UNIVERSITY OF SANTO TOMAS

FACULTY OF MEDICINE AND SURGERY

CLINICAL EPIDEMIOLOGY 3

Presentation Date:
November 6, 2014

Jo Michael Maniwan, Arrachaine Dior Manlapaz, Kristine Manuel, Levy

Jo Manuntag, Mary Angela Manzano, Claudine Maranan, Angelo
Marasigan, Kaiziel Marasigan, Katrina Maravilla, Mark Maranon,
Theresa Marcelo, Jorelle Marquez, Leya Imanuelle Martin, Rafael
Martires, Patricia Masangkay, Janice Matias, Aron Janelle Matic,
Charlicia Mc David, Michi Mejia, Miggo Mejico, Charles Mendez,
Jayvee Mendiola, Daniel Mendoza

1
TABLE OF CONTENTS

INTRODUCTION...3
Clinical Scenario.....3
Salient Features......3
Clinical Impression.....3
Differential Diagnosis.....4
Spectrum of Disease Diagram......5

CRITICAL APPRAISAL ON DIAGNOSIS....8

Clinical Question.....8
Search Strategy...8
Critical Appraisal Proper..15
Results....16
Resolution......18

CRITICAL APPRAISAL ON THERAPY.....19

Clinical Question...19
Search Strategy....19
Critical Appraisal Proper...24
Actual Results....27
Analysis Results....29
Resolution......32

CRITICAL APPRAISAL ON HARM....33

Clinical Question...33
Search Strategy....33
Critical Appraisal Proper..37
Results....38
Resolution......41

CRITICAL APPRAISAL ON PROGNOSIS....42

Clinical Question...42
Search Strategy....42
Critical Appraisal Proper......47
Results....48
Resolution......53

SUMMARY......53

APPENDIX

2
 INTRODUCTION

CLINICAL SCENARIO

A 36 year old female was admitted with an anterior neck mass, which she first noticed years
ago, and which progressively grew in size, up to the present. One year ago, she had easy fatigability,
palpitations and weight loss - all of which were relieved by medications. PPE PR = 90/min, RR = 20/min,
Temp = 37oC. The left-sided anterior neck mass is 12 X 10 X 10 cm. multilobulated, firm and moves with
deglutition.

SALIENT FEATURES

The subjective salient features of this case include the patients age (36 years old) and gender
(female). Other salient features include the patients verbalizations of fatigability, palpitation and weigh
loss - all of which were relieved by medication a year ago. Objective salient features include the
patients vital signs, and the presence of an anterior neck mass measuring 12x10x10 cm, multilobulated,
firm, and moves with deglutition.

CLINICAL IMPRESSION

Toxic Nodular Goiter

In our clinical scenario, we are presented with a 36 year old female with a progressively growing
left anterior neck mass with symptoms of hyperthyroidism or thyrotoxicosis: easy fatigability, weight
loss and palpitations. Other common symptoms of hyperthyroidism include hyperactivity, heat
intolerance and sweating; signs include tachycardia, tremors, warm moist skin, and muscle weakness.
Regarding the anterior neck mass, it is relatively large, multilobulated, firm in consistency, and moves
with deglutition.

A toxic nodular goiter, or toxic adenoma, presents as a thyroid gland that contains
autonomously functioning thyroid nodules that result in hyperthyroidism. This condition occurs more
commonly in women aged 20-40 years old, and is commonly secondary to iodine deficiency or, less
commonly, acquired somatic activating mutations in the TSH-R. Morphologically, this condition
produces a multilobulated mass with asymmetrically enlarged glands and may involve one lobe far more
than the other. Clinically, patients with this condition present with subclinical hyperthyroidism or mild
thyrotoxicosis. Collectively, the presence of hyperthyroidism, a nodular goiter, and the absence of
ophthalmopathy and dermopathy (as seen in Graves disease) is known as Plummer syndrome. In
addition to gross cosmetic effects, this enlarging mass may produce airway obstruction, dysphagia and
compression of large vessels in the neck and thorax thus prompting medical and surgical interventions
for these patients.

3
DIFFERENTIAL DIAGNOSES:

Papillary Thyroid Carcinoma

We present papillary thyroid carcinoma as a differential diagnosis to our case because our
patient presents with a left mass which is described as painless and moves with deglutition.
Consequently, these are some of the presenting signs of a thyroid carcinoma.

Approximately 74-80% of the thyroid cancers diagnosed each year is of the papillary type,
making it the most common type. It is usually diagnosed in women aged 30-50 years old. This data
applies to our patient as she is female and 36 years old.

The most common presentation of thyroid cancer is as an asymptomatic thyroid mass or a

nodule that can be felt in the neck. The nodule is commonly palpable, firm, non-tender and painless. In
our case the patient noticed an anterior multilobulated neck mass a year ago accompanied by symptoms
of easy fatigability, palpitations and weight loss. In papillary thyroid cancer, the nodule is fixed in its
location, with respect to surrounding tissues. It also moves with the trachea during swallowing. All of
these are consistent with the patients symptoms. Patients with thyroid carcinoma may also experience
easy fatigability, weight loss and lack of energy, which is consistent with the patients symptoms.

Although the patient has symptoms of thyroid cancer, it can be discounted in this case since
patients with papillary thyroid cancers usually have a tight or full feeling in the neck, hoarseness, or
signs of tracheal or esophageal compression. nodules in thyroid cancers are commonly observed to
have an average size of less than 5 cm along with an ill-defined border. The patients thyroid mass
measures 12x10x10 cm, with no signs of tracheal or esophageal compression such as a lump on the
throat sensation, hoarseness and difficulty in swallowing. Also, due to limited information, a positive
family history of thyroid cancer and previous exposure to radiation cannot be evaluated.

Nontoxic Nodular Goiter

This condition can be considered in this case due to its prevalence, since it is the most common
type of thyroid enlargement. Also, we can rule in the said disease, based on the presentation of the neck
mass. In this case, it was described as a 12x10x10 cm firm, left, anterior neck mass that has been
progressively growing for many years. A nontoxic goiter can be diffuse or nodular enlargement of the
thyroid gland that does not result from an inflammatory or neoplastic process.

In general, these thyroid nodules are usually not associated with abnormal thyroid hormone
secretion. Therefore, affected patients do not exhibit clinical symptoms or signs of thyroid dysfunction.
The only clinical features of nontoxic goiter are those of thyroid enlargement. Also the exact etiology of
nontoxic nodular goiters are generally unknown, but, in general, it can develop from hypofunctioning or
hyperfunctioning thyroid states. Iodine deficiency and ionizing radiation can be the significant risk
factors for the patient but due to limited information, these factors could not be assessed.

