine( I 131

)scan to

detect retrosternal extension before treatment.

• Treatment :-

Either in the form of medical treatment, surgery, or Radio-active

Iodine treatment.

• Follow up:-

By measuring T3, T4, and TSH levels recently after treatment then

after 3 months, 6 months then every year till patient becomes

euthyroid.

• Data collection

Retrospective data analysis of 200 cases of thyrotoxicosis with

primary and secondary types, age groups, sex, duration of illness,

methods of treatment and response to treatment seen at Nuclear

Medicine Unit between January 2008 to December 2010.

-:and conclude the relationship between

• Age group and type of thyrotoxicosis.

51

• Sex of patient and type of thyrotoxicosis.

• Percentage of thyroid uptake and response to Radio- active iodine

dose.

• Most predominant symptoms in each type of thyrotoxicosis.

• Thyroid hormone levels and the type of thyrotoxicosis.

• Type of treatment of each type of thyrotoxicosis.

• Response to different dose values of Radio- active iodine.

• Relationship between dose value of Radio -active iodine and onset

of hypothyroidism.

52

Statistical analysis

Statistical analysis was done using the Statistical Package of Social

Sciences (SPSS) version 17.00.

Data were assigned as parametric, nonparametric , parametric data

were analyzed using the Independent sample T test if it were two

groups, and one way analysis of variance ANOVA if more than two

groups.

Non parametric data were analyzed using the non parametric Man

Whtney U test, and Kruskal Wallis test for more than two groups.

Nominal data were analyzed using the Chi Square analysis.

Correlation analysis were conducted using the spearman correlation

coefficient where stated.

A P value of < 0.05 was considered significant in some instances, and

<0.001 in other instances.

53

RESULTS

Demographic Data

The current study included 200 patients with radio- active scanning

proven thyroid disease, 100 cases of primary type and 100 cases of

secondary type.

Their Mean ages were 39±12.33 with range (18 – 59 years).

Primary type Mean ages were 33±9.79 with range (18-50years) while

secondary Mean ages were 42±11.78 with range (25-59 years).

There was high significant difference between age and prevalence of

each type of thyrotoxicosis. P value <0.001 (0.000091).

Relationship between the different age group in each type ) 2 (Table

of thyrotoxicosis

Secondary type Primary type

Percent Number

P value

Percent Number

Age group

3% 3/100 0.001 24% 24/100 2nd

decade

11% 11/100 0.04 32% 32/100 3rd

decade

26% 26/100 0.06 36% 36/100 4th

decade

60% 60/100 0.03 8% 8/100 5th

decade

54

In the present observational part of the study there was a significant

difference in the incidence of the primary toxic goiter and the nodular

one in the second decade of life favoring the primary one at a

remarkable statistical significance of 0.001, the same was observed in

the third decade of life, nevertheless the situation is reversed in the

incidence in the fifth decade with a significance of 0.03, interestingly

there was no significant difference in the 4th

decade of life.

Figure (8) comparison between age group and percentage of cases of

each type of thyrotoxicosis

55

The study population was 120 female and 80 male patients. There

was significant difference between prevalence of each type of

thyrotoxicosis in both sex.

Primary type is more between females (66%) and males (35%) while

secondary type is more common among males (65%) and females

(34%). Non-parametric correlation coefficient of spearman (0.754).

Table (3) Relationship between sex and percentage of cases of each

type of thyrotoxicosis.

Secondary type P

value

Primary type

Percent Number Percent Number

Sex

65% 52/80 0.042 35% 28/80 Male

34% 41/120 0.046 66% 79/120 Female

figure showing sex and percentage of cases of each type of ) 9(Figure

.thyrotoxicosis

56

Concerning the impact of medical treatment on both types of

thyrotoxicosis:-

Those received medical treatment as a first line of treatment were

(76%) in primary type and (72%) in secondary type and those did not

and secondary type %) 24(received medical treatment in primary type

al treatment Frequency table of those received medic): 4( Table %)28(

in the two groups of patients

Secondary type Primary type

Percent Number Percent Number

Medical treatment

72% 72/100 76% 76/100 Receive treatment

28% 28/100 24% 24/100 Did not receive

treatment

Figure (10) Treatment frequency according to the type of

thyrotoxicosis and percentage of cases received medical treatment.

