This document provides an overview of thyrotoxicosis, including its epidemiology, pathophysiology, causes, clinical manifestations, diagnosis, and management. Some key points: - Thyrotoxicosis is defined as thyroid hormone excess and can be caused by hyperthyroidism, thyroiditis, or excess hormone ingestion. The major causes of hyperthyroidism are Graves' disease, toxic multinodular goiter, and toxic adenomas. - Clinical manifestations depend on severity and duration of thyrotoxicosis, and include symptoms like palpitations, sweating, weight loss as well as signs like goiter, tremor, eye changes. Diagnosis involves testing thyroid function through TSH,

1. Thyrotoxicosis
By HALLIDAY, C.A

2. • INTRODUCTION
• EPIDEMIOLOGY
• AETIOLOGY
• PATHOPHYSIOLOGY
• CLINICAL FEATURES
• DIAGNOSIS
• MANAGEMENT
• COMPLICATIONS
• FOLLOW UP
• PROGNOSIS
• CONCLUSION
• REFERENCE

3. Introduction
• Thyrotoxicosis is defined as the state of
thyroid hormone excess and is not
synonymous with hyperthyroidism, which is
the result of excessive thyroid function.
However, the major etiologies of
thyrotoxicosis are hyperthyroidism caused by
Graves’ disease, toxic multinodular goiter
(MNG), and toxic adenomas.

4. Epidemiology
• All thyroid diseases occur more frequently in
women than in men. Graves autoimmune disease
has a male-to-female ratio of 1:5-10. The male-
to-female ratio for toxic multinodular goiter and
toxic adenoma is 1:2-4. Graves ophthalmopathy is
more common in women than in men.
• Autoimmune thyroid diseases have a peak
incidence in people aged 20-40 years.

5. Thyroid Physiology
• Iodine Metabolism:
• The average daily iodine requirement is 0.1 mg.
•Sources : Fish, milk, and eggs or as additives in
bread or salt.
• In the stomach and jejunum, iodine is rapidly
converted to iodide and absorbed into the
bloodstream.
• Iodide is actively transported into the thyroid
follicular cells by an adenosine triphosphate (ATP)–
dependent process.
• The thyroid is the storage site of >90% of the
body's iodine content

7. Thyroid Hormone synthesis
• Iodide trapping, involves active (ATP-dependent) transport
of iodide across the basement membrane of the thyrocyte
via an intrinsic membrane protein, the sodium/iodine
(Na+/I–) symporter.
• Oxidation of iodide to iodine and iodination of tyrosine
residues on Tg, to form monoiodotyrosines (MIT) and
diiodotyrosines (DIT).
• Coupling of two DIT molecules to form tetraiodothyronine
or thyroxine (T4 ), and one DIT molecule with one MIT
molecule to form 3,5,3'triiodothyronine (T3).
• Thyroglobuin (Tg ) is hydrolyzed to release free
iodothyronines (T3 and T4) and mono- and diiodotyrosines
by stimulation of TSH and engulfing within thyroid follicle.
• The latter are deiodinated in the fifth step to yield iodide,
which is reused in the thyrocyte.

8. • In the euthyroid state, T4 is produced and
released entirely by the thyroid gland, whereas
only 20% of the total T3 is produced by the
thyroid. • Most of the T3 is produced by
peripheral deiodination (removal of 5'-iodine
from the outer ring) of T4 in the liver, muscles,
kidney, and anterior pituitary, a reaction that is
catalyzed by 5'-mono-deiodinase. • Thyroid
hormones are transported in serum bound to
carrier proteins such as T4-binding globulin, T4-
binding prealbumin, and albumin.

9. • Only a small fraction (0.02%) of thyroid
hormone (T3 and T4) is free (unbound) and is
the physiologically active component. • T3 is
the more potent of the two thyroid hormones,
although its circulating plasma level is much
lower than that of T4. • T3 is three to four
times more active than T4 per unit weight,
with a half-life of about 1 day, compared to
approximately 7 days for T4.

