CASE REPORT

Pembimbimg :
dr. Hj. Ihsanil Husna, Sp.PD

Disusun oleh :
Lulu Nuraini Rahmat
2015730080

MEDICAL PROFESSION PROGRAMME DEPT. OF INTERNAL MEDICINE

JAKARTA ISLAMIC HOSPITAL CEMPAKA PUTIH
FACULTY OF MEDICINE AND HEALTH
UNIVERSITY OF MUHAMMADIYAH JAKARTA
2019

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 PREFACE

Assalammu’alaikum wr wb,
Alhamdulillah, all praise to Allah SWT The Almighty and The Most Merciful.
Shalawat and salaam to Rasulullah Muhammad Peace Be Upon Him which bring us
from the darkest of time into the lights.
The writer also wish to express his deep and sincere gratitude for those who
have helped in completing this case report to fulfill the criteria for completing Medical
Profession Programme in Internal Medicine Department of Jakarta Islamic Hospital
Cempaka Putih, Faculty of Medicine University of Muhammadiyah Jakarta.
The writer wish this paper to be useful and add another dimension of knowledge
for the writer himself, medical profession student, and anyone else who never stop in
learning.
The writer acknowledge in the process of making this paper, there are a lot of
mistake and far from perfect, cause perfection are only belong to Allah SWT. All the
critics and advice are needed for the writer for the better of ourselves in this journey to
be the long life learner.
Wassalammu’alaikum wr wb.

Jakarta, June 2019

Writer

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 TABLE OF CONTENTS

PREFACE.......................................................................................................................... i
TABLE OF CONTENTS ................................................................................................. ii

CHAPTER I PATIENT DATA ........................................................................................ 3

1.1. Patient’s Identity .............................................................................................. 3
1.2. Anamnesis ........................................................................................................ 3
1.3. Physical Examination....................................................................................... 4
1.4. Laboratory Examination .................................................................................. 6
1.5. Resume ............................................................................................................. 6
1.6. Problem List ..................................................................................................... 6
1.7. Assessment ....................................................................................................... 6
CHAPTER II LITERATURE REVIEW – HYPERTYROID .......................................... 8
1.1. Anatomy .......................................................... Error! Bookmark not defined.
1.2. Physiology....................................................... Error! Bookmark not defined.
1.3. Definition ......................................................................................................... 8
1.4. Epidemiology ................................................................................................... 9
1.5. Etiology ............................................................................................................ 9
1.6. Pathophysiology and Pathogenesis ................................................................ 10
1.7. Clinical Manifestation .................................................................................... 11
1.8. Diagnosis ........................................................................................................ 14
1.9. Management ................................................................................................... 16
1.10. Differential Diagnosis ..................................... Error! Bookmark not defined.
1.11. Prognosis ........................................................................................................ 22

REFERENCES ............................................................................................................... 23

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 CHAPTER I
PATIENT DATA

1.1. Patient’s Identity

Name : Mr. E
Age : 27 years old (July, 3th 1991)
Address : Jl Kali Baru Timur No 3 Kel. Bungur, Senen, Central Jakarta
Marital Status : Married
Religion : Islam
Race : Betawi
Medical Record : 009910xx
Date of Admission : June, 12th 2019
Date of Examination : June, 12th 2019

1.2. Anamnesis
Chief Complaint :
Tremor since 6 months ago.
Another Complaint :
- Heart palpitations
- Nausea
- Sweating
- Fatigue
- Weight Loss
History of Present Illness
Mr.E, 27 y/o came to internal medicine clinic of RSIJ Cempaka Putih and
complaint about tremor he had 6 months earlier. This patient also complaint about
nausea without vomitus. In addition, patients also complain of frequent sweating even if
they are not under the bright sun or during heavy activity.
Patients also experience weight loss while appetite increased and patients easily
feel hungry. The patient has lost weight from 64 kg to 52 kg in the last 6 months. The

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patient also feels weak and slightly trembles in the fingers of both hands. Patients also
feel very easy to get tired even if they only do activities although simple and light
activity.
History of Past Illness :
- No history same problem
- Diabetes mellitus (-)
- Hypertension (-)
History of Family :
- None of his family has the same problem
- Diabetes mellitus (-)
- Hypertension (-)
- Thyroid cancer (-)
History of Allergy :
Patient has no allergy to food and drugs.
History of Treatment :
No history of treatment for this complaint.
Habits :
Smoking, No histroy of alcoholism, or drug abuse.