57

Concerning surgery as 2nd

line of treatment in both types of

thyrotoxicosis:-

Prevalence of surgery between patients of secondary type is 76% while

only 4 % of patient of primary type had previous surgery and 96% of

patient of primary type didn`t have surgery while only 24% of patient of

secondary type didn`t have previous surgery.

Cases with previous surgery) 5(Table

Secondary type Primary type

Percent Number Percent Number

Surgery

%76 76/100 4% 4/100 Had previous

surgery

%24 24/100 96% 96/100 Did not have

previous surgery

thyrotoxicosis and percentage of cases with previous ) 11(Figure

.surgery

58

The most common symptoms were palpitation, tachycardia, loss of

weight, tremors, nervousness, heat intolerance and neck swelling.

The most common symptoms in Graves' disease were tachycardia,

anxiety, loss of weight, tremors, heat intolerance and neck swelling.

The most common symptoms in Toxic nodular type were tachycardia,

palpitation and dyspnea.

Table (6) shows the predominant symptoms in each type of

thyrotoxicosis

The most common symptoms Type of

thyrotoxicosis

Tachycardia, anxiety, loss of weight,

tremors, heat intolerance and neck

swelling.

Graves' disease

Tachycardia, palpitation and dyspnea Toxic nodular type

59

TSH, T3, T4 levels were estimated with their reference ranges:-

TSH: 0.5- 5 mIU/L

T3: 60- 181 ng/mL

T4: 5.5- 12.3 ng/mL

.Relation between TSH level and type of thyrotoxicosis) 7(Table

Toxic multi-nodular type Grave' disease

Percent Mean& SD Number

P Vale

Percent Mean&SD Number

TSH Level

normal range

0.5-5)mIU/L)

30% 0.035±0.012 30/100 <0.05 68% 0.025±0.0032 68/100 0.05– 0.01

49% 0.091±0.001 49/100 <0.05 24% 0.073±0.013 24/100 0.06 - 0.1

21% 0.142±0.058 21/100 0.06 8% 0.123±0.031 8/100 0.11- 0.15

Graves' disease showed more statistically values of higher number of

cases in the first range (0.01 – 0.05) and Toxic multinodular type is higher

in the second range (0.06 – 0.1) stated in the table above however it

did not show any statistical difference in the third range (0.11-0.15)

mIU/L.

60

Table (8) Relation between T3 levels and type of thyrotoxicosis.

Toxic multinodular type Graves' disease

Percent MEAN&SD Number

P VALUE

Percent MEAN&SD Number

normal T3

Level range

(60- 181

ng/mL

30% 3.9±0.8 30/100 <0.001 5% 5.2± 0.6 5/100 185- 250

ng/ml

46% 6.77±O.78 46/100 0.071 33% 7.8±1.31 33/100 250-350

ng/ml

24% 11.91±0.42 24/100 0.05< 62% 14.7±2.38 62/100 >350 ng/ml

Toxic nodular goiter showed more predilictions to have higher number

of cases in the first ranges (185-250)ng/ml however Graves’ showed

higher number of cases in the third range(>350ng/ml), these results are

statistically significant. While the middle range(250-350ng/ml) did not

show statistical significant difference.