10. • The thyroid gland also is capable of autoregulation,
which allows it to modify its function independent of
TSH.
• As an adaptation to low iodide intake, the gland
preferentially synthesizes T3 rather than T4 , thereby
increasing the efficiency of secreted hormone.
• In situations of iodine excess, iodide transport, peroxide
generation, and synthesis and secretion of thyroid
hormones is inhibited.
• Excessively large doses of iodide may lead to initial
increased organification, followed by suppression, a
phenomenon called the WolffChaikoff effect.

12. CAUSES OF THYROTOXICOSIS
Primary Hyperthyroidism
• 1. Graves’ disease
• 2. Toxic multinodular goiter
• 3. Toxic adenoma
• 4. Functioning thyroid carcinoma metastases
• 5. Activating mutation of the TSH receptor
• 6. Struma ovarii
• 7. Drugs: iodine excess (Jod-Basedow
phenomenon)

13. Thyrotoxicosis Without Hyperthyroidism
• 1. Subacute thyroiditis
• 2. Silent thyroiditis
• 3. Other causes of thyroid destruction:
amiodarone, radiation, infarction of adenoma
• 4. Ingestion of excess thyroid hormone
(thyrotoxicosis factitia) or thyroid tissue
Secondary Hyperthyroidism
• 1. TSH-secreting pituitary adenoma
• 2. Chorionic gonadotropin-secreting tumors
• 3. Gestational thyrotoxicosis

14. Diffuse toxic goitre(Grave’s disease)
Graves’ disease accounts for 60–80% of
thyrotoxicosis. It is an autoimmune disease with
a strong familial predisposition, female
preponderance (5:1). • Peak incidence between
the ages of 40 to 60 years. • Graves' disease is
characterized by thyrotoxicosis, diffuse goiter,
and extrathyroidal conditions including
ophthalmopathy, dermopathy (pretibial
myxedema), thyroid acropachy, gynecomastia,
and other manifestations.

15. Etiology and Pathogenesis
• The exact etiology of the initiation of the autoimmune
process in Graves' disease is not known.
• A combination of environmental and genetic factors
contribute to Graves’ disease susceptibility.
• Genetic factors, including polymorphisms in HLA-B8
and HLA-DR3 and HLADQA1*0501. cytotoxic T-
lymphocyte-associated protein 4, CD25, PTPN22, Fc
receptor-like3, and CD226, as well as the TSH-R,
Smoking, Sudden increases in iodine intake•
Postpartum state, lithium therapy, and bacterial
infections have been suggested as possible triggers.

16. • Stimulate B lymphocytes, which produce antibodies
directed against the thyroid hormone receptor. • TSIs
or antibodies that stimulate the TSH-R, as well as TSH-
binding inhibiting immunoglobulins or antibodies have
been described. • The thyroid-stimulating antibodies
stimulate the thyrocytes to grow and synthesize excess
thyroid hormone, which is a hallmark of Graves'
disease. • Graves' disease also is associated with other
autoimmune conditions such as type I diabetes
mellitus, Addison's disease, pernicious anemia, and
myasthenia gravis.

17. Toxic Multinodular Goiter (Plummers
Disease)
• MNG occurs in up to 12% of adults.
• More common in women than men and
increases in prevalence with age.
• It is more common in iodine deficient regions

18. Toxic Adenoma
• A solitary, autonomously hyperfunctioning
thyroid nodule- Toxic Adenoma.
• • Thyrotoxicosis is usually mild.
• • Suggested by the presence of the palpable
thyroid nodule & by the absence of clinical
features suggestive of Graves' disease or other
causes of thyrotoxicosis

19. Pathophysiology
• The secretion of thyroid hormone is controlled
by a complex negative feedback mechanism
involving the interaction of stimulatory and
inhibitory factors. Thyrotropin-releasing
hormone (TRH) from the hypothalamus
stimulates the pituitary to release TSH.

20. • 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.

21. • 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.

22. • 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 T3 is 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

24. CLINICAL MANIFESTATIONS
• The clinical presentation depends on :-
• the severity of thyrotoxicosis,
• the duration of disease,
• individual susceptibility to excess thyroid
hormone, and
• the patient’s age.

25. • In the elderly, features of thyrotoxicosis may
be subtle or masked, and patients may
present mainly with fatigue and weight loss, a
condition known as apathetic thyrotoxicosis.

