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
درا ر ت ز دة ا از ا ة ا ر ا ددة
و ة ا ا وى
ل ا ا وى
درا
ا / أ ة ه ه ا
ا اف
أ.د / ا اه ا اد
أ ذ ا ورام وا ا وى
آ ا – ا ه ة
د / ن أ
رس ا ا وى
آ ا - ا ه ة
آ ا - ا ه ة
٢٠١3
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
I
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
II
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
III
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
IV
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 10 10 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.
V
H
HCG : Human Chorionic Gonadotropin.
I
123 I : Radioactive Iodine isotope 123.
131 I : 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.
VI
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.
99m Tc : 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
-6 uci=1x10 ci
VII
U.K: United Kingdom.
U.S: United States.
VIII
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).
1
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 T 3 and T 4. It is caused by uncontrolled excessive production of T 3 and T 4 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 T 4 level. (Dabon- Almirante, et al, 1998 and Ladenson, 2005).
The levels of T 3 and T 4 should subsequently be assessed. (Braverman, et al, 2005).
2
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
3 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.
4
Hyperthyroidism Introduction Thyrotoxicosis is the hyper metabolic condition associated with elevated levels of free thyroxine (FT 4) and/or free triiodo -thyronine (FT 3) 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) .
5
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).
6
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).
7
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 ).
8
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).
9
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 T 3 and T 4. It is caused by uncontrolled excessive production of T3 and T 4 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
10
(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).
11
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).
12
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).
13
TABLE 1 lists clinical manifestations of hyperthyroidism. (Reid and Wheeler,2005 and Baskin, et al, 2002).
14
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).
15
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 ).
16
(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 I 123 or I 131 . (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).
17
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
18 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).
19
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).
20
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).
Ad vantages of technetium 99- m pertechnetate : • 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).
Advantages of radio - active iodine :
• 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).
21
Figure (4) Tc 99m 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.
22
Figure (6) Tc 99m 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.
23
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).
24
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).
25
Differential Diagnosis of Hyperthyroidism Graves’ disease there is cases where in elevated levels of free thyroid hormones (T 3 and T 4) despite a normal-sized thyroid gland. There are also circumstances wherein patients would only develop T 3 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).
26
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).
27
Treatment of thyrotoxicosis
Treatment of Graves ’ Disease
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).
28
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 I 131 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).
29
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 I 131 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 I 131 .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).
30
TREATMENT WITH RADIO A- CTIVE IODINE
There has never been any debate that the goal of I 131 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 I 131 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
31
(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.
131 I administerated dose =
24 hour % RAIU
Equation (1) calculation of I 131 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 I 131 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
32
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 I 131 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).
33
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 I 131 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 I 131 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).
34
I 131 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 I 131 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 I 123 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).
35
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 I 131 . 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).
36
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 131 of I . ( 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 ).
37
Side effects and complications of radio-active iodine I 131 treatment and how to overcome:-
Acute radiation thyroiditis Is very rare after I 131 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).
38
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 I 131 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).
39
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 I 131 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 I 131 . (Sisson, et al, 2001).
40
LITHIUM AS ADJUVANT TO I 131
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 I 131 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 I 131 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).
41
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 I 131 treatment in pediatric patients (Rivkees, 2003).
Several authorities have promoted the administration of I 131 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
42 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).
43
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.
44
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).
45
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
46 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 I 131 therapy can be a challenging decision in patients with impaired renal function. Holst et al 2005 . reviewed the medical literature and concluded that the I 131 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 I 131 administration as soon as possible after dialysis and a delay in subsequent dialysis until the maximum I 131 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).
47
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).
48
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.
49
• 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.
50
• 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.
51
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.
52
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).
Table (2 ) Relationship between the different age group in each type of thyrotoxicosis
Secondary type P value Primary type Age group
Percent Number Percent Number
nd 3% 3/100 0.001 24% 24/100 2 decade
rd 11% 11/100 0.04 32% 32/100 3 decade
th 26% 26/100 0.06 36% 36/100 4 decade
th 60% 60/100 0.03 8% 8/100 5 decade
53
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 4 th decade of life.
Figure (8) comparison between age group and percentage of cases of each type of thyrotoxicosis
54
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 Primary type Sex value Percent Number Percent Number 65% 52/80 0.042 35% 28/80 Male
34% 41/120 0.046 66% 79/120 Female
Figure 9( ) figure showing sex and percentage of cases of each type of thyrotoxicosis .
55
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 received medical treatment in primary type 24( %) and secondary type 28( %) Table ( 4): Frequency table of those received medic al treatment in the two groups of patients
Secondary type Primary type Medical treatment Percent Number Percent Number 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.
56
Concerning surgery as 2 nd 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.
Table 5( ) Cases with previous surgery
Secondary type Primary type Surgery Percent Number Percent Number %76 76/100 4% 4/100 Had previous surgery %24 24/100 96% 96/100 Did not have previous surgery
Figure 11( ) thyrotoxicosis and percentage of cases with previous surgery .
57
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 Graves' disease swelling.
Tachycardia, palpitation and dyspnea Toxic nodular type
58
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
Table 7( ) Relation between TSH level and type of thyrotoxicosis .
Toxic multi-nodular type P Vale Grave' disease TSH Level normal range Percent Mean& SD Number Percent Mean&SD Number 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.
59
Table (8) Relation between T3 levels and type of thyrotoxicosis.
Toxic multinodular type P VALUE Graves' disease normal T3 Level range Percent MEAN&SD Number Percent MEAN&SD Number (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 P Graves' disease T4 level VALUE normal Percent MEAN&SD Number Percent MEAN&SD Number 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
60
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) %.
Table 10( ) show the relation between the percent of thyroid gland uptake and the response to radio -active iodine treatment
Response to radio-active iodine treatment . Percent of thyroid P Value Hypothyroid Toxic Euthyroid uptake(scan)
Normal
Percent Number Percent Number Percent Number (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
61 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. Dose Euthyroid Toxic Hypothyroid P Value
Number Percent Number Percent Number Percent 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
62 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
63 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.
Dose Euthyroid Toxic Hypothyroid P Value
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
64
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.
Table 13( ) Percentage of cases received one or more than one dose of radio -active iodine
One dose of radio-active More than one dose of radio- iodine active iodine Number Percent Number Percent
184/200 92% 16/200 8%
65
Figure 14( ) Percent of cases received one or more dose of radio -active 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
66 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
Dose 6 months 12 months More than 12 months P
Number Percent Number Percent Number Percent 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-
67 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 .
68
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 4 th 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
69 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 I 131 [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
70 cure, or the 1-year success rate of I 131 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 2 nd 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.
71
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/m l), these results are statistically significant. while the middle range (250-350 ng/ml) did not show statistical significant difference.
72
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
73 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
74 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).
75
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 I 131 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 I 131 became hypothyroid after one year of treatment on further follow up investigations.
76
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 I 131 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 I 131 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.
77
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 ±11.78 with 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.
78
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
79 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.
80
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