Table (9) Relation between T4 levels and type of thyrotoxicosis

Toxic multinodular type Graves' disease

Percent MEAN&SD Number

P

VALUE Percent MEAN&SD Number

T4 level

normal

range (5.5-

12.3

ng/mL)

28% 180.71±21.18 28/100 <0.001 11% 237.31±31.71 11/100 15- 25ng/dl

47% 299.37±23.11 47/100 >0.05 35% 278.11±29.72 35/100 26-40ng/dl

25% 289.23±29.18 25/100 0.05< 54% 398.11±38.33 54/100 >40ng/dl

61

Toxic multinodular goiter rendered higher number of cases in the

range of 15- 25ng/dl, on the contrary Graves' showed higher number of

cases in the > 40ng/dl group, both were statistically significant. Results

of the middle range 26-40ng/dl did not show significant difference

between the two diseases.

Thyroid gland uptake was estimated for all cases with normal

reference range = (0.5-4) %.

show the relation between the percent of thyroid gland) 10(Table

active iodine treatment-uptake and the response to radio

Response to radio-active iodine treatment.

P Value Hypothyroid Toxic Euthyroid

Percent Number Percent Number Percent Number

Percent of

thyroid

uptake(scan)

Normal

(0.5-4)%

<0.001 8% 4/45 67% 30/45 25% 11/45 4-10%

<0.05 36% 25/70 14% 10/70 50% 35/70 10-20%

0.04 51% 43/85 15% 13/85 34% 29/85 >20%

The relationship between thyroid uptake and response to radioactive

iodine treatment was noted here, as for the 4-10% uptake, there was a

significant difference with higher predilection of the toxic variant to

have higher response of about 67%. Thyroid uptake range 10-20%

showed a significant difference with higher predilection of the euthyroid

62

variant. Thyroid uptake range >20% showed a significant difference

with higher predilection of the hypothyroid variant.

In patient of primary type 40 patients received Radio-active Iodine

dose equal 12mci:- 18 patients became normal (45%), 15 patients

remained toxic (37%) while 7 patients turned hypothyroid (18%).

35 patients received Radio-active Iodine dose equal 15mci:- 23

patients (66%) of patients became normal, 6 patients (16%) remained

toxic & 6 patients (16%) turned hypothyroid with predominance of

normal thyroid outcome.

25 patients received Radio-active Iodine dose equal 20mci:-

3 patients (12%) became normal, 22 patients (88%) turned hypothyroid

with predominance of hypothyroid outcome.

Table (11) Relationship between response of primary type to different

dose values of radio-active iodine during2 years of follow up.

Euthyroid Toxic Hypothyroid Dose

Number Percent Number Percent Number Percent

P Value

12mci 18/40 45% 15/40 37% 7/40 18% 0.04

15mci 23/35 66% 6/35 16% 6/35 16% 0.03

20mci 3/25 12% 0% 22/25 88% <0.001

Different dose values of radioactive iodine has different impact on the

thyroid gland function, it was studied here briefly showing that at a

dose of 12mci; although there was no statistical significance between

the response of euthyroid and toxic state, but the value of 45% as

regard to the euthyroid state does count on clinical ground, it can be

noted here that sole reliance on statistical values should be

accompanied by clinical background, as for the higher doses of the

63

radioactive iodine they were significant difference between the

response to radio-active iodine dose equal to 15mci towards the

euthyroid variant while the statistical significant difference of the

response to radio-active iodine dose equal to 20mci was towards the

hypothyroid variant.

Figure (12) Relationship between response of primary type and dose

value of radio-active iodine.

35 patients of secondary type thyrotoxicosis received radio-active

iodine dose equal 20mci:- 10 patients (28%) became normal, 13

patients (37%) remained toxic and 12 patients (34%) turned

hypothyroid with no statistical significant difference in response.

45 patients of secondary type thyrotoxicosis received radio-active

iodine dose equal 25mci:- 22 patients (49%) became normal, 14

64

patients (31%) remained toxic and 9 patients (20%) turned hypothyroid

with predominance of euthyroid outcome.

20 patients of secondary type thyrotoxicosis received radio-active

iodine dose equal 29mci:- 10 patients (50%) became normal, 2 patients

(10%) remained toxic and 8 patients (40%) turned hypothyroid.

Higher doses in the multinodular goitre showed significant difference

only in the 25 & 29 mci range towards the euthyroid response.