26. Symptoms Signs
1. Hyperactivity, irritability,
dysphoria
2. Heat intolerance and
sweating
3. Palpitations
4. Fatigue and weakness
5. Weight loss with increased
appetite
6. Diarrhea
7. Polyuria
8. Oligomenorrhea, loss of
libido
9. Insomina
1. Tachycardia; atrial fibrillation
in the elderly
2. Tremor
3. Goiter
4. Warm, moist skin
5. Muscle weakness, proximal
myopathy
6. Lid retraction or lag
7. Gynecomastia

27. • Neurologic manifestations include :
• Nervousness, irritability, emotional lability,
psychosis, fine tremors, hyper-reflexia, ill-
sustained clonus muscle wasting, proximal
myopathy without fasciculation, Chorea is
rare.

28. • Cardiovascular manifestation :
• Sinus tachycardia(M/C), Atrial fibrillation (>50
years of age), Angina, Palpitations, bounding
pulse, Wide pulse pressure, aortic systolic
murmur, Supraventricular tachycardia, CHF,
Cardiomyopathy

29. • Gastrointestinal manifestations include –
• Weight loss, Thyrotoxicosis cause unexplained
weight loss, despite an enhanced appetite,
due to the increased metabolic rate.
• Weight gain occurs in 5% of patients, because
of increased food intake.
• increased appetite, vomiting, increased stool
frequency, diarrhoea, steatorrhoea

30. • Reproductive manifestations include –
• Menstrual disturbances (amenorrhoea or
oligomenorrhoea), infertility, repeated
abortions loss of libido Impotence
Gynaecomastia

31. • Graves’ ophthalmopathy .
• Onset :- within the year before or after the
diagnosis of thyrotoxicosis in 75% of patients
• Earliest manifestations sensation of grittiness,
eye discomfort, and excess tearing.
Proptosis, Periorbital edema, chemosis,
diplopia, compression of the optic nerve at
the apex of the orbit

32. Eye Signs in Hyperthyroidism :
• Von Graefe’s — Lid lag,
• Joffroy’s —Absence of wrinkling of forehead on
looking up
• Stellwag’s — Decreased frequency of blinking
• Dalrymple’s — Lid retraction exposing the upper
sclera
• Moebius sign : Inability or failure to converge the
eye balls
• Gifford's sign: Difficulty in eversion of the upper
lid

33. Grading of eye changes :
• “NO SPECS”
• 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 d/t optic nerve involvement

34. • Dermatological manifestations include :
• Increased sweating, warm and moist skin,
Diffuse alopecia, pruritus, palmar erythema
spider naevi, onycholysis, Pretibial myxedema,
Thyroid acropachy

37. • Thyroid
• • Usually diffusely enlarged to >2–3 times its
normal size.
• • The consistency is firm.
• • Thrill or bruit- increased vascularity of the
gland and the hyperdynamic circulation.

40. DIAGNOSIS
• Tests of Thyroid Function
• Serum Thyroid-Stimulating Hormone (Normal 0.5–5
U/mL): Serum TSH levels reflect the ability of the
anterior pituitary to detect free T4 levels. Small
changes in free T4 lead to a large shift in TSH levels
(Inverse relation).
• Total T4 (Reference Range 55–150 nmol/L) and T3
(Reference Range 1.5–3.5 nmol/L). Free T4 (Reference
Range 12–28 pmol/L) and Free T3 (3–9 pmol/L).
• Thyroid Antibodies : Thyroid antibodies include antiTg,
antimicrosomal, or anti-TPO and thyroidstimulating
immunoglobulin (TSI).

41. Diagnosis
• TSH Assay- single best test of Thyroid Hormone
action at cellular level.
• Subclinical hyperthyroidism - TSH level is
0.10.4mU/L with normal FT3 & FT4.
• Overt hyperthyroidism - TSH level is <0.03mU/L
with increased T3 & T4.
• Thyroid Storm - TSH level is <0.01mU/L.
• Free T4 (FT4)- approx 0.02% of total T4.
• Elevated in 90% of patients with hyperthyroidism.
• Decreased in 85% of patients with hypothyroidism.