4
Graves Disease

We can also consider Graves Disease in this case because Graves disease accounts for 60 to 80%
of all thyroid gland enlargements. There is an increased prevalence in women with a 5: 1 ratio compared
to men and it typically occurs between 20 and 50 years of age. To be noted is the fact that our patient is
a 36-year old female.

Clinical manifestations of Graves disease are those common to any cause of thyrotoxicosis, with
symptoms including weight loss and palpitations - all of which the patient manifested. However, our
patient had normal PR and temperature, indicating that the degree of her thyrotoxicosis may be mild.

In addition to the above, in Graves disease, the thyroid is usually enlarged to two to three
times its normal size, which should explain the 12x10x10 cm in our patient. Usually, the enlargement is
diffuse and involves both lobes, equally. In our patient, though, there is localization to the left lobe. It is
important to note that there have been recent reports of unilateral Graves disease (Chen & Green,
2011; Juhanni, Wagieh, & Al Ghamdi, 2010). Pre-existing functional or structural differences (either
congenital or acquired) between the two lobes may contribute to this rare presentation.

Conversely, Graves disease usually presents as a triad of thyrotoxicosis, diffuse goiter, and
extrathyroidal conditions (including ophthalmopathy, lid retraction, periorbital edema, proptosis
pretibial myxedema, thyroid acropachy, gynecomastia, and other manifestations) - all of which are not
manifested in our patient. Graves' disease also has a strong familial predisposition, but the case did not
include the family history, so the genetic risk factors specific to the patient cannot be evaluated.

SPECTRUM OF DISEASE

Lower Testing Threshold Pretest Probability Upper Testing Threshold

20% 55% 75%

Pretest Probability

The pretest probability we are using is 55% because, according to Medscapes toxic nodular
goiter (TNG) article last updated July 2013, the prevalence of hyperthyroidism caused by TNG is 15 to
30% in the US. However, this increases to 58% in areas of the world that are considered iodine-deficient,
and 10% of these will have hyperthyroidism from a solitary nodule. It is the second-leading cause of
hyperthyroidism, behind Graves disease. It is more common among women than men, with women
having a higher occurrence of palpable nodules of five to seven percent versus mens one to two.

5
 In our patient, her signs and symptoms of easy fatigability, palpitations, and weight loss are
indicative of mild thyrotoxicosis and she was successfully treated for these manifestations a few years
prior. The progressively enlarging mass, however, indicates that there is still an ongoing pathology that
has not been addressed by these drugs. In the case of toxic nodular goiter, it is usually adequately
treated with radioactive iodine or surgery, neither of which the patient has undergone, and thus we
considered this as our main diagnosis.

Upper Testing Threshold

The upper testing threshold limit is the estimate at which the patient most likely has toxic
nodular goiter, testing will cease, and therapy will begin. According to a study published by Brandt, et
al.in August 2013, mortality due to TNG was associated with cancer-related deaths but thyrotoxicosis in
general increased the risk of mortality in both Graves and TNG. However, according to the National
Cancer Society, the number of people that die from thyroid cancer between the ages of 35-44 is 2.1%.
Thus, we have decided to place our upper testing threshold at 75% because of the increasing success of
diagnosing cancer due to the advent of thyroid ultrasound and fine needle aspiration biopsy before it
reaches higher stages associated with higher mortality, as well as the fact that higher mortality rates are
seen in patients above fifty-five years of age.

Also, according to Medscape and Harrisons 12th edition, the most common cause of
hyperthyroidism is Graves' disease, at more than sixty percent, and it also demonstrates the symptoms
found in our patient. However, the stigmata of Graves' (e.g., orbitopathy, pretibial myxedema,
acropachy) is not present, and other systemic signs and symptoms are absent in our patient, such as
musculoskeletal, renal and dermatologic problems.

Regarding the ruling out of a premalignant or malignant cause of the nodule, thyroid cancer is
extremely rare, as its incidence is only 1.1% of all cancers, with 80% of them being papillary thyroid
cancer. The nodules found under this type of cancer are less than five centimeters, hard, with ill-defined
borders, and are adherent to nearby tissues. The nodule measured in our patient is too large for
papillary thyroid carcinoma. It is also much less common to find cancer in a "hot" nodule than a "cold"
one, the incidence being less than 1% and 15%, respectively.

As for nontoxic nodular goiter, it presents similarly upon physical examination but without the
signs and symptoms of hyperthyroidism. Because we do not know what kind of medication was given to
the patient previously, there is a chance that the cause of her previous manifestations did not come
from the thyroid.

6
Lower Testing Threshold

The lower testing threshold is the probability that the patient does not have toxic nodular goiter
but another illness that causes the multiloculated mass and hyperthyroidism. Mild thyrotoxicosis is
apparent in one of the three differential diagnoses. Graves accounts for as much as eighty percent of
these cases, and is common within our patients demographics, like age (36 years old) and gender
(female). It may also present with nodules, although it is relatively uncommon. Papillary thyroid
carcinoma rarely presents with thyrotoxicosis and is more commonly associated with an enlarged mass
alone. This is also seen in nontoxic nodular goiter. Taking into account these commonalities among our
four diagnoses, we have set our lower testing limit to 20%.

7
 CLINICAL APPRAISAL OF AN ARTICLE ABOUT DIAGNOSIS

CLINICAL QUESTION

In a 36 year-old female presenting with unilateral, anterior neck mass with accompanying symptoms of
hyperthyroidism, what is the accuracy of ultrasound in detecting the etiology of the disease?

Educational Prescription:

P Patient with unilateral anterior neck mass with accompanying symptoms of hyperthyroidism

I ultrasound

O Accuracy

M Cross-sectional study

SEARCH STRATEGY

SEARCH:

1. Using PUBMED, the initial research strategy key terms that were used can be traced from the clinical
question itself:

Key Terms: unilateral anterior neck mass, hyperthyroidism, ultrasound, accuracy, cross sectional study

Category: Diagnosis

Scope: Narrow

Boolean operator: AND

Initial Search Strategy: (Diagnosis/Narrow[filter]) AND (unilateral anterior neck mass AND
hyperthyroidism AND ultrasound AND accuracy AND cross sectional study)

Using PUBMED Clinical Queries, initial search returned 0 results.

8
2. Modification of the search in PubMed was done. The scope was changed to broad.