Table (12) Response of secondary type thyrotoxicosis and different

dose values of radio-active iodine.

Euthyroid Toxic Hypothyroid P Value Dose

Number Percent Number Percent Number Percent

20mci 10/35 28% 13/35 37% 12/35 34% 0.06

25mci 22/45 49% 14/45 31% 9/45 20% 0.04

29mci 10/20 50% 2/20 10% 8/20 40% 0.03

65

Figure(13) Secondary type response and dose value of radio-active

iodine.

Out of 200 patient of the study population 184 (92%) received one

dose of radio-active iodine treatment while only 16 patient (8%)

received more than one dose of radio-active iodine.

Percentage of cases received one or more than one dose of ) 13(Table

active iodine-radio

One dose of radio-active

iodine

More than one dose of radio-

active iodine

Number Percent Number Percent

184/200 92% 16/200 8%

66

active -Percent of cases received one or more dose of radio) 14(Figure

.iodine

Patients turned hypothyroid after radio-active iodine treatment

during 2 years follow up period were:-

7 patients received radio-active iodine of 12mci:- 1 patient (14%)

developed hypothyroid after 6 month, 2 patients (29%) developed

hypothyroid after 12 months& 4 patients (57%) developed hypothyroid

after more than 12 months.

6 patients received radio-active iodine of 15 mci:-1 patient (17%)

developed hypothyroid after 6 month, 2 patients (33%) developed

hypothyroid after 12 months& 3 patients (50%) developed hypothyroid

after more than 12 months.

34 patients received radio-active iodine of 20mci:- 13 patients (38%)

developed hypothyroid after 6 month, 8 patients (24%) developed

67

hypothyroid after 12 months& 13 patients (38%) developed

hypothyroid after more than 12 months.

9 patients received radio-active iodine of 25mci:- 4 patients (44%)

developed hypothyroid after 6 month, 2 patients (22%) developed

hypothyroid after 12 months& 3 patients (33%) developed hypothyroid

after more than 12 months.

8 patients received radio-active iodine of 29 mci: - 4 patients (50%)

developed hypothyroid after 6 month, 3 patients (38%) developed

hypothyroid after 12 months& 1 patient (12%) developed hypothyroid

after more than 12 months.

Table (14) Relationship between the dose value of radio-active iodine

and the onset of hypothyroidism

6 months 12 months More than 12 months Dose

Number Percent Number Percent Number Percent

P

value

12mci 1/7

14% 2/7 29% 4/7 57% 0.04

mci15 1/6 17% 2/6 33% 3/6 50% 0.05

20mci 13/34 38% 8/34 24% 13/34 38% 0.07

25mci 9/4 44% 2/9 22% 3/9 33% 0.05

29mci 4/8 50% 3/8 38% 1/8 12% 0.04

Onset of hypothyroidism following radioactive treatment is well known

and follow up is required to determine which dose render the least

iatrogenic complication. There were statistical significant differences in

the incidance of hypothyroidism after 6 months of the treating radio-

68

active iodine doses equal to 25mci& 29mci (44% & 50%)

respectivly.20mci showed no statistical significant difference in the 2

years follow up period Pvalue=0.07(>0.05).There were statistical

significant differences in the incidance of hypothyroidism after more

than 12 months of the treating radio-active iodine doses equal to

12mci& 15mci (57% & 50%) respectivly.

However the 12 mci was higher and statistically more significant than

15mci that seems confusing.

Figure (15) Relationship between onset of hypothyroidism and dose

value of radio-active iodine.

69

Discussion

The current study included 200 patients with laboratory data and

radio- active scanning proven thyrotoxic, 100 cases of primary type and

100 cases of secondary type. Their Mean ages were 39 ± 12.33 with

range (18 – 59 years).

Primary type Mean ages were 33± 9.79 with range (18-50) while

secondary type Mean ages were 42±11.78 with range (25-59 years).

