Last edited: 9/12/2021

1. HYPOTHYROIDISM
Hypothyroidism | Physiology, Pathophysiology, … Medical Editor: Ilia-Presiyan Georgiev

OUTLINE (B) EFFECTS ON TARGET CELLS

(1) Thyroid hormone diffuses across cell membranes
I) PHYSILOGY
II) PATHOPHYSIOLOGY Once inside cells the majority of T4 is converted to T3
III) CLINICAL FEATURES o By deiodinases
IV) DIAGNOSIS
V) TREATMENT T3 binds to intracellular receptors and binds to the DNA
VI) MYXEDEMA COMA o Modifies cellular activity
VII) REVIEW QUESTIONS (2) All cells
VIII) REFRENCES
Increases sodium-potassium ATPases
I) PHYSILOGY

(A) HYPOTHALAMIC PITUITARY THYROID AXIS

(1) The paraventricular nuclei (PVN) Stimulates glycogenolysis
o The breakdown of glycogen into glucose
inside the hypothalamus secrete thyrotropin-releasing
hormone (TRH) Stimulates glycolysis
o The breakdown of glucose into pyruvate
(2) TRH goes in o If oxygen is present pyruvate is converted into acetyl
the hypophyseal portal system and stimulates specific CoA
cells - the thyrotropes in the adenohypophysis  Acetyl CoA enters the Krebs cycle
o They secrete thyroid stimulating hormone (TSH) Stimulates lipolysis
into the bloodstream o The breakdown of lipids into fatty acids and glycerol
(3) TSH goes to
the follicles of the thyroid gland and binds to receptors
(TSH-R) present on the cell membrane.
o TSH-R stimulate specific genes in the nucleus to
produce and released into the luminal space. The
protein is called thyroglobulin
o Iodide uses sodium-iodine symporters to go inside
the cell and then into the luminal space.
o TSH-R stimulate a specific protein called thyroid
peroxidase
 Converts iodide to iodine
 Combines iodine and thyroglobulin producing
iodinated thyroglobulin
Figure 2 Effects of thyroid hormone on all cells.
The iodinated thyroglobulin is endocytosed back into
follicular cell (3) Liver
o Proteases cleave thyroid hormone (T3 and T4) out of Stimulates LDL uptake
the iodinated thyroglobulin and release it into blood o By increasing the number of LDL receptors (LDL-R)
Regulates the production of steroid hormone binding
globulins
o e.g. thyroxine binding globulin
(4) Heart
↑ beta-receptor sensitivity
o ↑ heart rate and contractility
Maintains vasomotor tone
(5) Bones
Maintains balance between
o Bone resorption via osteoclasts
o Bone deposition via osteoblasts
Maintains bone maturation and development
(6) Brain
Increases sympathetic nervous system activity
(7) GI tract
Increases GI motility
Increases GI secretions

Figure 1 Synthesis of thyroid hormone.

Hypothyroidism ENDOCRINE PATHOLOGY: Note #1. 1 of 6

(8) Skeletal muscles
Maintains normal muscle contraction
Stimulates muscle development and regeneration
Maintains calcium ATPases on sarcoplasmic reticulum
(9) Integumentary system
Maintains good blood flow to skin, hair and nails
o Stimulates growth
o Usually they return to euthyroid state after
1 year
(iii) Subacute granulomatous thyroiditis
o Most commonly due to viral infection of thyroid
follicles
 Injures follicular cells

Maintains good blood flow to sebaceous glands and o Acute injury from virus
eccrine sweat glands
o Stimulates secretions
(10) Fibroblasts
o Usually they return to euthyroid state over
Maintains the production of glycosaminoglycan and time
other extracellular proteins
(iv) Drug induced thyroiditis
o Most commonly due to amiodarone, lithium or radio-
iodine ablation use
o These drugs when used long term can injure follicular
cells

o Chronic use damages the cells

(v) Riedel's Thyroiditis

o Chronic Inflammatory condition associated with
various autoimmune diseases related to ↑ IgG4
production

Figure 3 Effects of thyroid hormone on target organs. o Related autoimmune diseases

 Autoimmune Pancreatitis
 Retroperitoneal fibrosis
II) PATHOPHYSIOLOGY  Noninfectious Aortitis
(A) PRIMARY HYPOTHYROIDISM (vi) Iodine-Deficiency
(1) Destruction of thyroid gland o Common in areas of the world where iodine is not
fortified
Thyroid hormone leaks out of injured cells
o Most common type of hypothyroidism worldwide
o Produces transient hyperthyroidism
o ↓ in Iodine
 Hypothyroidism develops shortly after
(2) Causes:

(i) Hashimoto thyroiditis (vii) Wolff Chaikoff Effect

o Most common in women o High Iodine loads create a negative feedback
o Anti-TPO antibodies and anti-thyroglobulin mechanism
antibodies are produced  Inhibits
 Destroy thyroid follicular cells • Iodine uptake into follicular cells
• Thyroid peroxidase
o Chronic injury from antibodies • Proteases
 Effectively decrease thyroid hormone production
o Short lived

o The underlying cause behind Hashimoto thyroiditis is

believed to be autoimmune involving
 HLA DR3, HLA DR4, HLA DR5 alleles
 An environmental trigger
o Most common type of hypothyroidism in the USA

(ii) Postpartum thyroiditis

o Can occur up to 1 year postpartum
o Anti-TPO antibodies and anti-thyroglobulin
antibodies are produced
 Destroy thyroid follicular cells

o Acute injury from antibodies

Figure 4 Causes of primary hypothyroidism.

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 (B) CENTRAL HYPOTHYROIDISM ↓ Na/K ATPase activity
o ↓ ATP demand
(1) Hypofunction of
hypothalamus and anterior pituitary leads to ↓TRH and ↓ glycogenolysis
↓TSH respectively o The breakdown of glycogen into glucose
↓ glycolysis
(2) Causes: o The breakdown of glucose into pyruvate

(i) Damage to Hypothalamus ↓ lipolysis

o The breakdown of lipids into fatty acids and glycerol
o Trauma and lesions to the hypothalamus
(2) Heart
↓ Beta-receptor sensitivity
(ii) Damage to Anterior pituitary ↓ Heart rate
Minimal ↓ in contractility
o Tumor and infarction of the anterior pituitary ↑↑ Vasoconstriction
o Bradycardia and hypertension
(3) Bones
↓ Bone Growth and Maturation
o Short stature
(4) Brain
Figure 5 Causes of central hypothyroidism. ↓ Sympathetic nervous system activity
o Leads to lethargy, fatigue, weakness, depression,
(C) CONGENITAL HYPOTHYROIDISM
memory deficits
(1) Abnormal development Delayed relaxation of deep tendon reflexes (Woltman
of the thyroid gland sign)
(5) GI tract
(2) Causes: ↓ GI motility and secretions
o Causes constipation
(i) Maternal autoimmune mediated thyroid
destruction (6) Skeletal muscles

o The mother produces anti-thyroid antibodies ↓ Muscle contractions and growth

 Destroys fetal thyroid gland o Decreased expression of calcium ATPases
o Which may cause muscle pain
 Called myopathy
(ii) Thyroid Agenesis or Dysgenesis o With muscle damage
o Abnormal development of the thyroid gland  Creatine kinase released
 The thyroid doesn't develop or develops o Proximal muscle weakness
abnormally o Myoedema present
 When a muscle is hit with an object it generates a
localized edema due to hypothyroidism
(iii) Sporadic Dyshormonogenetic Goiter
(7) Integumentary system
o Defects in the enzyme thyroid peroxidase
↓ Blood flow to skin hair and nails for growth
o Thin and brittle hair
o Nails are thin and brittle
↓ Blood flow to sebaceous glands and eccrine sweat
glands for secretions
o Decreased sweating and sebum production
 Dry skin
(8) Liver
↓ number of LDL receptors
o ↓ LDL uptake
 ↑LDL in the blood
Figure 6 Causes of congenital hypothyroidism. (9) Reproductive system
↓ Thyroid hormone stimulates hypothalamus
III) CLINICAL FEATURES
The decrease in thyroid hormone causes all physiological
effects of thyroid hormone on target cells decreased
exponentially
(1) Metabolic effects
↓ metabolism
o Weight gain
o ↓ appetite
o ↓ body temperature

Hypothyroidism ENDOCRINE PATHOLOGY: Note #1. 3 of 6

 (2) Differentiating the cause
of the primary hypothyroidism
Hashimoto thyroiditis
o Most common in women
o Anti-TPO antibodies and anti-thyroglobulin
antibodies are positive
(10) Fibroblasts o Most common type of hypothyroidism in the USA
In hypothyroidism the balance between o ↑ serum thyroglobulin
glycosaminoglycan production and degradation is lost Postpartum thyroiditis
o Can occur up to 1 year postpartum
o Anti-TPO antibodies and anti-thyroglobulin
 Glycosaminoglycans hold a lot of water antibodies are positive
o Usually return to euthyroid state
This usually presents as pretibial myxedema o ↑ serum thyroglobulin
o Progresses to periorbital edema and carpal tunnel Subacute granulomatous thyroiditis
syndrome o Painful thyroid on palpation
 Progresses to generalized edema o ↑ erythrocyte sedimentation rate (ESR)
o Flu-like symptoms
(11) Goiter
o Usually they return to euthyroid state
o ↑ serum thyroglobulin
Drug induced thyroiditis
o Most commonly due to amiodarone, lithium or
radio-iodine ablation use
o ↑ serum thyroglobulin
Riedel's Thyroiditis
o Painless hard thyroid
o Possible compression of nearby structures
 Recurrent laryngeal nerve → hoarseness
 Trachea → difficulty breathing
 Esophagus → dysphagia
o Test for serum IgG4
o Biopsy of thyroid tissue to confirm
Iodine deficiency
o Most common cause world wide
o Serum Iodine levels must be checked
Associated conditions should be checked for
o ↑ LDL
 Due to decreased LDL receptor uptake
o ↑ CK
 Due to myopathy and muscle damage
o ↓ Glucose
 Due to ↓ glycogenolysis and gluconeogenesis
o ↓ Na
 Possibly due to ↑ ADH release

Figure 7 Clinical features of hypothyroidism.