Category: Diagnosis

Scope: Broad

Final Search Strategy: (Diagnosis/Broad[filter]) AND (unilateral anterior neck mass AND
hyperthyroidism AND ultrasound AND accuracy AND cross sectional study)

Number of hits: 14

9
10
11
 Title of the Study
Color Flow Doppler Sonography
for the Etiologic
Diagnosis of Hyperthyroidism
Murat Faik Erdogan, Cuneyd
Anil, Mustafa Cesur, Nilgun Bas
kal, and Gu rbuz Erdogan
Assays for thyroid-stimulating
hormone receptor antibodies
employing different ligands and
ligand partners may have similar
sensitivity and specificity but are
not interchangeable.
Pedersen IB1, Handberg
A, Knudsen N, Heickendorff
L, Laurberg P.
Hypocalcaemia following total
thyroidectomy: An analysis of
806 patients.
Nair CG, Babu MJ, Menon R,
Jacob P.
Diagnostic value of dynamic
contrast medium enhanced
magnetic resonance imaging in
preoperative detection of
thyroid carcinoma.
Tezelman S1, Giles Y, Tunca F,
Gok K, Poyanli A, Salmaslioglu A,
Terzioglu T.
Thyroid carcinoma diagnosis
based on a set of karyometric
parameters of follicular cells.
Kirillov VA1, Yuschenko YP,
Paplevka AA, Demidchik EP.
TSH-receptor antibody
measurement for differentiation
of hyperthyroidism into Graves'
disease and multinodular toxic
goitre: a comparison of two
competitive binding assays.
Pedersen IB1, Knudsen N, Perrild
H, Ovesen L, Laurberg P.
Year Objectives
2007 The aim of the present study is
to determine the value of
CFDS in the etiological diagnosis
of hyperthyroidism.
2010 The aim of this study was to
evaluate the performances of
two sensitive hTSHR-Ab assays
with a specific focus on the
clinical importance of
differences in results.
2013 This prospective observational
study aims to define the factors
likely to predict hypocalcaemia
following total thyroidectomy.
2007 To assess the diagnostic value
of dynamic contrast medium-
enhanced magnetic resonance
imaging (DCE-MRI) in detection
of thyroid carcinoma compared
with fine-needle aspiration
biopsy and frozen section
analysis in multinodular goiter.
2001 To develop a quantitative
approach to thyroid carcinoma
diagnosis.
2001 The aim of this study was to
compare the performance of a
new TRAb assay based on
competitive binding to
recombinant human TSH-
receptors (H-TRAb) with an
assay employing purified
porcine TSH-receptors (P-TRAb).
Furthermore, to evaluate the
Comments
The objective of the
study matched our
objective.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
12

Serum levels of carboxyterminal
cross-linked telopeptide of type I
collagen (ICTP) in the differential
diagnosis of the syndromes of
inappropriate secretion of TSH.
Persani L1, Preziati D, Matthews
CH, Sartorio A, Chatterjee VK,
Beck-Peccoz P.
A study of biological and
histological criteria of thyroid
autoimmunity in diffuse goiters
with hyperthyroidism].
[Article in French]
Leprat F1, Felicie-Dellan E,
Trouette H, Latapie MJ, Masson
B, De Mascarel A, Latapie JL,
Roger P.
Thin-needle aspiration biopsy in
the preoperative diagnosis of
non-toxic nodular goiter].
[Article in Slovak]
Hnilica P1, Podoba J Jr.
Bispecific thyroglobulin and
thyroperoxidase autoantibodies
in patients with various thyroid
and autoimmune diseases.
Ruf J1, Feldt-Rasmussen U,
Hegeds L, Ferrand M, Carayon
P.
Circulating antibodies to DNA-
related antigens in patients with
autoimmune thyroid disorders.
Loviselli A1, Velluzzi F, Pala R,
Marcello A, Nurchis P, Mathieu
A, Bartalena L, Martino E, Grasso
L.
applicability of the H-TRAb
assay to discriminate between
patients with hyperthyroidism
due to Graves' disease (GD) and
multinodular toxic goitre
(MNTG).
1997 To study the usefulness of this
specific marker of bone
resorption in the differential
diagnosis of thyroid disorders.
1997 To study the intensity of
intrathyroidal autoimmune
process (IAP) and the levels of
TBIAb, TPO- and Thyroglobulin-
antibodies in 105 cases with
diffuse goiter, hyperthyroidism
and elevated RAIU.
1995 To ascertain the diagnostic
reliability of fine needle
aspiration biopsy in
preoperative examination of
non-toxic goiters
1994 To determine if TGPO aAb, are
of clinical relevance compared
to TG and TPO aAb.
The study was done 20
1992 To evaluate the prevalence of
several antibodies to DNA-
related nuclear antigens
(AbDRENA) in sera of patients
with autoimmune and non-
autoimmune thyroid disease.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The study was done 17
years ago.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The study was done 17
years ago.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The study was done 19
years ago.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
years ago.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The study was done 22
years ago.
13
Detection of thyroid-stimulating
antibodies in thyroid diseases,
employing rat thyroid fragment
perifusion.
Attali JR, Valensi P, Darnis D,
Weisselberg C, Sebaoun J.
In vitro generation of NADPH as
an index of thyroid stimulating
immunoglobulins (TGI) in
goitrous disease.
McMullan NM, Smyth PP.
Clinical experience with a human 1984
thyroid cell bioassay for thyroid-
stimulating immunoglobulin.
Rapoport B, Greenspan FS, Filetti
S, Pepitone M.
1987 To investigate the presence of
thyroid-stimulating antibodies
(TSAb) in the sera of 48 patients
using the technique of
perifusing rat thyroid
fragments.
1984 To measure the total NADPH
formation in guinea pig thyroid
tissue following incubation with
thyroid stimulators and applied
to the measurement of such
stimulators in IgG concentrates
prepared from human plasma.
To assess the clinical use of
thyroid stimulating
immunoglobulin in patients
with Hashimoto's thyroiditis
(without concurrent Graves'
ophthalmopathy),
nontoxic goiter,
and toxic nodular goiter.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The study was done 27
years ago.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The study was done 30
years ago.
The paper is not
relevant to the case
because the objective
of the study did not
match our objective.
The study was done 30
years ago.

Final article:

Color Flow Doppler Sonography for the Etiologic

Diagnosis of Hyperthyroidism

Murat Faik Erdogan, Cuneyd Anil, Mustafa Cesur, Nilgun Bas kal, and Gu rbuz Erdogan

14
 CRITICAL APPRAISAL PROPER

RELEVANCE

Was the objective of the paper relevant to your clinical question?

Yes, the researchers are interested in finding the accuracy of ultrasound as a diagnostic test in
patients with unilateral anterior neck mass with accompanying symptoms of hyperthyroidism. The
objective of the study was relevant because their aim was to determine the value of Color Flow Doppler
Sonography (CFDS) in the etiological diagnosis of hyperthyroidism.

VALIDITY GUIDES

Was there an independent, blind comparison with a reference standard?

Yes, there was an independent and blind comparison with a reference standard. Laboratory
diagnosis of hyperthyroidism was determined using serum thyroid hormones, serum thyroid stimulating
hormone (sTSH) levels, and auto-antibody levels. 99mTc scans and 131I uptakes (RAIU) of the thyrotoxic
group were also performed. CFDS was performed in all of the cases, and blood flow patterns were
evaluated by an experienced sonographist who was unaware of the diagnoses.

