Risk Factors and Clinical Manifestations in Hyperthyroidism: A Systematic Review

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Anidha et al. | Amerta Nutrition Vol. 7 Issue 2SP (December 2023). 344-351
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SYSTEMATIC REVIEW
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Risk Factors and Clinical Manifestations in Hyperthyroidism: A

Systematic Review
Faktor Resiko dan Manifestasi Klinis Pada Hipertiroid: Tinjauan Sistematis
Yusrita Anidha1*, Wilis Cahyaning Ayu1, Nur Mufida Wulan Sari1, Siti Rahayu Nadhiroh2
1Program Studi Magister Kesehatan Masyarakat, Fakultas Kesehatan Masyarakat, Universitas Airlangga, Surabaya,
Indonesia
2Departemen Gizi, Fakultas Kesehatan Masyarakat, Universitas Airlangga, Surabaya, Indonesia
ABSTRACT
ARTICLE INFO Background: The recommended iodine intake for adult women is 150-300µg and for
men <150µg, which functions in maintaining normal thyroid function. Hyperthyroid
Received: 29-09-2023 condition is characterized as increased synthesis or secretion of hormones by the
Accepted: 31-12-2023 thyroid gland. A family history of Graves' disease is the most frequently found risk factor,
Published online: 31-12-2023 namely 60-80% worldwide. The prevalence of hyperthyroidism cases in Indonesia is
around 6.8%
*Correspondent: Objectives: Comprehensively identifying risk factors and clinical manifestations of
Yusrita Anidha hyperthyroidism in case studies.
yusrita.anidha- Methods: This research was carried out with a systematic review using two databases,
[email protected] namely Pubmed and Scopus. The literature search strategy was carried out using
Convidence software by including predetermined inclusion and exclusion criteria. There
DOI: were 11 selected pieces of literature published from January 2016 to October 2022
10.20473/amnt.v7i2SP.2023.34 Discussion: A total of 11 case studies showed that women dominated cases of
4-351 hyperthyroidism with a ratio of 3:1. Through a systematic review conducted by
researchers, it shows that Graves' disease is the leading risk factor and clinical
Available online at: manifestations such as swelling of the thyroid gland, difficulty breathing, progressive
https://e- weight gain, tremors, and heart palpitations are often found.
journal.unair.ac.id/AMNT Conclusion: Patients who are female and have a family history of Graves’ disease are
the most common risk factors found with clinical manifestations of swollen thyroid
Keywords: gland, difficulty breathing, progressive weight gain, tremors, and palpitations.
Risk factors, Hyperthyroidism,
Case studies
INTRODUCTION States at 1.2% and in Europe at 0.8%5. Specifically, the

Hyperthyroidism is a condition of increased condition of hyperthyroidism based on age is more
production and secretion of thyroid hormone by the common in women. In general, to diagnose
thyroid gland. This condition is characterized by thyrotoxicosis and determine the cause, a thorough,
increased T3 (triiodothyronine) and T4 (thyroxine) due to careful and thorough history and physical examination is
the immune system attacking the thyroid gland. The most required, assisted by supporting examinations such as
significant risk factor is genetic, which is 80%, followed by laboratory examination of levels of Thyroid Stimulating
environmental factors at 20% which comes from Hormone (TSHs), Free Thyroxine 4 (FT4), and sometimes
exposure to cigarette smoke and a person's stress level 1. tri-iodothyronine ( T3) total4,6.
The body's need for iodine functions as a synthesis of In 1990, the salt iodization program was
thyroid hormone to help regulate cell metabolic activity. introduced, and it was widely recognized that iodization
Iodine is also important for cell replication and is closely could reduce the prevalence of iodine deficiency in the
related to the development of fetal brain cells in the population7. Mild cases can usually be treated with the
womb2. Consuming iodine is very important to support best sources of iodine salt from dairy foods such as milk,
thyroid function, but excessive consumption can inhibit egg yolks, and sea fish. On the other hand, some
the formation of thyroid hormone, It can cause problems can be observed from a public health
hypothyroidism or swelling of the thyroid gland 3. perspective that pregnant women, fetuses, neonates and
The prevalence of hyperthyroidism cases in infants are the groups most vulnerable to iodine
Indonesia is around 6.9%4. This percentage contrasts with problems because of the irreversible health risks that can
the overall prevalence of hyperthyroidism in the United cause brain damage and impaired intellectual
Copyright ©2023 Faculty of Public Health Universitas Airlangga