Congenital Hypothyroidism
o Neonatal screening within 24-48 hours after birth is
IV) DIAGNOSIS mandated by law
o ↑ TSH and ↓ Free T4 → Congenital Hypothyroidism
(1) Differentiating between
primary and central hyperthyroidism
↓ Free T4 should be low in both V) TREATMENT
TRH and TSH are key due to negative feedback
o ↓ TRH means the hypothalamus is not producing TRH (1) Levothyroxine
Synthetic form of T4
Can be taken up by cells and converted to T3
 Hypothalamus lesion or trauma o Exerts its metabolic effect
• MRI of the brain is required Monitor dosage efficacy with TSH levels
o ↓ TSH means the pituitary isn't producing TSH o ↑ TSH

o Pituitary tumor or infarction o ↓ TSH

 MRI of the brain is required
o ↑TSH and ↑TRH means pituitary is responding to ↓T4
levels o Normal TSH

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 Consider factors that alter levothyroxine dosage VII) REVIEW QUESTIONS
o ↑ dosage needed if on estrogen
 Estrogen→ ↑ TBG → ↓ freely circulating 1) Which nucleus produces TRH?
Levothyroxine a) Arcuate
o ↓ dosage needed if on corticosteroids b) Preoptic
 Steroids→ ↓ TBG → ↑ freely circulating c) Supraoptic
Levothyroxine d) Paraventricular

2) Which enzyme creates iodinated thyroglobulin?

a) Thyroid peroxidase
b) Thyroid deiodinase
c) Thyroid iodinase
d) Thyroid carboxylase

3) Which is the most common cause of hypothyroidism

worldwide?
a) Hashimoto thyroiditis
b) Iodine-Deficiency
c) Riedel's Thyroiditis
d) Drug induced thyroiditis

4) Which condition is associated with autoimmune

diseases?
a) Hashimoto thyroiditis
b) Subacute granulomatous thyroiditis
c) Riedel's Thyroiditis
d) Wolff Chaikoff Effect

5) Which condition causes congenital hypothyroidism?

a) Sporadic Dyshormonogenetic Goiter
Figure 8 Treatment of hypothyroidism. b) Riedel's Thyroiditis
c) Drug induced thyroiditis
d) Hashimoto thyroiditis
VI) MYXEDEMA COMA

(1) Causes 6) Which symptom is NOT caused by hypothyroidism?

a) Weight gain
Infection (sepsis) b) Bradycardia
Surgery c) Diarrhea
Trauma d) Infertility
(2) Main clinical features
Hypotension/Shock 7) Which symptom is NOT caused by hypothyroidism?
o Due to loss of SNS drive and severe Bradycardia a) Increased appetite
b) Hypotension
Bradycardia
c) Erectile dysfunction
o Due to loss of SNS drive
d) Myopathy
Delirium or altered mental status and coma
Hypothermia
o Due to decreased metabolic activity 8) Which hormone is key to diagnosing
hypothyroidism?
(3) Treatment a) TSH
IV levothyroxine (T4) and liothyronine (T3) b) TRH
IV hydrocortisone until concomitant adrenal insufficiency c) Both
has been ruled out d) Neither
Once stable treat underlying causes

9) What is levothyroxine
a) Synthetic TRH
b) Synthetic TSH
c) Synthetic T3
d) Synthetic T

10) Which symptom is not typical for myxedema coma

a) Hypertension
b) Bradycardia
c) Delirium
d) Hypothermia

Figure 9 Myxedema coma.

Hypothyroidism ENDOCRINE PATHOLOGY: Note #1. 5 of 6

 VIII) REFRENCES
Use style “Ref”

(example)
● APA citation guide. (2016). http://www.bibme.org/citation-
guide/apa/
● Lipson, C. (2011). Cite right: A quick guide to citation styles –
MLA, APA, Chicago, the sciences, professions, and more (2nd ed).
United States of America: The University of Chicago Press, Ltd.,
London.
● Ferraro, A. (Photographer). (2014). Liberty enlightening the
world [digital image]. Retrieved from
https://www.flickr.com/photos/afer92/ 14278571753/in/set-
72157644617030616

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