Did the patient sample include an appropriate spectrum of patients to whom the test will be used?

Yes, the study included a patient sample that has similar demographic and general
characteristics with our patient of interest. Fifty-five patients with hyperthyroidism (29 Graves disease
[GD] and 26 toxic adenoma [TA]), 24 patients with Hashimotos thyroiditis (HT), and 39 euthyroid
controls (24 nontoxic diffuse goiter [DG] and 15 nontoxic nodular goiter [NG]) were included in the
study. The demographic characteristics and laboratory results of the study groups are shown below.

15
Was the reference standard done regardless of the result of the diagnostic test being evaluated?

Yes. Laboratory diagnosis of hyperthyroidism was determined using serum thyroid hormones,
serum thyroid stimulating hormone (sTSH) levels, and auto-antibody levels in all patients prior to CFDS.
131
99mTc scans and I uptakes (RAIU) of the thyrotoxic group were also performed.

Were the methods for performing the test described in sufficient detail to permit replication?

Yes. The authors described in details how to perform the CFDS as well as the frequency of the
transducer used and also the brand of Doppler ultrasonography that they used. The authors also
described the criteria on how the results will be interpreted. This will allow other researchers to
replicate the study being done.

Overall, is the study valid?

Yes, overall the study is valid since all the criteria were met.

WHAT ARE THE RESULTS?

What were the likelihood ratios for the different possible test results?

The computation for likelihood ratios, post-test odds and post- test probability will be based on
the researchers (article) computed specificity and sensitivity since there was no raw data provided for
toxic adenoma. The sensitivity and specificity used herein were based on the quoted statement below.

According to the ROC analysis, the highest value of the calculated Youden index was 0.695. It
gave us the peak systolic velocity (PSV) value where the most favorable sensitivity and specificity values
met (14.5 cm/s). Thus, perinodular PSV values above 14 cm/s were found to have 96% diagnostic
sensitivity and 73% specificity for Toxic Adenoma (TAs) compared with Non-toxic nodular goiter (NG).

Sensitivity = A / (A + C) = 96.0%

Specificity = D / (B + D) = 73.0%

LR (+) = Sn / (1 Sp) = 3.56

LR (-) = (1 Sn) / Sp = 0.05479

Pre Test Probability= 55%

Pre Test Odds = P / (1 P) = 1.22

(+) Post Test Odds = Pre Test Odds x LR (+) = 4.3432

16
 (-) Post Test Odds = Pre Test Odds x LR (-) = 0.06684

0.8128 or 81.28%
(+) Post Test The post-test probability of Toxic
O / (O + 1) =
Probability = adenoma if CFDS is positive is
81.28%

0.06265 or 6.265%
(-) Post Test The post-test probability of Toxic
O / (O + 1) =
Probability= Adenoma if CFDS is negative is
6.265%

Posttest Lower Pretest Upper Posttest

Probability testing Probability testing Probability
(-) = threshold = 55% threshold (+) =
6.265% = 20% = 75% 81.28%

The post-test probability of the disease, if positive for CFDS, is 81.28%, and if negative for CFDS,
the post-test probability is 6.265%. Thus, if the patient tested positive, treatment should be started, and
if negative, no additional testing is needed and the patient is assumed to be free of the disease.

CAN THE RESULTS HELP ME IN CARING FOR MY PATIENT?

Will the reproducibility of the test result and its interpretation be satisfactory in my setting?

Yes. Color flow Doppler ultrasound is widely available in secondary and tertiary hospitals in the
Philippines. Since the technique and pre-procedural preparations of the study were adequately
described, the procedure itself will be reproducible in the Philippines, especially in Manila. The
interpretation should be done while doing the procedure and they should be trained adequately as to
limit the error that may be caused by this human factor.

17
Are the results applicable to my patient?

Yes. The results are applicable to our patient because there are characteristics of the study
population that are similar to the case scenario of our patient. These included patients with:
Hyperthyroidism and nodular goiter (Toxic Adenoma and Nontoxic Nodular Goiter (NG) Patients); Mean
Age for Toxic Adenoma 50 (2270) years old

Will the results change my management?

Yes. The results will affect the management because different etiologies of hyperthyroidism
entail different approaches and management. The management of a patient that would be diagnosed
with diffuse toxic goiter will be approached in a different way in contrast to a patient that would be
diagnosed with a toxic adenoma. This only highlights the importance of this study in diagnosing the
patient of interest.

RESOLUTION OF THE PROBLEM IN THE SCENARIO

The emphasis of the result of the CFDS was determined to have high specificity (96%) and
sensitivity (73%), this means that the chances of the anterior neck mass to be classified under an
accurate aetiology are high; and the post-test probability (81.28%) exceeded the upper threshold limit
which is 75%. Based on the study and the results of the critical appraisal, color flow doppler sonography
is an accurate test to determine the etiology of thyroid mass in patients with accompanying symptoms
of hyperthyroidism. It would then be advisable to have our patient to undergo the procedure to
determine the proper intervention.

18
 CRITICAL APPRAISAL OF AN ARTICLE ABOUT THERAPY

Radioactive iodine is considered the treatment of choice for TNG. Except for pregnancy, there
are no absolute contraindications to radioiodine therapy.

Antithyroid drugs and beta blockers are used for short courses in the treatment of TNG; they are
important in rendering patients euthyroid in preparation for radioiodine and in treating hyperthyroidism
while awaiting full clinical response to radioiodine.

The role of therapy with thioamides (eg, PTU, methimazole) is to achieve euthyroidism prior to
definitive treatment with radioiodine therapy. Antithyroid drugs are often administered for 2-8 weeks
before radioiodine therapy in order to avoid the risk of precipitating thyroid storm. The general
recommendation is to stop antithyroid agents at least 4 days prior to radioiodine therapy in order to
maximize the radioiodine effect.

CLINICAL QUESTION

Will Propylthiouracil be effective in inducing a euthyroid state in patients with toxic nodular goiter?

Educational Prescription

P: Patients diagnosed with toxic nodular goiter

I: Propylthiouracil

O: Euthyroid state

M: RCT

SEARCH STRATEGY

1. The initial research strategy key terms that were used can be traced from the clinical question itself.

CLINICAL QUESTION: Will Propylthiouracil be effective in inducing a euthyroid state in patients with toxic
nodular goiter?

Key Terms: toxic nodular goiter, prophylthiouracil, euthyroid state

Category: Therapy

Scope: Narrow

Boolean operator: AND

19
Initial Search Strategy: (Therapy/Narrow[filter]) AND (toxic nodular goiter AND prophylthiouracil AND
euthyroid state)

Using PUBMED Clinical Queries, initial search returned 0 results.