1.3. Physical Examination

Generalis Status : Mild ill
Consciusness : Compos mentis (E4 V5 M6)
Vital Sign
Blood Pressure : 139/83 mmHg
Hearte Rate : 95 times/minutes
Respiration Rate : 20 times/minutes
Temperature : 36,8 oC
Anthropometric Status
Weight : 52 kg
Height : 163 cm
BMI : 19,6 kg/m2
Nutritional Status : Normoweight

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General Physical Examination
Head : Normocephal (+)
Eyes : Anemic Conjungtiva (-/-), Icteric Sclera (-/-), Light reflex (+/+).
Exophtalmus (+/+)
Nose : Normonasi (+), Secret (-/-), Epistaksis (-/-)
Ear : Secret (-/-)
Mouth : Oral mucose moist, Cyanosis (-), Coated Tongue (-)
Neck : Tyroid enlargment (+/+) symmetric, smooth, size 1x1 cm,
pain (-), Lymph node enlargement (-), JVP (-)
Thorax
Inspection : Normochest (+), chest move symmetrically (+/+)
Palpation : Same vocal fremitus in dextra and sinistra
Percussion : Sonor (+/+)
Auscultacion : Vesicular breath sounds (+/+), Ronkhi (-/-), Wheezing (- / -)
Cor
Inspection : Ictus cordis not seen on ICS V LMCS
Palpation : Ictus cordis not palpable on ICS V LMCS
Percussion : Right heart margin: Sternal line sinistra ICS-V
Left heart margin : Midclavicular line sinistra ICS -V
Auscultation : Regular 1st & 2nd heart sound (+), Murmur (-), Gallop (-)
Abdomen
Inspection : Flat, scar (-), darm contour (-) darm steifung (-)
Auscultation : Bowel Sound (+)
Palpation : Suprapubic pain (+), Epigastric Pain (-), Organomegaly (-), Skin
turgor (+)
Percussion : Bladder percusion : dull. Other region are tympanic.
Extremities
Superior : Edema (-/-), Cyanosis (-/), Warm acral (+/+), RCT <2 seconds (+/+).
Hyperhidrosis (+/+)
Inferior : Edema (-/-), Cyanosis (-/), Warm acral (+/+), RCT <2 seconds (+/+)

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1.4. Laboratory Examination

TSH 0.05 uU/ml (N; 0,5 - 6 uU/ml)

T3 320 ng/dl (N: 80 – 180 pg/d)
FT4 9 ng/dl (N: 0,7 – 1,9 ng/dl)

1.5. Resume
Mr.E, 27 y/o complaint about tremor he had 6 months earlier. This patient also
complaint nausea without vomitus. In addition, patients also complain of frequent
sweating even if they are not under the bright sun or during heavy activity. Patients
also experience weight loss while appetite increased and patients easily feel hungry.
The patient has lost weight from 64 kg to 52 kg in the last 6 months. The patient
also feels weak and slightly trembles in the fingers of both hands. Patients also feel
very easy to get tired even if they only do activities although simple and light
activity.
Physical Examination :
Moderate ill
Composmentis (GCS : 15)
Vital Sign :
Blood Pressure : 139/83 mmHg
Heart Rate : 95 x/minute
Respiratory Rate : 20 x/minute
Temperature : 36,8 °C
General Status :
Exophtalmus, enlarged thyroid gland.
1.6. Problem List
- Tremor e.c Hyperthyroid

1.7. Assessment
1. Thyrotoxicosis e.c Suspect Grave’s Disease DD/ Multinodular goiter
S Complained of tremor since 6 months ago. Nausea (+), Sweating (+), Fatigue,
(+) Weight Loss (+), Tremor (+).

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O Vital Sign
Vital Sign:
BP, RR, T, HR : withing normal limits
BMI : Normal Weight
Physical Examination :
Physical Examination :
Eyes : Exophthalmos (+/+)
Neck : Enlarged thyroid gland (+), symmetric, smooth, size 1x1cm, pain (-)
Ekstremities Superior : Sweating (+/+)
A Tremor e.c Hypertiroid
P Planning : Diagnostic:
- T4, T3 and TSH level
- Ultrasonografi with color-Doppler
Planning : Non Therapeutics
- Bed rest
Planning : Therapeutics
- Propylthiouracil (PTU)
- Initial dose : 100-200mg (3 times/day every 6-8h)