Open access under a CC BY – SA license | Joinly Published by IAGIKMI & Universitas Airlangga
How to cite: Anidha, Y., Ayu, W. C., Sari, N. M. W., & Nadhiroh, S. R. (2023) Risk Factors and Clinical Manifestations in Hyperthyroidism: A Systematic Review:
Faktor Resiko dan Manifestasi Klinis Pada Hipertiroid: Tinjauan Sistematis. Amerta Nutrition, 7(2SP), 344–351.
p-ISSN: 2580-9776 (Print) 345
development5. The recommended iodine intake for adult "hyperthyroidism," "case reports," or "case study." This
women is 150-300µg and for men <150µg to function in research literature refers to previously established
maintaining normal thyroid function, while in pregnant inclusion and exclusion criteria. Several inclusion criteria
women, iodine intake increases along with the needs of in this study include: (i) research identifying risk factors
the fetus5. Only 18% of pregnant women and 19% of for hyperthyroidism, (ii) research identifying clinical
breastfeeding women use iodine supplementation, manifestations of hyperthyroidism, and (iii) literature
according to data from The National Health and Nutrition consisting of case studies/case reports. Meanwhile, the
Examination Survey (NHANES) 2011-20145. The World exclusion criteria in this study, are (i) research involving
Health Organization (WHO) recommends 250 mcg of participants with other comorbidities such as metabolic
iodine daily for pregnant and breastfeeding women8. syndrome, diabetes, hypertension, cancer, and others;
Therefore, the author aims to identify risk factors and (ii) research conducted at the experimental animal or
clinical manifestations of hyperthyroidism cellular level; and (iii) unpublished articles and duplicate
comprehensively. articles. The literature search used Confidence software
to facilitate article extraction. The Preferred Reporting
METHODS Items for Systematic Reviews and Meta-analyses
This research was conducted with a systematic (PRISMA) diagram of the literature search strategy used
review using the PubMed and Scopus databases in the in this study is presented in Figure 1.
period 2016-2022 with the keywords "risk factor,"
Duplication articles, journal

articles with a time span of
Search results for electronic-based articles (n = more than 5 years, journal
2765) consist of Pubmed (n = 1628) and Scopus (n articles that are not in the
= 1137). category of research articles,
and journal articles that are
not full text (n = 2621)
The first screening results are based on the title Articles that do not match
and abstract (n = 144). the theme reviewed
(n=114)
The selection results are in accordance with the Articles that do not fulfill
theme that has been reviewed (n = 30). the inclusion criteria
(n=19)
Results of the articles that have gone through the

screening process and taken into account eligibility
are 11 articles.
Figure 1. PRISMA flow diagram of the article selection process
DISCUSSION were found in the adult age (>25 years). The results of the
Researchers obtained 11 works of literature with literature extraction presented in Table 1 showed that
quite diverse respondent characteristics. One case was females are more dominant in experiencing cases of
found in the adolescent age (15 years), while ten points hyperthyroid disorders with a ratio of 3:1.

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Table 1. Characteristics of selected research