2. Modification of the search in PubMed was done.

The key terms were adjusted to: toxic nodular goiter AND prophylthiouracil

Category: Therapy

Scope: Narrow

Boolean operator: AND

Search Strategy: (Therapy/Narrow[filter]) AND (toxic nodular goiter AND prophylthiouracil)

PUBMED Clinical Queries - number of results: 2

20
21
3. The researchers read the 1st article; however the population and objective of the study were different
from the population and objective of the researchers.

ARTICLE 1: Sources of circulating 3,5,3'-triiodothyronine in hyperthyroidism estimated after blocking of

type 1 and type 2 iodothyronine deiodinases.

Laurberg P1, Vestergaard H, Nielsen S, Christensen SE, Seefeldt T, Helleberg K, Pedersen KM.

Clinical Question: Title of Article:

Will Propylthiouracil be effective
in inducing a euthyroid state in
patients with toxic nodular
goiter?
Objective To determine the effectiveness
of Propylthiouracil in inducing a
euthyroid state in patients with
toxic nodular goiter
Sources of circulating 3,5,3'-
triiodothyronine in
hyperthyroidism estimated after
blocking of type 1 and type 2
iodothyronine deiodinases.
to assess the role of
iodothyronine deiodinase type 1
(D1) and type 2 (D2) for T(3)
production and to estimate the

22
 sources of T(3) in
hyperthyroidism.
Population Patients diagnosed with toxic Patients with Graves'
nodular goiter hyperthyroidism and
multinodular toxic goiter

4. The researchers read the 2nd article and the PIOM were a match.

Clinical Question: Title of Article:

Will Propylthiouracil be effective Propylthiouracil before 131I

in inducing a euthyroid state in Therapy of Hyperthyroid
patients with toxic nodular Diseases: Effect on Cure Rate
goiter? Evaluated by a
Randomized Clinical Trial

Population Patients diagnosed with toxic patients with Graves disease or

nodular goiter toxic nodular goiter
Intervention Propylthiouracil Propylthiouracil
Outcome euthyroid state euthyroid state or
hypothyroidism
Method Randomized Clinical Trial Randomized Clinical Trial

FINAL ARTICLE

Propylthiouracil before 131I Therapy of Hyperthyroid Diseases: Effect on Cure Rate Evaluated by a

Randomized Clinical Trial

S. J. BONNEMA, F. N. BENNEDBK, A. VEJE, J. MARVING, AND L. HEGEDU S

23
 CRITICAL APPRAISAL PROPER

RELEVANCE

Is the objective of the article comparing therapeutic interventions similar to your clinical dilemma?

Yes. the article has the same intervention as our clinical dilemma. Our clinical dilemma aims to
determine the effectivity of propylthiouracil in inducing a euthyroid state in patients with toxic nodular
goiter. In the article, propylthiouracil was used to induce a euthyroid state in patients with toxic nodular
goiter who are about to undergo radioiodine treatment.

VALIDITY GUIDES

Was the assignment of patients to treatment randomized?

Yes. The patients were randomized Using computer-generated numbers in closed envelopes.
During a period of 2 yr, 287 hyperthyroid patients were referred for 131I therapy (Fig. 1). 195 out of 287
were ineligible. Of the 81 patients who were eligible for the study and was initially included, 40 patients
were randomized to the +PTU group, and 41 patients to the -PTU group.

Were all patients who entered the trial properly accounted for and attributed at its conclusion? Was
follow up complete?

Yes, the follow up was sufficiently long and complete.

24
 The study population consisted of patients with recurrent Graves disease or toxic nodular
goiter. 287 patients were referred for the treatment but 195 were not eligible and 11 declined
participation. The remaining 81 patients were then included but 80 patients completed 1year follow-up.
23 individuals had Graves disease and 57 had toxic nodular goiter. The patients were then randomized
and grouped in the +PTU (40 patients, 39 completed follow-up) and PTU (41 patients, all completed
follow-up). Thyroid function test was monitored after 3, 6, and 12 weeks and every 3 months after for a
follow-up period of 1 year. After 1 year, only 1 patient from the +PTU group was lost to follow-up.

*+PTU = with pretreatment, -PTU = without pretreatment

Were all patients analyzed in the group to which they were randomized?

Yes, the patients in the groups were analyzed first within their groups and then compared to the
other groups via different statistical tests. There was no crossing over of the treatment modalities and
all the data were analyzed independently. The patients were analyzed in the groups to which they were
randomized as shown in this table.

Baseline data were presented as the mean, +/- SD or as median and range of not normally
distributed. X2test, one- and two-way ANOVA, and Mann-Whitney test were used to compare the
baseline characteristics and also to analyze the differences in the outcome. Logistic regression analysis
was also used for correlations. P<0.05 was considered statistically significant.

Were patients, their clinicians and study personnel blind to treatment?

No, there was no blinding done in the study.

25
Were the groups similar at the start of the trial?

Yes. The baseline characteristics stratified for disease and randomization are shown in Table 1.
No major differences were found between the groups with respect to the randomization. However,
patients with toxic nodular goiter compared with those suffering from Graves disease had larger thyroid
glands and lower levels of thyroid hormones. Twenty-three individuals had Graves disease, and 57 had
toxic nodular goiter (autonomously functioning toxic nodule in 20 and toxic multinodular goiter in 37
individuals).

Aside from the experimental intervention, were the groups treated equally?

Yes, aside from the PTU administration in the +PTU group. The interventions given to the
patients were the same.

The only difference in the two groups Treatment is the administration of Prophylthiuracil before
Radioiodine Treatment. The PTU dose in the +PTU group was adjusted guided by thyroid function tests,
and 131I therapy was given when stable euthyroidism had been obtained (i.e. two consecutive sets of
thyroid hormones within the normal range). PTU was discontinued 4 d before 131I therapy, with no
subsequent resumption.

Aside from the Prophylthiouracil, both groups were treated equally:

In both groups, B-blockade (propranolol) was instituted if severe hyperthyroid symptoms were
present.

In the post-131I period, thyroid function was monitored after 3, 6, and 12 wk and thereafter
every 3 months for a follow-up period of 1 year.

26
 If the patient had hyperthyroid symptoms in the early post-131I period, these were managed by
B-blockers.

In case the hyperthyroidism persisted/recurred beyond 6 wk, PTU was instituted (-PTU group) or
resumed (+PTU group), and this medication was subsequently tapered during the follow-up period.

If this was not successful, a second 131I dose was eventually administered at the earliest, 9
months after the initial therapy. Hypothyroidism was treated with levothyroxine. If a low dose of
levothyroxine was required, a trial of discontinuation was made within the follow-up period to ensure
that the hypothyroidism was not transient.

OVERALL, IS THE STUDY VALID?