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 CHAPTER II
LITERATURE REVIEW – HYPERTYROID

The thyroid gland is a midline structure located in the anterior neck. The thyroid
functions as an endocrine gland and is responsible for producing thyroid hormone and
calcitonin, thus contributing to the regulation of metabolism, growth, and serum
concentrations of electrolytes such as calcium.
Many disease processes can involve the thyroid gland, and alterations in the
production of hormones can result in hypothyroidism or hyperthyroidism. The thyroid
gland is involved in inflammatory processes (e.g., thyroiditis), autoimmune processes
(e.g., Graves disease), and cancers (e.g., papillary thyroid carcinoma, medullary thyroid
carcinoma, and follicular carcinoma).
In addition to considering its role in metabolism, growth, regulation of certain
electrolytes, and its involvement in many disease processes, the thyroid gland deserves
consideration for its anatomical location and its close relationship to important
structures including the parathyroid glands, recurrent laryngeal nerves, and certain
vasculature.

1.1. Definition
Hyperthyroidism is a pathological disorder in which excess thyroid hormone is
synthesised and secreted by the thyroid gland. It is characterised by normal or high thyroid
radioactive iodine uptake (thyrotoxicosis with hyperthyroidism or true hyperthyroidism).
Thyrotoxicosis without hyperthyroidism is caused by extrathyroidal sources of thyroid hormone
or by a release of preformed thyroid hormones into the circulation with a low thyroid
radioactive iodine uptake Hyperthyroidism can be overt or subclinical. Overt hyperthyroidism is
characterised by low serum thyroid-stimulating hormone (TSH) concentrations and raised serum
concentrations of thyroid hormones: thyroxine (T4), tri-iodothyronine (T3), or both. Subclinical
hyperthyroidism is characterised by low serum TSH, but normal serum T 4 and T3
concentrations.

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1.2. Epidemiology
Prevalence of hyperthyroidism is 0·8% in Europe, and 1·3% in the USA.
Hyperthyroidism increases with age and is more frequent in women. Data for ethnic
differences are scarce, but hyperthyroidism seems to be slightly more frequent in white
people than in other races. The incidence of mild hyperthyroidism is also reported to be
higher in iodine-deficient areas than in iodine-sufficient areas, and to decrease after
introduction of universal salt iodisation programmes.

1.3. Etiology
Table 1. Causes of Thyrotoxicosis

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1.4. Pathophysiology and Pathogenesis
Normally, the secretion of thyroid hormone is controlled by a complex feedback
mechanism involving the interaction of stimulatory and inhibitory factors (see the image
below). Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates the
pituitary to release TSH.

Figure 3. Hypothalamic-pituitary-thyroid axis feedback. Schematic representation of

negative feedback system that regulates thyroid hormone levels. TRH = thyrotropin-
releasing hormone; TSH = thyroid-stimulating hormone.

Binding of TSH to receptors on the thyroid gland leads to the release of thyroid
hormones—primarily T4 and to a lesser extent T3. In turn, elevated levels of these
hormones act on the hypothalamus to decrease TRH secretion and thus the synthesis of
TSH.
Synthesis of thyroid hormone requires iodine. Dietary inorganic iodide is
transported into the gland by an iodide transporter, converted to iodine, and bound to
thyroglobulin by the enzyme thyroid peroxidase through a process called organification.
This results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT),
which are coupled to form T3 and T4; these are then stored with thyroglobulin in the
thyroid’s follicular lumen. The thyroid contains a large supply of its preformed
hormones.
Thyroid hormones diffuse into the peripheral circulation. More than 99.9% of
T4 and T3 in the peripheral circulation is bound to plasma proteins and is inactive. Free

10
T3is 20-100 times more biologically active than free T4. Free T3 acts by binding to
nuclear receptors (DNA-binding proteins in cell nuclei), regulating the transcription of
various cellular proteins.
Any process that causes an increase in the peripheral circulation of unbound
thyroid hormone can cause thyrotoxicosis. Disturbances of the normal homeostatic
mechanism can occur at the level of the pituitary gland, the thyroid gland, or in the
periphery. Regardless of etiology, the result is an increase in transcription in cellular
proteins, causing an increase in the basal metabolic rate. In many ways, signs and
symptoms of hyperthyroidism resemble a state of catecholamine excess, and adrenergic
blockade can improve these symptoms.
In Graves disease, a circulating autoantibody against the thyrotropin receptor
provides continuous stimulation of the thyroid gland. This stimulatory immunoglobulin
has been called long-acting thyroid stimulator (LATS), thyroid-stimulating
immunoglobulin (TSI), thyroid-stimulating antibody (TSab), and TSH-receptor
antibody (TRab). These antibodies stimulate the production and release of thyroid
hormones and thyroglobulin; they also stimulate iodine uptake, protein synthesis, and
thyroid gland growth. Anti–thyroid peroxidase (anti-TPO) antibody is assessed in a
nonspecific test for autoimmune thyroid disease. Although the anti-TPO antibody is not
diagnostic for Graves disease, it is present in 85% of patients with the disorder and can
be quickly measured in local laboratories.