Research Sex Age Thyroid Risk Factors Comorbidities Clinical Symptoms Laboratory Data Treatments Recovery Time
(M/F (Old Disorders
TSH Free T3 Free T4
) )
(Kulkarni et M 45 Toxic adenoma Family Graves’ Disease • Thyroid Gland 0.02 2.21 10.74 g/dL Pharmacological 8 Days
al.) 20219 history (+) mIU/L ng/mL Anti-thyroid
• Hoarseness medication
• Breathing 5% Lugol's iodine 8
Difficulties drops (60 mg)
• Mild tachycardia Methimazole 10 mg
Propranolol 20 mg
Hydrocortisone 10
mg
Surgery
Asif et al., M 37 Psychosis Family Graves’ Disease • Thyroid Gland (<0.01 (9.27 (3.4 ng/dL) Pharmacological 1 week
202210 History (+) uIU/mL) pg/mL) normal:(0.9 Anti-thyroid
• Mood Swings normal: normal: -1.8 ng/dL) medication
• Insomnia (0.27- (1.80- Methimazole 30mg
• Talking more 4.20 4.60 Propranolol 80 mg
• Acting paranoid uIU/mL) pg/mL) Hydrocortisone
• Hyperactive 100mg
(Kazakou et F 33 Fetal Family Graves' disease • Intrauterine 1.7 N/A 18.53 Pharmacological 30 + 3 weeks
al., 2018)11 Hyperthyroidis History in pregnant growth U/ml pmol/L Anti-thyroid
m women retardation normal: Normal: medication
• Oligohydramnio (1-3) (12-22) Methimazole,
s Propranolol are
• Increased heart given to newborns
rate (signs of The infant died →
heart failure) severe infection and
• Fetal shortness of breath
tachycardia
• Hydrops
(Overcash et F 27 Fetal Goiter Consuming Hypothyroidis • Infant neck 2.73 2.0 8.3 g/dL Pharmacological -
al., 2016)3 excessive m during hyperextension IU/mL ng/mL (normal: Anti-thyroid
iodine pregnancy → due to the (normal (1.8– 7.5–10.3 medication
supplements presence of : 0.4– 3.7 g/dL) Synthroid 75µg
during • Polyhydramnios 3.6 ng/mL)
pregnancy with amniotic IU/mL) .
fluid

p-ISSN: 2580-9776 (Print) 347
(M/F (Old Disorders
TSH Free T3 Free T4
) )
(Pangaribuan F 31 Postpartum Postnatal • Diabetes • Thyroid Gland 75.41 0.53 0.46 Pharmacological 6 Days
& Santi Thyroiditis inflammatio Mellitus Type 2 (+) grade 2 mU/ml Euthyrox 1x100
Syafril, n of the • Dyslipidemia • Hoarseness mcg, Lantus
2021)12 thyroid gland • Feeling tired injection 10 IU SC
easily Additional therapy
of Simvastatin 1x 20
mg.
Onwukwe., et F 44 Autoimmune Family Graves’ Disease • Progressive 100 1.4 3.2 pmol/L Pharmacological -
al 202213 Thyroid history weight gain mIU/L pmol/L Anti-thyroid
• Constipation (0.30- medication
• Cold intolerance 3.5) Thyroxine
200mcg/hari
Punitha et al., F 60 Papillary Thyroid Hypertension • Thyroid gland (+) N/A N/A N/A Pharmacological 6 cycles
201914 Thyroid Cancer carcinoma • Coughing Anti-cancer drugs →
• Shortness of Vincristine,
breath Cyclophosphamide,
• Odinophagia Doxorubicin
Chemotherapy
→corticosteroids
Tsai et al., F 66 Thyroid - Osteoporosis • Progressive 0.09 400 1.6 ng/dL Anti-thyroid -
202215 dysfunction weight loss mIU/L pg/dL (0.8-1.7) medication
• Anxiety (0.3-4.7) (222-
• Insomnia 383)
• Heat intolerance
• Tremors
• Heart
palpitations

p-ISSN: 2580-9776 (Print) 348
(M/F (Old Disorders
TSH Free T3 Free T4
) )
Dey Parijat., M 48 Graves Family • Pain in the eye <0.01
Graves’ Disease 21.6 35 pmol/L Pharmalogical 3 days of
202016 orbitopathy history area mUL pmol/L Anti-thyroid treatment
• Conjunctival medication (1 mg Decompressio
hyperemia Methylprednisolone n surgery
• Eyelid swelling )
• Reduced visual
acuity (6/18)
• Reduced colour
vision
Subramonian. F 15 Thyroid - Myalgias • Fatigue 0.01 >30.8 75.4 pmol/L Pharmacological 4 months
, et al 202117 Dysfunction Hypertension • Heat Intolerance mU/L pmol/L Anti-thyroid
• Mumbling medication →
• Myalgias methimazole
• Heart Rate 0.5mg/kg/day &
148x/min and bisoprolol 2.5mg
irregular 1x/day
• Blood Pressure Synchronized
138/72mmHg cardioversion
Borrego., et al F 53 Anxiety Endocrine Thyroid • Heart <0.005 21 4 pmol/L Pharmacological -
201618 disorders system dysfunction palpitations mU/L pmol/L Anti-thyroid
disorders • Trembling medication
• Shortness of
breath
• Nausea
• Psychiatric
disorders
Notes: M = Male; F = Female; TSH = thyroid-stimulating hormone; T3 = L-triiodothyronine; T4 = thyroxine; N/A = not available
Normal Values: TSH, 0.35-5.5 µU/mL; Free T3, 222–383 pg/dL; Free T4, 0.9-1.8ng/dL