Yes. Overall, the study is valid since majority of the validity guide questions were answered with
a yes.

WHAT ARE THE RESULTS?

How large was the treatment effect?

The outcome our group chose to measure the cure rate defined as obtainment of either
euthyroidism after treatment.

(+) (-)

Cured Cured

(+) PTU before

radioiodine
therapy 20 19 39

(-) PTU before

radioiodine
therapy 25 16 41

TOTAL 45 35 80

Proportion of treatment who developed outcome : 20/39 = 51.28%%

Proportion of control who developed outcome : 25/41 = 60.38%

27
Test Result Significance

Risk in Control ( Rc) 0.6038 60.38% risk of developing the

negative outcome in the
control group

Risk in Treatment ( Rt) 0.5128 51.28% risk of developing the

negative outcome in the
treatment group

Relative Risk (RR) 0.8433 The risk of having the negative

with the treatment is 84.32% of
Rt/Rc what the patient was treated
with the control

Absolute Risk Reduction (ARR) 0.0955 The negative effect is

prevented in 9.55% of the
Rc Rt patients taking the treatment

Relative Risk Reduction (RRR) 0.1567 15.67% reduction in the risk of

obtaining the negative effect
1 RR with the treatment compared
to the control

Number needed to Treat (NNT) 10.47 You would need to treat 10

people with PTU before
1/ARR radioiodine to prevent 1
negative outcome

28
29
30
How precise was the estimate of treatment effect?

The study reported that the cure rate occurred at 51.28% of the Treatment and in 60.38% of the
control. The confidence interval (CI) for the RRR is -0.20 to .51. The presence of a wide CI indicates that
the study result of RRR is not precise. The confidence interval for the ARR is -0.120 to 0.314 which also
means that the ARR is not precise. Since the values fall within the CI, then the results are not statistically
significant at 0.05 level. This value is indicated by using CatMaker Analysis.

Can the results be applied to my patient care?

Yes, because our patient has the same characteristics with that, of the patients in the case. The
patients in the study are affected by thyroid nodular disease, in which in our case, the patient has
enlarged anterior neck mass and has signs and symptoms of hyperthyroid disease. While patients
excluded in the study are those that are pregnant and has allergy to PTU, wherein our patient was not as
well.

31
Were all clinically important outcomes considered?

Yes. Total serum T3, T4 and TSH were all measured every 3, 6, 12 weeks and every 3 months
after, FT3 and FT4 were calculated as well. Antithyroid peroxidase antibodies as well as Thyroid tc
scintigraphy was performed at the start and at the end of the follow-up. Baseline thyroid volume via
ultrasound was performed then compared 1 year after.

Are the likely treatment benefits worth the potential harm and cost?

Yes. Prophylthiouracil costs about 6-7 pesos/ 50mg tablet (generic tablet made by Rhea PhilUsa)
and is affordable. With the relatively low incidence (0.5 to 1%) of adverse effects (hepatotoxicity, skin
eruptions, urticarial and leukopenia), it is safe to say that PTU can be safely administered. Regarding
Iodine 131, it costs about 5-10 thousand pesos on the average but treatment cost may vary depending
on the dosage needed. Though a little bit expensive, it provides a long-term management thus making it
more cost-effective. With its side effects being non-fatal and manageable, and the benefit of it is long-
term management of hyperthyroidism, it is safe to say that Iodine 131 treatments benefit outweigh the
harm.

RESOLUTION OF THE STUDY

The article is valid. The study has shown that PTU pretreatment can cause euthyroid state in
toxic nodular patients however; it also showed that PTU can reduce the cure rate of Iodine 131
treatment compared to when Iodine 131 is given alone. With regards to harm and cost, there is
relatively low incidence of adverse effects when using PTU and the cost is affordable. For Iodine 131
treatment, although it is more expensive than PTU, it provides long-term management and is given in
one dose, thus making it more cost-effective. The group would then, recommend Iodine 131 treatment
without PTU pretreatment to treat toxic nodular goiter.

32
 CRITICAL APPRAISAL ON AN ARTICLE ABOUT HARM

CLINICAL QUESTION

What are the adverse effects of radioiodine therapy in patients with toxic nodular goiter?

Educational Prescription

P- Patients with toxic nodular goiter

I- Radioiodine therapy

O- Harmful effect

M- Cohort

SEARCH STRATEGY

Using PUBMED, the initial research terms based on the clinical question: toxic nodular goiter,
radioiodine therapy, harmful effect, cohort

yielded 0 results

Category: Etiology

Scope: Narrow

33
Modifying the search strategy by omitting the other keywords and typing toxic nodular goiter,
radioiodine therapy and hypothyroidism showed 8 results under clinical studies.

Category: Etiology

Scope: Narrow

34
Upon reading the 8 articles under clinical study categories, the group found that the first article was
appropriate to answer the clinical question

35
FINAL ARTICLE

Development of hypothyroidism during long-term follow-up of patients with toxic nodular goiter after
radioiodine therapy

Kahraman D, Keller C, Schneider C, Eschner W, Sudbrock F, Schmidt M, Schicha H, Dietlein M, Kobe C.

36
 CRITICAL APPRAISAL PROPER

RELEVANCE

Is the objective of the article on harm similar to your clinical dilemma?

Yes. The article aims to show the effect of the long-term follow-up of patients with toxic nodular
goiter after radioiodine therapy

VALIDITY GUIDELINES

Were there clearly identified comparison groups?

No. All patients underwent radioactive test.

Were the exposures and outcomes measured in the same way in the groups compared?

No. Fifty-nine patients with clinical hyperthyroidism were treated with antithyroid drugs. Of
these 59 patients, 6 received a combination of levothyroxine ana anti-thyroid drugs. Fifty-four patients
with subclinical hyperthyroidism received levothyroxine. All patients underwent radioactive test.

Was the follow up sufficiently long and complete?

Yes. The study seeks to observe the development of hypothyroidism during long term follow up
of patients with toxic nodular goiter after radioiodine therapy. The study defined follow up as the time
in months from radioiodine treatment to the last follow up examination available or to the first
observation showing a TSH level above the normal upper limit/ Follow up examinations were conducted
3 months, 1 year and up to 8 years after radioiodine treatment. Mean follow up time was 29 months
with a range of 3-88 months. This time frame is deemed sufficient enough to observe for
hypothyroidism in the subjects.

Is the temporal relationship between the exposure and outcome correct and dose response gradient
present?