1.5. Clinical Manifestation

Excess thyroid hormone affects many different organ systems. Commonly reported
symptoms are palpitations, fatigue, tremor, anxiety, disturbed sleep, weight loss, heat
intolerance, sweating, and polydipsia. Frequent physical findings are tachycardia,
tremor of the extremities, and weight loss.

Table 3. Signs and Symptoms of Thyrotoxicosis (Descending order of Frequency)

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 Thyrotoxicosis may cause unexplained weight loss, despite an enhanced
appetite, due to the increased metabolic rate. Weight gain occurs in 5% of patients,
however, because of increased food intake. Other prominent features include
hyperactivity, nervousness, and irritability, ultimately leading to a sense of easy
fatigability in some patients. Insomnia and impaired concentration are common;
apathetic thyrotoxicosis may be mistaken for depression in the elderly. Fine tremor is a
frequent finding, best elicited by having patients stretch out their fingers while feeling
the fingertips with the palm. Common neurologic manifestations include hyperreflexia,
muscle wasting, and proximal myopathy without fasciculation. Chorea is rare.
Thyrotoxicosis is sometimes associated with a form of hypokalemic periodic paralysis;
this disorder is particularly common in Asian males with thyrotoxicosis, but it occurs in
other ethnic groups as well.
The most common cardiovascular manifestation is sinus tachycardia, often
associated with palpitations, occasionally caused by supraventricular tachycardia. The
high cardiac output produces a bounding pulse, widened pulse pressure, and an aortic

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systolic murmur and can lead to worsening of angina or heart failure in the elderly or
those with preexisting heart disease. Atrial fibrillation is more common in patients >50
years of age. Treatment of the thyrotoxic state alone converts atrial fibrillation to normal
sinus rhythm in about half of patients, suggesting the existence of an underlying cardiac
problem in the remainder.
The skin is usually warm and moist, and the patient may complain of sweating
and heat intolerance, particularly during warm weather. Palmar erythema, onycholysis,
and, less commonly, pruritus, urticaria, and diffuse hyperpigmentation may be evident.
Gastrointestinal transit time is decreased, leading to increased stool frequency, often
with diarrhea and occasionally mild steatorrhea. Women frequently experience
oligomenorrhea or amenorrhea; in men, there may be impaired sexual function and,
rarely, gynecomastia. The direct effect of thyroid hormones on bone resorption leads to
osteopenia in long-standing thyrotoxicosis; mild hypercalcemia occurs in up to 20% of
patients, but hypercalciuria is more common. There is a small increase in fracture rate in
patients with a previous history of thyrotoxicosis.

Lid retraction, causing a staring appearance, can occur in any form of

thyrotoxicosis and is the result of sympathetic overactivity. However, Graves’ disease is
associated with specific eye signs that comprise Graves’ ophthalmopathy. This
condition is also called thyroid-associated ophthalmopathy, because it occurs in the
absence of hyperthyroidism in 10% of patients. Most of these individuals have
autoimmune hypothyroidism or thyroid antibodies. The onset of Graves’
ophthalmopathy occurs within the year before or after the diagnosis of thyrotoxicosis in
75% of patients but can sometimes precede or follow thyrotoxicosis by several years,
accounting for some cases of euthyroid ophthalmopathy.
Some patients with Graves’ disease have little clinical evidence of
ophthalmopathy. However, the enlarged extraocular muscles typical of the disease, and
other subtle features, can be detected in most patients when investigated by ultrasound
or computed tomography (CT) imaging of the orbits. Unilateral signs are found in up to
10% of patients. The earliest manifestations of ophthalmopathy are usually a sensation
of grittiness, eye discomfort, and excess tearing. About one-third of patients have
proptosis, best detected by visualization of the sclera between the lower border of the
iris and the lower eyelid, with the eyes in the primary position. Proptosis can be