There was high significant difference between age and prevalence of

each type of thyrotoxicosis. (P value < 0.001(0.000091)).

In the present observational part of the study there was a significant

difference in the incidence of the primary toxic goiter and the nodular

one in the second decade of life favoring the primary one at a

remarkable statistical significance of 0.001, the same was observed in

the third decade of life, nevertheless the situation is reversed in the

incidence in the fifth decade with a significance of 0.03, interestingly

there was no significant difference in the 4th

decade of life.

The peak age-specific incidence of Graves' disease was between 20

and 49 years in two studies, (Zimmerman, 2009).

The incidence of thyrotoxicosis increased with age, and women were

affected two to eight times more than men across the age range.

Recent further analysis suggested that the incidence of thyrotoxicosis

was increasing in women but not in men between 1997 and 2001.

(Leese, et al, 2008).

The study population was 120 female and 80 male patients; Primary

type is more between females (66%) and males (35%) while secondary

70

type is more common among males (65%) and females (34%). Non-

parametric correlation coefficient of spearman (0.754)

Women have a higher reported incidence of Graves’ disease than

men, with a female to male incidence ratio of approximately 7:1 to 10:1

as confirmed by (Nayak and Hodak, 2007).

According to (Basaria and Salvatori, 2004), toxic nodular goiter

occurs more commonly in women than men. In women and men older

than 40 years the prevalence rate of palpable nodules is 5-7% and 1-2%

respectively.

Patients of both types of thyrotoxicosis received medical treatment

in the form of anti-thyroid medications as first line of treatment for

period ranged from 3 months to more than 1 year before asking for

other lines of treatment were 76% of primary type and 72% of

secondary type while only 24% of primary type and 28% of secondary

type did not receive medical treatment.

As confirmed in (Zweig, et al, 2006), maintenance doses of 5–10 mg of

methimazole or 50–100 mg of propylthiouracil twice daily keep most

patients euthyroid. For patients who cannot take medications by

mouth, propylthiouracil has been administered rectally.

koornstra, et al,(1999). see that Antithyroid medication has a

significant role in rendering patients euthyroid before treatment with

I131

or thyroidectomy.

Alexander, et al, (2002). treated 261 patients with hyperthyroidism

caused by Graves’ disease with I131

[mean dose, 14.6 mCi (540 MBq)].

Patients pretreated with antithyroid medication for greater than 4

months were at higher risk for treatment failure.

On the other hand, Braga, et al. demonstrated that methimazole

pretreatment has no effect on the final result, the time required for

71

cure, or the 1-year success rate of I131

therapy. (Braga, et al, 2002 and

Andrade, et al , 2001).

In contrast, Ahmad, et al, (2002). demonstrated that the frequency of

hypothyroidism was lower in patients treated with antithyroid drugs

prior to RAI compared with patients who did not received antithyroid

drugs. Ahmed et al 2002. studied risk factors that allow estimates of

the probability of developing hypothyroidism following radioactive

iodine treatment.

Concerning surgery as line of treatment in both types of

thyrotoxicosis prevalence of surgery between patients as 2nd

line of

treatment are more in multi-nodular patients76% than in diffuse type

4% .while 96% of cases of diffuse type and 24% of multi-nodular

patients did not have previous surgery.

Some surgeons promote thyroidectomy as the treatment of choice for

Graves’ disease (Lal, et al, 2005). However, at present very few patients

with uncomplicated Graves’ disease are treated by surgery, as

confirmed by (Wartofsky, et al, 1991).

Lal, et al, (2005). reported on 103 surgical patients for whom the

indications were patient preference (26%), cold nodule (24%), eye

symptoms (20%), large goiter size (18%), allergy to anti-thyroid

medications (15%), and young age (14%) .

In another series, eye involvement was also used as an indication for

thyroidectomy, and there was improvement in 130 of 500 patients

(Bhansali and Chandalia, 2002).

The most common symptoms were palpitation, Tachycardia, loss of

weight, tremors, nervousness, heat intolerance, thyroid opthalmopathy

and neck swelling.