42. • Radioactive iodine uptake I123, I131 & Tc99
- Varies directly with functional state of thyroid.
- 24 hr thyroid uptake is measured.
- Normal value range – 10-25%
- Used to confirm Hyperthyroidism.

43. • Thyroid scan using I123 or Tc99 evaluate
nodules as
- Warm/ Normal
- Hot/ Hyperfunctioning.
- Cold/ Hypofunctioning
• Ultrasonography to differentiate between
cystic, mixed or solid lesion in gland.

45. • Thyroid USS
• a diffusely abnormal-
appearing thyroid gland;
it is enlarged,
heterogeneous and
hypoechoic.
• The Doppler image on
the right shows diffusely
increased vascularity
throughout the thyroid.
This appearance is called
a ‘thyroid inferno’. These
are the typical
sonographic features of
Graves disease.

46. • T3 resin uptake test (RT3U)- Indirect measure of
unbound fraction of T4. • It quantitates the
degree of saturation of TBG sites by T3 & T4. • It
is directly proportional to FT4 & inversely
proportional to TBG sites.
• FT4 index = T4 x RT3U. Normal value- 1.4-4.9
• In 2–5% of patients, only T3 is increased (T3
toxicosis).
• The converse state of T4 toxicosis-
hyperthyroidism is induced by excess iodine.

47. • TRH stimulation test used to test pituitary
function.
• • Measurement of TPO antibodies is useful in
differential diagnosis.
• • Measurement of TBII or TSI will confirm the
diagnosis but is not needed routinely.

48. • Other tests
• Serum Antimicrosomal Antibodies -Anti-Tg and anti-
TPO antibodies are elevated in up to 75% of patients.
• Antithyroglobulin antibodies- elevated TSH-R or
thyroid-stimulating antibodies (TSAb) are diagnostic of
Graves' disease and are increased in about 90% of
patients.
• Long acting thyroid stimulators (LATS).
• Thyroglobulin, is a protein made by cells in the thyroid.
mostly used as a tumor marker test to help guide
thyroid cancer treatment.
Occasionally ordered to help determine the cause of
hyperthyroidism and to monitor the effectiveness of
treatment for conditions such as Graves disease

50. Other Investigations
• Complete blood count, to rule out anaemia,
thrombocytopenia and agranulocytosis.
• • Urinalysis- Albumin, Sugar, Microscopy
• • RBS, Serum creatinine/u/e
• • ECG- Sinus tachycardia, ST elevation, QT
shortening, atrial fibrillation/flutter,
ventricular ectopic

51. • Chest X-ray
• PA view- position of trachea, deviation,
retrosternal goiter, calcification.
• Lateral view and barium swallow- pressure
effects on trachea and oesophagus

52. • Flow volume loop- best
indications of airway
obstruction.
• CT scan and MRI scan-
for airway evaluation
and extension of
thyroid

53. Treatment
• Medical therapy
• Radioiodine ablation
• Surgery
• For the medical therapy, there are two types
of regimen;
- Titration regimen
- Block and replace regimen

54. • Antithyroid drugs
• Carbimazole (CBZ), Methimazole, propylthiouracil
(PTU)
• belonging to the thioureas group • also blocks
the conversion of T4 to T3 in the peripheral
tissues.
• PTU is started at a dose of 100 mg • CBZ at a dose
of 10 to 20 mg thrice daily.
• Most patients become euthyroid within 4 to 8
weeks of therapy. The dose is then reduced to a
maintenance dose.

55. • Iodides
• It is the fastest acting thyroid inhibitor.
• It reduces iodide transport, oxidation and
organification and to block the release of T4 and
T3 from the thyroid gland.
• The preparations used include Lugol's iodine (3 to
5 drops thrice daily). 5% sol has 5% iodine and
10% pot iodide.
• The major use of iodide is in preoperative
preparation and in the management of thyrotoxic
storm

56. • Beta-blockers
• block beta-adrenergic receptors and provide
relief from symptoms like tremors, palpitations,
anxiety and heat intolerance. • decrease the
heart rate, cardiac output and oxygen
consumption in thyrotoxicosis. •
• The drugs used are propranolol (40 to 180
mg/day) or atenolol (25 to 100 mg/day). •
contraindicated in patients with congestive
cardiac failure, asthma