Yes. The exposure (preliminary radioiodine testing) was done prior to the outcome which is the
measurement of the TSH, fT3 and fT4 which are used as parameters in the classification of patients
under clinical and subclinical hyperthyroidism, euthyroidism, subclinical and clinical hypothyroidism.
With regard to dose response gradient, the study compared the relationship between an increase in
achieved thyroid dose and the incidence of hypothyroidism. 13 (5%) patients received doses lower than
120 Gy, 146 (55%) had doses ranging from 120 to 187 Gy, in 87 (33%) patients had doses that ranged
from 188 to 254, and in 19 (7%) it exceeded 254 Gy. The TSH, fT3 and fT4 were subsequently measured
and compared in the follow up.

Overall is the study valid?

Yes, since most of the validity guides have been satisfied, the study can be considered as valid.

37
RESULTS

Total patients: 265

Cure rate, 3 months: 85%

Cure rate, 1 year: 98%

Cure rate, end: 98%

Hypothyroidism, 3 months: 32%

Hypothyroidism, 1 year: 55%

Hypothyroidism, end: 73%

Above an achieved thyroid dose of more than 120 Gy, there was no significant association between the
dose achieved in the thyroid and the cure rate on follow-up.

An achieved thyroid dose of above 254 Gy was associated with a statistically significant higher
incidence of hypothyroidism at 12 months (P = 0.049), and at the end of follow-up (P = 0.002)

38
<120 Gy - 13 (5%) - 60% (8)

120-187 - 146 (55%) - 72% (105)

188-254 - 87 (33%) - 72% (63)

>254 - 19 (7%) - 95% (18)

<120: 60% incidence of hypothyroidism post-treatment

>120: 73.8% incidence of hypothyroidism post-treatment

39
APPLICABILITY

Are the patients similar to my own?

Majority (75%) of the subjects included in the study are adult women with toxic nodular goiter
or nodular goiter and subclinical hyperthyroidism who had been treated with anti-thyroid drugs.
Considering our patient is a 36 year-old female who has toxic nodular goiter who is currently on
medications for thyroid suppression, it is prudent to infer that the appraised article has almost
similar characteristics of its subjects to our ongoing case scenario.

Should I attempt to stop the exposure?

The exposure should be allowed to continue with the goal to achieve euthyroid state.
However, it is noteworthy that even though the recommended dose of radioiodine was employed in the
study, there was still a high percentage (73%) of patients who developed hypothyroidism, 8 years after
radioiodine therapy. It was also suggested by the authors to further decrease the dose beyond the
recommended Germman and EANM guidelines for radioiodine therapy in benign thyroid disorders.
This finding might support the suggestion that in future intended thyroid doses could beneficially be
lowered in patients treated with a calculated dose regimen for toxic nodular goitre to minimize the risk

40
of hypothyroidism while maintaining high cure rates of hyperthyroidism. It is also prudent to monitor
patients who have undergone radioiodine therapy through follow-up to address the need for thyroid
suppression or life-long thyroxine replacement.

RESOLUTION OF THE PROBLEM IN THE SCENARIO

Radioiodine therapy should be continued to the patient, with the ultimate goal of rendering the
patient euthyroid. Although it has been reported in the study that there is 73% incidence of
hypothyroidism despite calculated dose regimen with an estimated radiation dose of 150 Gy in patients
with toxic nodular goiter, the authors have suggested a further lowering of the dose to minimize
incidence of hypothyroidism.

41
 CLINICAL APPRAISAL ON AN ARTICLE ABOUT PROGNOSIS

CLINICAL QUESTION

What is the mortality among patients with toxic nodular goiter (hyperthyroid) after undergoing
radioiodine treatment?

Educational Prescription

P: patients with toxic nodular goiter (hyperthyroid)

I: radioiodine therapy

O: mortality

M: population-based cohort study

SEARCH STRATEGY

Using PUBMED, the initial research strategy key terms that were used can be traced from the clinical

question itself:

Key Terms: toxic nodular goiter, mortality, hyperthyroidism, radioiodine, treatment

Category: Prognosis

Scope: Narrow

Boolean operator: AND

Initial Search Strategy: (Prognosis/Narrow[filter]) toxic nodular goiter AND mortality AND
hyperthyroidism AND radioiodine AND treatment

42
Using PUBMED Clinical Queries, initial search returned 15 results.

Modification of the search using filters was done.

Filters used were as follows:

Publication Dates

10 years

Species

Humans

43
Six (6) possibly relevant result was yielded.

44
The researchers read the abstracts of the search results.

The first four articles were excluded based on the following:

Comparison of mortality in hyperthyroidism during periods of treatment with thionamides and

after radioiodine

The article focused more the prognostic effect of co-administered thioamides.

Mechanisms in endocrinology: Heart failure and thyroid dysfunction

The article studied heart failure caused by thyroid dysfunction and not specifically radioiodine
treatment.

Radioiodine treatment for pediatric Graves' disease

The article is specific for pediatric cases and thus not applicable.

Review: The association of thyroid dysfunction with all-cause and circulatory mortality: is there
a causal relationship?

The article is only a review and not a study.

The fifth article seemed the most promising and relevant since it dealt with mortality post-radioiodine
therapy among hyperthyroid patients.

45
The researchers read the obtained article and found that the article was indeed relevant because it
discussed how the mortality is affected by radioiodine treatment and even going so far as to suggest
several possible etiologies.

What is the mortality among patients with nodular thyroid disease (hyperthyroid) after undergoing
radioiodine treatment?

FINAL ARTICLE

Increased Cardiovascular and Cancer Mortality after Radioiodine Treatment for Hyperthyroidism

Saara Metso, Pia Jaatinen, Heini Huhtala, Ansel Auvinen, Heikki Oksala, and Jorma Salmi

46
 CLINICAL APPRAISAL PROPER

RELEVANCE

Is the objective of the article on prognosis similar to your clinical dilemma?

Yes, the article entitled, Increased Cardiovascular and Cancer Mortality after Radioiodine
Treatment for Hyperthyroidism seeks to answer our clinical dilemma. We want to determine the
mortality among patients with toxic nodular goiter after undergoing radioiodine treatment. In
accordance to our clinical question, the article was made to compare the mortality of hyperthyroid
patients treated with RAI with that of an age and gender related matched reference population to find
out if RAI is an independent risk factor for cardiovascular and cancer mortality for patients with toxic
nodular goiter.

PRIMARY VALIDITY GUIDES

Was there a representative sample of patients without the outcome at the start of observation?

Yes, there was a representative sample of patients without the outcome at the start of
observation. Information on etiology, previous treatment of hyperthyroidism, including the dates and
doses of RAI as well as vital statuses were obtained from computerized databases in Tampere University
Hospital and Finnish Population Register Centre. A total of 2793 patients who received RAI were
included with 457 of these were men and 2336 were women.

Was follow-up sufficiently long and complete?

Yes, the follow-up period of the control subject started at the same time as that of the
corresponding patient, which falls within January 1965 to June 2002 period. In both patient and control
groups, the follow-up ended on the date of death, emigration, or the common closing date (December
2003), whichever was first. The study reported a median follow-up time was 9.0 year for the patients
and 9.4 year for the controls which has been completed well through high quality registers.