72

Tachycardia, anxiety, loss of weight, tremors, heat intolerance, thyroid

opthalmopathy and neck swelling were common in patients of Graves'

disease while tachycardia, palpitation and dyspnea were the

predominant in Toxic nodular type.

Tachycardia is the most common cardiovascular sign of

thyrotoxicosis. Thyrotoxic patients may also experience palpitations

attributable to increased force of cardiac contraction. (Larsen, et al,

2002).

Apathetic hyperthyroidism is a common presentation in the elderly

and is characterized by weight loss, weakness, palpitations, dizziness, or

memory loss and physical findings of sinus tachycardia or atrial

fibrillation. (Dabon-Almirante, et al, 1998).

Thyrotoxicosis causes neuropsychiatric changes resulting in

restlessness, agitation, anxiety, emotional liability, psychosis, and even

coma. (Wartofsky, 2005).

The clinical presentation of the thyrotoxicosis of TMNG is usually mild.

Because of the presentation in older age groups, however, TMNG often

presents with cardiovascular manifestations of thyrotoxicosis, such as

palpitations, tachycardia, and atrial fibrillation. (Larsen, et al, 2002).

Graves' disease showed more statistically values of number of cases in

the first range (0.01 – 0.05) and Toxic multinodular type is higher number

of cases in the second range (0.06 – 0.1) however it did not show any

statistical difference in the third range (0.11-0.15) mIU/L.

Toxic nodular goiter showed more predilections to have higher

number of cases in the first range (185- 250 ng/ml) however Graves'

showed higher number of cases in the third range(>350 ng/ml), these

results are statistically significant. while the middle range (250-350

ng/ml) did not show statistical significant difference.

73

Toxic multinodular goiter rendered higher number of cases in the

range of 15- 25ng/dl, on the contrary Graves' showed higher number of

cases in the range > 40ng/dl group, both were statistically significant.

Results of the middle range 26-40ng/dl did not show significant

difference between the two diseases.

Low TSH level accompanied by raised free T3& T4 levels, indicates

primary hyperthyroidism, most commonly caused by Grave's disease,

multinodular goiter, or toxic adenoma. In these cases clinical criteria

can usually separate the three common causes of primary

hyperthyroidism. (Coles, et al, 1999).

Thyroid opthalmopathy and diffuse thyroid uptake of thyroid scanning

make the diagnosis of Graves' disease likely. (Coles, et al, 1999).

Low TSH, normal free T3& T4 are usually seen in thyroxin ingestion or

in subclinical primary hyperthyroidism, typically seen in elderly people.

Further investigations reavels multinodular goiter. (Ross, 1994).

The relationship between thyroid uptake and response to radioactive

iodine treatment: for the 4-10% uptake, there was a significant

difference with higher predilection of the toxic variant.Thyroid uptake

range 10-20% showed a significant difference with higher predilection

of the euthyroid variant. Thyroid uptake range >20% showed a

significant difference with higher predilection of the hypothyroid

variant.

Most dosimetric methods have the benefit of including a measure of

thyroid size in their formulas, thereby administering a dose of RAI

proportional to size of the gland. This theoretically increases the

74

probability of cure. In addition, the use of isotope uptake

measurements, as part of the dose calculation protocol, can confirm

the absence of thyroiditis and identify patients with extremes of

isotope uptake or turnover, which may predict failure of RAI treatment.

(Meier, et al, 2001).

Different dose values of radioactive iodine has different impact on

the thyroid gland function, showing that at a dose of 12mci; although

there was no statistical significance between the response of euthyroid

and toxic state, but the value of 45% as regard to the euthyroid state

does count on clinical ground, it can be noted here that sole reliance on

statistical values should be accompanied by clinical background, as for

the higher doses of the radioactive iodine they were significant

difference between the response to radio-active iodine dose equal to

15mci towards the euthyroid variant, while the statistical significant

difference of the response to radio-active iodine dose equal to 20mci

was towards the hypothyroid variant.