13
measured using an exophthalmometer. In severe cases, proptosis may cause corneal
exposure and damage, especially if the lids fail to close during sleep. Periorbital edema,
scleral injection, and chemosis are also frequent. In 5–10% of patients, the muscle
swelling is so severe that diplopia results, typically, but not exclusively, when the
patient looks up and laterally. The most serious manifestation is compression of the
optic nerve at the apex of the orbit, leading to papilledema; peripheral field defects; and,
if left untreated, permanent loss of vision.
The “NO SPECS” scoring system to evaluate ophthalmopathy is an acronym
derived from the following changes:
0 = No signs or symptoms
1 = Only signs (lid retraction or lag), no symptoms
2 = Soft tissue involvement (periorbital edema)
3 = Proptosis (>22 mm)
4 = Extraocular muscle involvement (diplopia)
5 = Corneal involvement
6 = Sight loss
Although useful as a mnemonic, the NO SPECS scheme is inadequate to
describe the eye disease fully, and patients do not necessarily progress from one class to
another; alternative scoring systems (e.g., the EUGOGO system developed by the
European Group On Graves’ Orbitopathy) that assess disease activity are preferable for
monitoring and treatment purposes. When Graves’ eye disease is active and severe,
referral to an ophthalmologist is indicated and objective measurements are needed, such
as lid-fissure width; corneal staining with fluorescein; and evaluation of extraocular
muscle function (e.g., Hess chart), intraocular pressure and visual fields, acuity, and
color vision.

1.6. Diagnosis
Serum TSH should be measured first, because it has the highest sensitivity and
specificity in the diagnosis of thyroid disorders. If low, serum free T4 or free T4 index,
and free or total T3 concentrations should be measured to distinguish between
subclinical hyperthyroidism (with normal circulating hormones) and overt
hyperthyroidism (with increased thyroid hormones). It also identifies disorders with

14
increased thyroid hormone concentrations and normal or only slightly raised TSH
concentrations, as in patients with TSH-secreting pituitary adenomas or peripheral
resistance to thyroid hormone. The modalities preferred for assessing the cause of
thyrotoxicosis vary widely. Different population characteristics, cultural backgrounds,
and socioeconomic reasons partly explain these differences. American Thyroid
Association (ATA) and American Association of Clinical Endocrinologists (AACE)
guidelines for hyperthyroidism and thyrotoxicosis recommend a thyroid radioactive
iodine uptake test, unless the diagnosis of Graves’ disease is established clinically.

A thyroid radioactive iodine uptake test in patients with Graves’ disease would show
diffusely increased uptake. However, radioactive iodine uptake would be normal or high
with an asymmetrical and irregular pattern in toxic multinodular goitre, and a localised
and focal pattern in toxic adenoma, with suppressed uptake in the remaining thyroid
tissue. Radioactive iodine uptake in patients with thyrotoxicosis from extrathyroidal
sources of thyroid hormone or from release of preformed thyroid hormones, as in silent
or painful thyroiditis, will be very low.

Figure 4. Evaluation of thyrotoxicosis. aDiffuse goiter, positive TPO antibodies or

TRAb, ophtalmopathy, dermopathy. bCan be confirmed by radionuclide scan. TSH,
thyroid stimulating hormone.

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 Table 4. Wayne Index

1.7. Management

The three options for treating patients with hyperthyroidism are antithyroid drugs
(ATDs), radioactive iodine ablation, and surgery. All three therapeutic options would be
effective in the treatment of patients with Graves’ disease, whereas patients with toxic
adenoma or toxic multinodular goitre should have either radioactive iodine therapy or
surgery, since these patients rarely go into remission. In patients with toxic nodular
goitre, ATDs are generally used to restore euthyroidism before definitive treatment with
surgery or radioactive iodine, and infrequently used as long-term treatment when the
other two therapies are contraindicated or the patient has a short life expectancy.