p-ISSN: 2580-9776 (Print) 349
Risk Factors for Hyperthyroid Conditions disorders such as toxic adenoma, psychosis, autoimmune
Hyperthyroidism refers to a condition when the thyroid, and thyroid papillary cancer. Clinical
body produces too affects many thyroid hormones so manifestations, as in Table 1, generally show clinical
that the thyroid gland is too active in working, affecting symptoms such as swelling of the thyroid gland, difficulty
metabolism in the body19. Several conditions that can breathing, progressive weight gain, tremors, and
affect excess hormone production include Graves' palpitations9,13,14. Researchers also found manifestations
disease, excessive consumption of iodine supplements, that appear in visual disturbances, namely pain in the eye
inflammation of the thyroid gland after childbirth, and area, conjunctival hyperemia, swollen eyelids, reduced
endocrine system disorders3,10,12. Through the systematic visual acuity (6/18), and reduced color vision; this
review above, researchers also identified several factors condition is related to thyroid eye disease16.
that increase the chance of hyperthyroidism. A family
history of Graves' disease is the most dominant risk factor Assessment
for the appearance of hyperthyroidism in patients as they Diagnosis in hyperthyroid patients is carried out
get older20. Graves' disease is an autoimmune condition by conducting examinations related to clinical
that occurs due to loss of immunotolerance, causing manifestations. Laboratory examinations performed to
thyrotropin receptor antibodies (TRAb) to form, bind to, establish the diagnosis of hyperthyroidism are
and stimulate thyroid-stimulating hormone (TSH) examinations of Free Thyroxine 4 (FT4), tri-iodothyronine
receptors. This condition will massively increase the (T3), and Thyroid Stimulating Hormone (TSHs) levels. In
synthesis and secretion of thyroid hormones6. neonatal hyperthyroidism, diagnosis is made by looking
Researchers also found cases with a maternal history of at the history of autoimmune disease in the mother, anti-
excessive iodine supplementation 3. Although iodine thyroid medications taken during pregnancy, premature
consumption is significant to support thyroid function, birth, intrauterine growth restriction, microcephaly,
excessive consumption can stimulate thyroid hormone narrow sutures, increased body temperature, irritable,
production resulting in hyperthyroidism or swelling of the very restless, hyperactive, tachypnea (breathing very
thyroid gland2. Excess consumption of iodine quickly) hyper-reflection, tachycardia (heart rate
supplements in special conditions can result in the >160x/min), arrhythmia (heart rhythm disturbance),
appearance of goiter in the fetus in the womb. During enlarged heart ventricles, heart failure, and
pregnancy, iodine crosses the placenta through active hypertension20. Researchers found cases of congenital
transport and iodine toxicity occurs when consumption is hyperthyroidism that were detected through ultrasound
>1.1mg/day21. This can happen because the immature examination and recognized clinical manifestations in the
fetus cannot degrade intracellular iodine, so it will fetus, namely extension of the neck with a mass around
develop a hyperthyroid condition 22. The the neck so that the infant's head was looked up
recommendation for pregnant women is 200µg/day21. accompanied by fetal tachycardia 11.
Women have a 3-10x higher risk of thyroid Elevated free T4 levels do not always correlate
dysfunction compared to men23; right out of eleven cases with the thyroid gland's size. Enlargement of the thyroid
found were dominated by female patients. According to gland in Graves' disease is generally evenly distributed
endocrinologists, the thyroid gland synthesizes thyroid and palpably tender. In thyroid tumors, the lump is
hormones used for complex metabolic processes, such as palpated hard, even without thyroid function
sexual activity, the nervous system, muscles, and abnormalities. Goiter gland is palpable consistency,
skeleton. However, women are more vulnerable and very nodular, painful, murmur, and bruit. Patients with
sensitive to hormonal changes, so excess iodine often symmetrical thyroid enlargement are accompanied by
causes more significant complications in women than eye abnormalities. Eye abnormalities or orbitopathy are
men. The particular condition of hyperthyroidism is also symptoms that often occur in graves’ disease16.
found in postpartum pregnant women 6, characterized by Laboratory examination is done by recognizing the
elevated serum triiodothyronine T3 and/or thyroxin T4 presence of increased FT4 and FT3 levels, decreased TSH
and sometimes undetectable serum TSH20. levels, and positive TRAb. In cases with suspicion of Toxic
Adenoma, radiologic examination is needed to confirm
Manifestations the diagnosis11.
Manifestations in hyperthyroidism adjust to the Researchers found cases of hyperthyroidism
type of thyroid disorder that occurs. Special conditions in experienced by pre-elderly and elderly groups with
pregnant women with hyperthyroidism show fetal clinical clinical manifestations such as progressive weight loss,
symptoms such as intrauterine growth retardation, insomnia, heat sensitivity, anxiety disorders, tremors,
oligohydramnios, increased pulse rate (signs of heart shortness of breath, hypertension, and odinophagia14,15.
failure), and fetal tachycardia 11. Fetal hyperthyroidism In one case, thyroid dysfunction was found to be
occurs when excessive TSH antibody receptors cross the accompanied by osteoporosis15.
placenta. These antibodies stimulate adenylate cyclase in
fetal thyrocytes, resulting in hyperthyroidism 24,25. In this Treatments
case, checking the TSH antibody receptor during 20-24 Treatment for hyperthyroid conditions is
weeks of gestation is important. If the level exceeds the adjusted to the cause of the problem. Age, physical
normal limit by three times, close monitoring should be condition, and severity of the patient's condition should
done24. be considered. According to the American Thyroid
Ten kinds of literature were found involving adult Association Guidelines, hyperthyroid states with Graves'
patients aged >25 years with quite diverse thyroid disease should choose safe and effective treatments for