Leslie, et al, (2003). studied 88 patients with Graves’ hyperthyroidism

who had not previously been treated with radioactive iodine. The

patients were randomized to one of four dose-calculation methods:

low-fixed, 235 MBq (6mci); high-fixed, 350 MBq (9mci); low-adjusted,

2.96 MBq (80uCi)/g thyroid adjusted for 24 h RAI uptake; and high-

adjusted, 4.44 MBq (120uCi)/g thyroid adjusted for 24-hour RAI uptake.

Subjects were followed for a mean of 63 months to assess clinical

outcomes. Mean treatment doses were similar in the different outcome

groups.

Leslie, et al, (2003).. could not demonstrate any advantage to using

an adjusted dose method. Survival analysis did not demonstrate any

75

difference in the time to outcome between the fixed and adjusted dose

methods .

Mazzaferri, et al, (2001). in their study on 813 hyperthyroid patients,

divided them into two groups. The first group received 185 MBq(5 mci),

and the second group received 370 MBq (10 mci). At the end of their

study period, the first group had an incidence of hypothyroidism of

41.3%, and the second group had an incidence of 60.8 %.

35 patients of secondary type thyrotoxicosis received radio-active

iodine dose equal 20mci:- 10 patients (28%) became normal, 13

patients (37%) remained toxic and 12 patients (34%) turned

hypothyroid with no statistical significant difference in response.

45 patients of secondary type thyrotoxicosis received radio-active

iodine dose equal 25mci:- 22 patients (49%) became normal, 14

patients (31%) remained toxic and 9 patients (20%) turned hypothyroid

with predominance of euthyroid outcome.

20 patients of secondary type thyrotoxicosis received radio-active

iodine dose equal 29mci:- 10 patients (50%) became normal, 2 patients

(10%) remained toxic and 8 patients (40%) turned hypothyroid.

Higher doses in the multinodular goitre showed significant difference

only in the 25 & 29 mci range towards the euthyroid response.

In 1 study (7- 15mci) were administered to patients of toxic nodular

goiter; 92% of 146 patients became euthyroid within 3 months, and

97% became euthyroid at 1 year. 3% became clinically or biochemically

hypothyroid. (Giovanella, et al, 2000).

A similar study of 130 patients also found that 92% were cured, but a

high proportion needed a second treatment. (Nygaard, et al, 1999).

76

In the population study 100 case of primary type of thyrotoxicosis

were followed up for one year after the first dose of radio-active iodine

treatment. 92% of cases became euthyroid or turned hypothyroid thus

no more doses of radio-active iodine is needed. While only 8% of cases

remained toxic and asked for second dose of radio-active iodine.

Retrospective review of I131

for thyrotoxicosis at Waikato Hospital,

during the 3 year period prior to 1 December 2010.

Results: A total of 326 doses of I131 were given to 285 patients. Follow

up data were available on 283 patients. Median follow-up was 2.3 years

. The diagnosis was GD for 61.1% and TMNG for 34.3%. Most patients

(98.2%) received a fixed dose of 15mci I131. At last follow up cure had

been achieved in 72.1% after the first dose. ( Allahabadia, et al,2001;

Allahabadia, et al,2000; Metso, et al, 2004 and Boelaert, et al, 2009).

Onset of hypothyroidism following radioactive treatment is well

known and follow up is required to determine which dose render the

least iatrogenic complication. There were statistical significant

differences in the incidance of hypothyroidism after 6 months of the

treating radio-active iodine doses equal to 25mci& 29mci (44% & 50%)

respectivly. 20mci showed no statistical significant difference in the 2

years follow up period (P value >0.05). There were statistical significant

differences in the incidance of hypothyroidism after 12 months of the

treating radio-active iodine doses equal to 12mci& 15mci (57% & 50%)

respectivly.

About 20% of all cases treated with radio-active iodine I131

became

hypothyroid after one year of treatment on further follow up

investigations.