The main antithyroid drugs are thionamides; propylthiouracil, carbimazole (not

available in the United States), and the active metabolite of the latter, methimazole. All
inhibit the function of TPO, reducing oxidation and organification of iodide. These
drugs also reduce thyroid antibody levels by mechanisms that remain unclear, and they
appear to enhance spontaneous rates of remission. Propylthiouracil inhibits deiodination
of T4 → T3. However, this effect is of minor benefit, except in the most severe
thyrotoxicosis, and is offset by the much shorter half-life of this drug (90 min)
compared to methimazole (6 h). Due to the hepatotoxicity of propylthiouracil, the U.S.
Food and Drug Administration (FDA) has limited indications for its use to the first

16
trimester of pregnancy, the treatment of thyroid storm, and patients with minor adverse
reactions to methimazole. If propylthiouracil is used, monitoring of liver function tests
is recommended.
ATA/AACE guidelines recommend thiamazole as the preferred drug in Graves’
disease. The exceptions are therapy during the first trimester of pregnancy and in
patients with adverse reactions to thiamazole. Thiamazole has several advantages over
propylthiouracil, such as better efficacy; longer half-life and duration of action, allowing
once-daily dosing compared with two to three times daily dosing of propylthiouracil;
and less severe side-effects. Reports of liver damage in patients who had received
propylthiouracil prompted the ATA and the US Food and Drug Administration to
reassess the role of propylthiouracil in the management of Graves’ disease,
recommending against propylthiouracil as the first-line therapy. Although combined
early treatment with ATD and potassium iodide has been suggested, this approach is not
generally recommended.

Protocols for ATD therapy and follow-up

There are two approaches to the treatment of Graves’ disease: titration and block
and replace. With titration, the dose of ATD is titrated over time to the lowest dose
needed for maintaining a euthyroid state. In the block and replace regimen, a higher
dose of ATD is used with concurrent replacement with levothyroxine. The two
regimens are equally effective but the block and replace regimen seems to be associated
with a higher incidence of side-effects than does the titration method. Therefore, the
titration regimen should be the first-line approach, even if some authors regard both
approaches as equally safe.
The starting dose of thiamazole depends on the severity of the hyperthyroidism
and the size of the thyroid gland: mild hyperthyroidism and small glands need 10–15
mg of thiamazole daily, and severe hyperthyroidism and large thyroids need 20–40 mg
daily. The equivalent dose of carbimazole is 140% of that of thiamazole. The starting
dose of propylthiouracil is usually 50–150 mg administered three times daily. Thyroid
function should be checked 4–6 weeks after initiation of therapy and then every 2–3
months once the patient is euthyroid, although we usually see the patient every 4
months when they are euthyroid. TSH might remain suppressed for several months,

17
which is why serum T4 and T3 should be monitored to assess efficacy of therapy. Once
euthyroidism is achieved, a maintenance dose of thiamazole of 5–10 mg daily, or 50 mg
propylthiouracil two or three times daily, or lower, should be continued for 12–18
months, and some suggest an even longer duration of therapy.
A drawback of ATD therapy is the high rate of relapse of hyperthyroidism after
the drug has been discontinued. Relapse is more frequent in the first year than
subsequent years, particularly in the first 6 months after stopping the drug, but
uncommon after 4–5 years. The risk of recurrence varies greatly among patients, but is
estimated to be 50–55% according to a Cochrane review of 26 randomised clinical
trials. Patients at higher risk of recurrence are those with severe hyperthyroidism, large
goitre, high T3:T4 ratios, persistently suppressed TSH, and high baseline concentrations
of TRAb. Assessment of TRAb concentrations at the end of treatment might be useful
to identify patients in whom hyperthyroidism will recur after discontinuation of therapy.
A prospective study suggested that a second course of thionamide drugs after recurrence
of hyperthyroidism can result in long-term remission. Nevertheless, further studies are
needed to confirm these data, and to compare the efficacy and side-effects of the second
course of ATD therapy with those of radioactive iodine ablation or surgery.

Side-effects
Minor side-effects of ATDs occur in about 5% of patients. These side-effects
include pruritus, arthralgia, and gastrointestinal distress. In patients with minor skin
reactions, an antihistamine can be added or one ATD can be substituted for the other.
Major side-effects of ATDs are rare. Agranulocytosis, in which the absolute
granulocyte count is less than 500 cells/mm³, is the most frequent major side-effect and
can be life-threatening. Patients usually present with fever or sore throat, or both, and
sometimes with other less common symptoms such as chills, diarrhoea, and myalgia.
The annual incidence of agranulocytosis has been estimated to be 0·1–0·3%, and
generally occurs within 90 days after initiation of therapy. When patients receiving
ATDs present with these symptoms, a white blood cell count with differential should be
obtained and the ATD should be immediately discontinued if the granulocyte count is
less than 1000 cells/mm³. Treatment of agranulocytosis and its associated infections
might be also necessary, such as administration of broad-spectrum antibiotics and