Were the criteria for determining the prognostic factors and outcome explicit and credible?

Yes, the criteria for determining the prognostic factors and outcome were explicit and credible.
The study has a well-established criteria for the prognostic factors such as the age and the dose of RAI
treatment. The risk of death increased in patients older than 60 year at treatment. Moreover, mortality
increased with the dose of RAI and was elevated in patients with nodular thyroid disease. All of which
were based on several assessments of both specific causes and all causes of death indicated in the
Finnish causes of death register.

47
 The classification used to determine mortality was beforehand already established. It based on
the ICD 9 and 10, used between 1987 and 1995 thereafter, respectively. The classification utilized by the
present study differed from the ICD in a few details. In the ICD, infectious diseases are classified
according to the origin of infectious disease whereas in the study the deaths due to all infections of CNS,
Respiratory, Genitourinary and Gastrointestinal systems were classifies as infectious disease. Also, the
study used the underlying cause of death.

Was there adjustment for other prognostic factors?

Yes, the dose of RAI has been subspecified into three (55258 MBq, 259369 MBq and 370
2664 MBq) all of which were based on both patient and disease characteristics which may affect the
choice of treatment.

OVERALL, IS THE STUDY VALID?

Yes. The study is indeed valid based on the primary validity guides mentioned above.

RESULTS

How large is the likelihood of the outcome to occur in those with the prognostic factor in a specific period
of time? Was it statistically significant?

Monitoring after Radioactive Iodine Therapy is done by blood samples every 1-3 months during
the first year and subsequently, 1-3 year intervals after. Here, the patient is evaluated to be euthyroid,
hypothyroid or relapsed hyperthyroidism, and the worse case scenario, complications leading to death.

Based on Table 2, the incidence of mortality for patients diagnosed with toxic nodular goiter is,
659.9, while the incidence of mortality for the control is 566.2. Given these values, the Relative Risk (RR)
of mortality resulting to Radioactive iodine therapy (RAI) is 1.17 (1.06-1.28). A RR value greater than 1
indicates poor prognosis. However, since RR= 1.17, the chance of developing the outcome is only slightly
higher if the patient has the prognostic factors. Thus, this mode of treatment may cause death to
patients. On the other hand, given that both upper and lower values of the confidence interval are
greater than 1, this further confirms poor prognosis for RAI.

Relative Risk (RR)

RR = Incidence of outcome of prognostic factor group/ Incidence of outcome of NO prognostic factor

group =

Statistical significance

Confidence Interval

48
49
50
Prognostic Factors Affecting Mortality in Patients Receiving RAI Treatment for Hyperthyroidism

Clinical Bottom Line: Mortality in patients treated with RAI for hyperthyroidism is increased with the
dose of RAI. Patients treated with RAI for hyperthyroidism have an advanced cerebrovascular mortality,
as well as cancer, compared with an age and sex- matched control group. It is recommended that
patients that have received RAI treatment undergo a lifelong follow-up of careful screening for these
diseases. Citation/s: Metson, Saara et al. "Increased Cardiovascular and Cancer Mortality after
Radioiodine Treatment for Hyperthyroidism."The Journal of Clinical Endocrinology & Metabolism. 92(6)
2007. 21902196 Lead author's name and fax:

Saara Metso, M.D., Department of Internal Medicine, Tampere University Hospital, P.O. Box 2000, FIN-
33521 Tampere, Finland. E-mail: saara.metso@pshp.fi.

Three-part Clinical Question: What is the mortality among patiens with nodular thyroid disease
(hyperthyroid) after undergoing radioiodine treatment?

Search Terms: toxic nodular goiter AND mortality AND hyperthyroidism AND radioiodine AND treatment

The Study:

The Study Patients: Hyperthryoid patients treated with Radioiodine for hyperthyroidism

51
Prognostic Factor: Age, Dosage of RAIThe Outcome: Mortality There was a well-defined sample at a
uniform (early) stage of illness. Follow-up was long enough; follow-up was complete. There were not
blind, objective outcome criteria. Adjustment was made for other prognostic factors. There was
validation in an independent test-set of patients.

The Evidence:

Prognostic Factor|Outcome|Result|Measure|Confidence Interval|Independent..?

Age |Mortality (Median Follow Up: 9.0 Years) | Poor Prognosis |1.12 (1.30- 1.20) | 95% |yes

Total Dosage of RAI55-258 MBq|Mortality (Median Follow Up: 9.0 Years)| Poor Prognosis|1.05 (0.94-
1.81) | 95% |yes

Total Dosage of RAI259- 369 MBq|Mortality (Median Follow Up: 9.0 Years) | Poor Prognosis|1.15 (1.00-
1.33) | 95% |yes

Total Dosage of RAI370-2664 MBq |Mortality (Median Follow Up: 9.0 Years) |Poor Prognosis |1.18
(1.03- 1.36) | 95% |yes

Comments:

Appraised by: Charlicia McDavid, Michelle Gale R. Mejia, Miggo Vittorio Mejico, Charles Mendez, Joel
Vergil M. Mendiola, Daniel Mendoza; Sunday, November 02, 2014Email: charli.mcda@gmail.com

CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?

Are the study patients similar to my own?

Yes, the patient in our case scenario is similar to the patients included in the study. Patients
included in the study were described in the article, which mentioned the inclusion criteria based on
commonly clinical and laboratory findings. Similarly, the patient in our case is a female with
multilobulated neck mass and clinical manifestations of hyperthyroidism, hence diagnosed with Toxic
Nodular Goiter by the Diagnosis group. Moreover, the study protocol compared the mortality of
hyperthy- roid patients including patients with TNG treated with RAI with that of an age- and gender-
matched reference population.

Can I use the results to decide on the intervention or reassure my patient?

Yes, the prognostic factors investigated in the journal can be used as a basis in determining the
outcome of our patient. The results can be used to decide whether our patient will have higher mortality
rate if she would undergo RadioIodine Treatment. Hence, this would help in deciding on a better
intervention for our patient and this would also help in weighing the risks over the benefits of this kind
of treatment.

52
 The findings of the study are also helpful in assessing other prognostic factors that would
increase the mortality rate in hyper-thyroid patients including our patient with TNG.

RESOLUTION OF THE PROBLEM IN THE SCENARIO

Treatment of toxic nodular goiter with radioiodine may have its beneficial effects, however
recent research suggest long-term complications post-treatment. Although this may be attributed to the
hyperthyroidism in the first place, patients treated with radioiodine have increased risk in having
cerebrovascular disease that would lead to death in the long run. If the patient chooses to undergo RAI,
life-long follow up and screening for such diseases is recommended.

53