77

Howarth, et al, (2001). compared low radiation doses to the thyroid

(60 vs. 90 Gy), trying to minimize the number of patients requiring

thyroid hormone replacement after I131

therapy .Euthyroidism was

achieved in 46% of the patients and 47% were rendered hypothyroid at

the final follow-up 3 years.

A dose of 60 Gy yielded a 39% response rate at 6 months while

minimizing early hypothyroidism, but no significant advantage in the

response rate was gained with a dose of 90 Gy. For a more rapid

therapeutic effect, the authors recommended doses in excess of 120

Gy, recognizing that there will be an increased rate of hypothyroidism.

Ceccarelli, et al, (2005). administered 7.4 MBq (200 uCi) of I131

per

gram corrected for uptake. As a single dose had a success rate of 94%,

and60% of their patients were hypothyroid by 20 years.

By comparison, (Ahmad, et al, 2002).reported that the cumulative

incidence of hypothyroidism following RAI treatment was 38.2% after 6

months. The incidence increased to 55.8% after 1 year and to 86.1% at

10 years.

78

:Conclusion

There are two main types of thyrotoxicosis : primary diffuse toxic

type and secondary multinodular type

There was significant difference between age and prevalence of each

type of thyrotoxicosis. P value < 0.001

Primary type Mean ages were 33 ± 9.79 with range (18-50) while

secondary Mean ages were 42 ±11.78with range (25-59 years).

Primary type is more between females (66%) than males (35%) while

secondary type is more common among males (65%) than females

(34%). Non-parametric correlation coefficient of spearman (0.754)

The most common symptoms were palpitation, Tachycardia, loss of

weight, tremors, nervousness, heat intolerance and neck swelling.

Thyroid hormones levels are higher in primary type than secondary

type thyrotoxicosis with no overall significant difference.

Graves' disease show higher percent of thyroid uptake affecting the

response to radio-active iodine treatment clinically but not in the point

of view of statistical significance.

Most patients prefer medical treatment in the form of symptoms

relief and anti-thyroid medications as first line of treatment before

asking for surgery or radio-active iodine treatment.

On other hand more patients avoid the risk of surgery as a line of

treatment in primary type while physicians prefer surgery as a line of

treatment of toxic nodular type.

79

Radio-active iodine treatment has a very important role in

treatment of both types of thyrotoxicosis and many patients prefer it as

a main line of treatment.

Doses of Radio-active iodine varies according to type of

thyrotoxicosis, size of the gland, level of thyroid hormones, percent of

gland uptake and even the general conditions of the patient.

Radio-active iodine is safe, effective in both types of thyrotoxicosis,

its effect appears shortly after the first dose and very small percent

need a second dose.

Single high dose of radio-active iodine is better to avoid the risk of

re-exposure to second dose.

Different dose values of radioactive iodine has different impact on the

thyroid gland function, it was studied here briefly showing that at a

dose of 12mci; although there was no statistical significance between

the response of euthyroid and toxic state, but the value of 45% as

regard to the euthyroid state does count on clinical ground.

Higher doses in the multinodular goitre showed significant

difference of response only in the 25 & 29 mci range.

Hypothyroidism is a common outcome after radio-active iodine

treatment that should be considered. Hypothyroidism should be

diagnosed clinically and biochemically and thyroxin replacement

therapy should be started once the diagnosis is confirmed.

Onset of hypothyroidism following radioactive treatment is well

known and follow up is required to determine which dose render the

least iatrogenic complication. There were statistical significant

differences in the incidance of hypothyroidism after 6 months of the

80

treating radio-active iodine doses equal to 25mci& 29mci (44% & 50%)

respectivly. Twenty (20mci) showed no statistical significant difference

in the 2 years follow up period (P value >0.05). There were statistical

significant differences in the incidance of hypothyroidism after 12

months of the treating radio-active iodine doses equal to 12mci& 15mci

(57% & 50%) respectivly.

81

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