18
granulocyte colony-stimulating factor, which has been shown to reduce the recovery
time. Trial of another ATD is contraindicated in this circumstance because of the
documented cross-reactivity between thiamazole and propylthiouracil. The ATA/AACE
guidelines suggest that all patients have a baseline complete blood count before
initiation of therapy, but recommend against routine monitoring during therapy. This
practice is also accepted outside of the USA, except in Japan where periodic monitoring
of white blood cells is recommended every 2 weeks during the first 2 months of therapy.
Patients should be instructed to recognise symptoms of agranulocytosis, and to
discontinue the drug and contact their physicians as soon as possible, once fever or sore
throat occur. A survey showed a lack of knowledge of this potentially serious side-effect
in patients taking ATDs. Other very rare haematological side-effects of ATDs include
aplastic anaemia, thrombocytopenia, and hypoprothrombinaemia.
Another major side-effect is hepatotoxicity, which occurs in 0·1–0·2% of
patients. It usually develops within 3 months of therapy and the incidence peaks in the
first 30 days of treatment. The most common manifestation of hepatotoxicity in patients
taking either thiamazole or propylthiouracil is hepatitis. Hepatotoxicity can rarely
present as acute liver failure, which is associated with propylthiouracil more frequently
than with thiamazole, and might require liver transplant. The ATA/AACE guidelines
recommend obtaining a serum liver profile at baseline, but recommend against periodic
monitoring unless the patient complains of symptoms of hepatic dysfunction, such as
pruritic rash, jaundice, light-coloured stool, or dark urine. In patients taking thiamazole,
cholestasis can occur; this side-effect is rare with propylthiouracil, for which liver
problems are mainly related to hepatocellular necrosis.
Vasculitis is a very rare complication that has been reported during therapy with
ATDs. Vasculitis is often associated with antineutrophil cytoplasmic antibody and is
more frequent in patients taking propylthiouracil than in those taking thiamazole.
Patients might present with fever, arthralgia, and skin involvement, or might have organ
failure—mainly of the kidneys and lungs.

Radioactive iodine therapy

Radioactive iodine therapy is safe and cost-effective and can be the first-line
treatment for Graves’ disease, toxic adenoma, and toxic multinodular goitre. Absolute

19
contraindications include pregnancy, breastfeeding, planning pregnancy, and inability to
comply with radiation safety recommendations. In patients with thyroid nodules whose
biopsy samples are suspicious for or diagnostic of thyroid cancer, radioactive iodine is
contraindicated and surgery is recommended. Radioactive iodine therapy has been
shown to be responsible for de-novo development or worsening of Graves’ orbitopathy,
although others disagree. Therefore, radioactive iodine therapy is contraindicated in
patients with active moderate-to-severe or sight-threatening Graves’ orbitopathy. In
patients with mild active Graves’ orbitopathy, radioactive iodine treatment should be
followed by prophylactic steroid treatment (0·3–0·5 mg/kg of prednisone daily, starting
1–3 days after radioactive iodine and tapered over 3 months).
Management of patients receiving radioactive iodine therapy
Some patients, especially elderly patients and those with comorbidities (in
particular cardiovascular complications) or severe thyrotoxicosis, might need
pretreatment with ATDs. The need for pretreatment and the effect of ATDs on
radioactive iodine therapy is debatable. Some argue that thiamazole pretreatment has no
effect on the efficacy of radioactive iodine therapy, but is protective because it lowers
baseline thyroid hormone concentrations before radioactive iodine therapy. Others
suggest that it is not protective against exacerbation of thyrotoxicosis. When an ATD is
used before radioactive iodine therapy, thiamazole is the preferred drug, because
propylthiouracil has been related to higher rates of treatment failure. ATD should be
stopped 3–5 days before radioactive iodine therapy, then restarted 3–7 days later, and
withdrawn as soon as thyroid function normalises.
Follow-up of patients who receive radioactive iodine therapy
Thyroid function should be monitored 1–2 months after radioactive iodine
therapy. Some suggest measuring free T4 no more than 6 weeks after radioactive iodine
therapy, to detect hypothyroidism, especially in patients at risk for developing or
worsening Graves’ orbitopathy. If the patient is still thyrotoxic 1–2 months after
radioactive iodine therapy, thyroid function should be monitored every 4–6 weeks until
the patient is euthyroid or hypothyroid.
Side-effects
Except for ophthalmopathy, adverse effects of radioactive iodine are rare and not
well established. One side-effect is acute thyroiditis. It occurs in 1% of patients, lasts for