57. • Radioiodine Therapy
• Radioiodine is simple and economical therapy.
• Indicated in patients above 40 years, especially those who
fail to respond to antithyroid drugs and failures of surgery.
• Contraindicated during pregnancy and lactation and in
severe thyrotoxicosis or in patients with large or malignant
thyroids.
• A dose that will deliver about 5,000 to 8000 rads to the
thyroid will be effective in ameliorating the
hyperthyroidism in Graves' disease.
• The patients should be euthyroid prior to radioiodine
therapy to prevent thyroid storm.
• The main drawbacks are hypothyroidism, risk of
carcinogenesis, and teratogenicity after the use of
radioiodine, though the precise likelihood of the latter two
remain contentious.

58. Diet
• No special diet must be followed by patients
with thyroid disease. However, some
expectorants, radiographic contrast dyes,
seaweed tablets, and health food
supplements contain excess amounts of iodide
and should be avoided because the iodide
interferes with or complicates the
management of antithyroid and radioactive
iodine therapies.

59. Thyroid storm
• Is a life threatening emergency
• Characterized by sudden appearance of
clinical signs of hyperthyroidism due to the
abrupt release of T4 and T3 into circulation.
• Mortality is as high as 25% to 30%.
• Commonly associated with Grave's disease.

60. • Predisposing conditions:
• Medical factors : • Infection • Fever • Uncontrolled
toxicity • Irregular drug intake • Pregnancy, toxemia of
pregnancy • Radio iodine therapy • DKA
• Surgical factors:
• Anxious and nervous patient before surgery,
• Too much handling of gland just before surgery.
• This can occur both intraoperative or in the immediate
post operative period, but the latter is more common
between 6-18 hours post operatively.

61. • Management requires :
• 1. Intensive monitoring and supportive care, 2. Identification and
treatment of the precipitating cause, and 3. Measures that reduce
thyroid hormone synthesis.
• propylthiouracil (500–1000 mg loading dose and 250 mg every 4
h) should be given orally or by nasogastric tube or per rectum. If not
available, methimazole can be used in doses up to 30 mg every 12h.
• One hour after the first dose of propylthiouracil, stable iodide is
given to block thyroid hormone synthesis via the Wolff-Chaikoff
effect (the delay allows the antithyroid drug to prevent the excess
iodine from being incorporated into new hormone).
• A saturated solution of potassium iodide (5 drops SSKI every 6 h)
or, where available, ipodate or iopanoic acid (500 mg per 12 h) may
be given orally. Sodium iodide, 0.25 g IV every 6 h, is an alternative.

62. • Propranolol should also be given to reduce
tachycardia and other adrenergic manifestations
(60–80 mg PO every 4 h; or 2 mg IV every 4 h).
High doses of propranolol decrease T4 → T3
conversion. Short-acting IV esmolol can be used
to decrease heart rate.
• Additional therapeutic measures include :
glucocorticoids (e.g., hydrocortisone 300 mg IV
bolus, then 100 mg every 8 h), antibiotics if
infection is present, cooling, oxygen, and IV
fluids.

63. REFERENCE
• Blick C, Jialal I. Thyroid, Thyrotoxicosis. 2018 Jan. [Medline]. [Full Text].
• Doubleday AR, Sippel RS. Hyperthyroidism. Gland Surg. 2020 Feb. 9 (1):124-35. [Medline].
[Full Text].
• Frost L, Vestergaard P, Mosekilde L. Hyperthyroidism and risk of atrial fibrillation or flutter: a
population-based study. Arch Intern Med. 2004 Aug 9-23. 164(15):1675-8. [Medline].
• [Guideline] Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of
thyrotoxicosis: management guidelines of the American Thyroid Association and American
Association of Clinical Endocrinologists. Thyroid. 2011 Jun. 21(6):593-646. [Medline].
• [Guideline] Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association
Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of
Thyrotoxicosis. Thyroid. 2016 Oct. 26 (10):1343-1421. [Medline]. [Full Text].
• Simmonds MJ, Brand OJ, Barrett JC, Newby PR, Franklyn JA, Gough SC. Association of Fc
receptor-like 5 (FCRL5) with Graves' disease is secondary to the effect of FCRL3. Clin
Endocrinology