p-ISSN: 2580-9776 (Print) 350
patients26. In some developed countries such as America. contribute to article writing, revisions, or critical
Japan. And some countries in Europe, , health evaluation.
professionals are more inclined to use the treatment of
anti-thyroid medications27. Previous studies have also Conflict of Interest and Funding Disclosure
shown that all three treatment methods (anti-thyroid The authors have indicated that they have no
medications, radioactive iodine, and surgery) show good potential/perceived conflicts of interest to disclose, and
results on the long-term quality of life of patients28. In no funding organization provided a specific grant for this
some cases, anti-thyroid medication is most commonly research.
given in patients with toxic adenoma, psychosis, fetal
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Risk Factors and Clinical Manifestations in Hyperthyroidism: A

INTRODUCTION States at 1.2% and in Europe at 0.8%5. Specifically, the

Copyright ©2023 Faculty of Public Health Universitas Airlangga

Duplication articles, journal

Results of the articles that have gone through the

Figure 1. PRISMA flow diagram of the article selection process

Copyright ©2023 Faculty of Public Health Universitas Airlangga

Table 1. Characteristics of selected research

Copyright ©2023 Faculty of Public Health Universitas Airlangga

Copyright ©2023 Faculty of Public Health Universitas Airlangga

Copyright ©2023 Faculty of Public Health Universitas Airlangga

Copyright ©2023 Faculty of Public Health Universitas Airlangga

Copyright ©2023 Faculty of Public Health Universitas Airlangga

13. Onwukwe, C. H., Nwalozie, J. C., Kalu, O. K. & (2014).

Copyright ©2023 Faculty of Public Health Universitas Airlangga

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