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a few weeks, and is easily treated with non-steroidal anti-inflammatory drugs (NSAIDs)
and β blockers for the associated exacerbation of hyperthyroidism. Some patients with
severe cases might need glucocorticoids. Other adverse effects of radioactive iodine
therapy have been postulated, but no clear consensus has been reached. Increased risks
of cardiovascular diseases and cerebrovascular events are considered, but whether the
events are caused by hyperthyroidism itself or radioactive iodine therapy is unclear.
Cancer incidence is slightly higher in patients who are hyperthyroid than in those who
are euthyroid, but is not associated with type of thyroid treatment. Finally, impairment
of gonadal function has been shown with higher doses of radioactive iodine usually
used in the treatment of thyroid cancer, but not with the lower doses used for
hyperthyroidism. No adverse effects were reported on the health of offspring of patients
given radioactive iodine for hyperthyroidism before pregnancy.
Thyroidectomy
Thyroidectomy is the most successful treatment for Graves’ hyperthyroidism.
Total thyroidectomy is recommended, since the frequency of successful outcomes are
significantly higher than with subtotal thyroidectomy (odds ratio 40·37, 95% CI 15·03–
108·44), with no differences in the rate of complications. Thyroidectomy is particularly
recommended in patients with the following characteristics: large goitres or low uptake
of radioactive iodine (or both); suspected or documented thyroid cancer; moderate-to-
severe ophthalmopathy, for which radioactive iodine therapy is contraindicated; and
finally, a preference for surgery. Conversely, thyroidectomy should be avoided in
patients who are not good surgical candidates. Pregnancy is only thought to be a relative
contraindication.
Preoperative management and follow-up of patients who receive thyroidectomy
Before surgery, patients should be euthyroid. Pretreatment with ATD reduces
the risk of thyroid storm precipitated by surgery, and β blockers control hyperthyroid
symptoms. Pretreatment with inorganic iodide, such as potassium iodide (50 mg iodide,
three times daily, for 7–10 days before surgery) can also be considered in patients with
Graves’ disease. Inorganic iodide reduces thyroid hormone release and thyroid
vascularity, which in turn decreases intraoperative blood loss. After surgery,
levothyroxine replacement should be started and TSH concentration monitored 6–8

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weeks after surgery. Oral calcium and calcitriol supplementation can be used before
surgery and according to postoperative serum calcium concentrations.
Side-effects
Surgical complications are rare, occurring in 1–3% of patients. The most
frequent complication is hypocalcaemia due to permanent hypoparathyroidism,
followed by permanent recurrent laryngeal nerve injury. The risk of these complications
is lower when thyroidectomy is done by a high-volume thyroid surgeon.

1.8. Prognosis
Hyperthyroidism from toxic multinodular goiter and toxic adenoma is
permanent and usually occurs in adults. After normalization of thyroid function with
antithyroid medications, radioactive iodine ablation usually is recommended as the
definitive therapy. Long-term, high-dose antithyroid medication is not recommended.
Toxic multinodular goiters and toxic adenomas probably will continue to grow slowly
in size during antithyroid pharmacotherapy.
Generally, the thyrotoxic areas are ablated, and patients may remain euthyroid.
Those who become hypothyroid after radioactive iodine therapy are easily maintained
on thyroid hormone replacement therapy, with T4 taken once daily.
Patients with Graves disease may become hypothyroid in the natural course of
their disease, regardless of whether treatment involves radioactive iodine or surgery.
Eye disease may develop at a time distant from the initial diagnosis and therapy.
Generally, after the diagnosis, the ophthalmopathy slowly improves over years.
Thyroid hormone excess causes left ventricular thickening, which is associated
with an increased risk of heart failure and cardiac-related death. Thyrotoxicosis has
been associated with dilated cardiomyopathy, right heart failure with pulmonary
hypertension, and diastolic dysfunction and atrial fibrillation.
An increase in the rate of bone resorption occurs. Bone loss, measured by bone
mineral densitometry, can be seen in severe hyperthyroidism at all ages and in both
sexes. In mild subclinical disease, however, bone loss has been convincingly shown
only in postmenopausal women.

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