Hypothyroidism

Prof. Dr. Hamid Saeed

 Hypothyroidism

• Hypothyroidism is an underactive thyroid gland.

• Hypothyroidism means that the thyroid gland can't make

enough thyroid hormone to keep the body running normally.

• People are hypothyroid if they have too little thyroid hormone

in the blood.
 Gross Anatomy
• Located in neck
• lobes

• isthmus

• Relations
• Larynx

• Trachea

• Recurrent laryngeal nerves

• Parathyroid glands

• Carotid sheath

• Blood supply
• Sup. thyroidal a.

• Inf. thyroidal a.
 Histology
• Thyroid follicles
• Simple cuboidal-
columnar

• Colloid
– Thyroglobulin
• Rich vascularization

• Parafollicular cells
• Inactive gland,
• colloid is abundant
• follicles are large
• cells lining the follicle are flat
• Active gland,
• follicles are small
• cells lining the follicle are
cuboid/laminar
• Edge of cells are scalloped
• forming many small ‘resorption
lacunae’
 Thyroid Hormone

• Tyrosine
• 3-Monoiodotyrosine (MIT)

• 3,5-Diiodotyrosine (DIT)

• 3,5,3’,5’-Tetraiodothyronine (T4)

• 3,5,3’-Triiodothyronine (T3)

• 3,3’,5’-Triiodothyronine
(Reverse T3, rT3)
 Thyroid Hormone synthesis
Normal thyroid hormone synthesis requires a normally developed thyroid gland, a series of highly regulated biochemical
steps, and an adequate nutritional iodide intake.
▪
After iodide uptake in thyrocytes by the sodium-iodide symporter (NIS), it is transported at the apical membrane into the
follicular lumen, partly by pendrin, then oxidized by thyroperoxidase (TPO) and incorporated into selected tyrosyl
residues of thyroglobulin (TG). this results in formation of mono- and diiodotyrosines.
▪
Iodotyrosines are subsequently coupled by TPO to form thyroxine (T4) and triiodothyronine (T3). after pinocytosis of TG
into thyrocytes, it is hydrolyzed in lysosomes and T4, T3 are released into the bloodstream.
▪
Defects in all major steps in thyroid hormone synthesis have been identified. clinical defects in thyroid hormonogenesis
typically result in goiter development if the condition is not recognized early because of thyroid gland stimulation by
thyrotropin. The severity of the defects varies and results in a clinical spectrum from severe
congenital hypothyroidism to a euthyroid metabolic state with an enlarged thyroid.
▪
Usually, defective hormonogenesis requires biallelic mutations in the involved gene products (autosomal recessive
inheritance). Therefore, hormone synthesis defects are more commonly found in inbred families and populations;
monoallelic mutations in the dual oxidase DUOX2 are associated with transient hypothyroidism.
Thyroid Hormone
Biosynthesis
• Iodide (I-) Trapping

• The thyroid will be able to concentrate

iodide against a strong electrochemical
gradient

• Pump Iodine from serum to follicular cell

• The ratio of iodide in thyroid : serum (T:S

ratio) = 25:1
• It is an active transport

• I- pump is needed

• Pump is linked to the ATPase-dependent Na+/K+ pump

• This pump is stimulated by TSH

• Requires influx of Na+ as cotransport

Oxidation of Iodide

• Oxidation of I- involves a heme-containing peroxidase

(Thyroperoxidase)

• occurs in the luminal surface of the follicular cell

• a tetrameric protein with a MW of 60k

• Requires H2O2 as an oxidizing agent

• H2O2 produced by an NADPH-dependent enzyme
• Resembles cytochrome c oxidase

• Anti-thyroid drugs (thio-urea drugs) inhibit oxidation

• thyroid hormone synthesis inhibited
 Iodination of tyrosine
• Oxidised I- reacts with tyrosyl residues in thyroglobulin
in a reaction that involves thyroperoxidase.

• Iodinate to form MIT & DIT

• 1stly: The 3 position of the aromatic ring is iodinated

• 2ndly: The 5 position is iodinated

• Organification reaction

• Occur in luminal thyroglobulin

• Once iodinated, iodine does not readily leave the

thyroid
• Attached to tyrosyl residue in the thyroglobulin
Coupling of Iodotyrosyls
• When the tyrosyls are iodinated, forming

iodotyrosyls (MIT/DIT), coupling will occur to form

T3 & T4 respectively.

• This reaction is also catalysed by thyroperoxidase,

by stimulating free radical formation of iodotyrosine.

• 2 DIT = T4
• 1 MIT + 1 DIT = T3
• Drugs that inhibit oxidation also inhibits coupling
• The thyroid hormones formed (T3/T4) remain as
integral parts of thyroglobulin
• Still attached to thyroglobulin, stored in lumen of
follicles until degraded later
 Hydrolysis of thyroglobulin
•Tgb hydrolysis is stimulated by TSH
•Tgb hydrolysis is inhibited by I-
•After TSH stimulation, thyroglobulin (Tgb) is engulfed by endocytosis and reenters
into the follicular cell.

• The Tgb engulfed will be within a phagosome when in the follicular cell.

• The phagosome will then fuse with lysosomes to form phagolysosomes.

• Various acid proteases & peptidases hydrolyses the Tgb into amino acids &
iodotyronines.

• T3 & T4 are discharged from the follicular cells & subsequently pass thru the basal
membrane by facilitated diffusion and enters the capillary lumen.

• The iodine removed from MIT & DIT is scavenged by deiodinase. Iodine can be
 Thyroid Hormone Synthesis
RC

C=O

OH- CH3CH

C=O

RC

• Tyrosine in Thyroglobulin
 Thyroid Hormone Synthesis
RC

C=O
I

OH- CH3CH

C=O

RC

• Thyroperoxidase attaches Iodine to 3 position---MIT

 Thyroid Hormone Synthesis
RC

C=O
I

OH- CH3CH

C=O

I RC

• Thyroperoxidase attaches Iodine to 5 position---DIT

 Thyroid Hormone Synthesis
RC

C=O
I
I

OH- O CH3CH

C=O

I
I RC

• Thyroperoxidase attaches ring from one DIT to adjacent

DIT = Thyroxine (T4)
 Thyroid Hormone Synthesis
RC

C=O
I
I

OH- O CH3CH

C=O

I RC

• Thyroperoxidase attaches ring from one MIT to adjacent

DIT = Triiodothyronine (T3)
 Thyroid Hormone Synthesis
RC

C=O
I
I

OH- O CH3CH

C=O

I
RC

• Thyroperoxidase attaches ring from one DIT to adjacent

MIT = Reverse T3
Thyroid hormone transport
• Most T3 & T4 are bound to plasma proteins (99.96%)

• Small unbound free hormones

• Active

• Responsible for biologic activity

• Involved in
• Feedback control

• Tissue action

• Hormone metabolism

• Fecal excretion (out of body)

 • Synthesis decreased by
• androgens

• glucocorticoid therapy
• Plasma proteins:
• liver disease
• Thyroxine-binding globulin (TBG)
• glycoprotein
• Thyroxine-binding pre-albumin (TBPA)
• Molecular weight 50k
• Albumin
• 100x more affinity than TBPA
• Non specific
• Produced in liver

• Synthesis increased by oestrogens • Rapid dissociation rates makes it a major

• pregnancy, birthcontrol pills source of carrier of free hormones
 Difference between T3 and T4
• There are more T4 produced

• There are more free unbound T3

• T4 are more highly bound

• T4 has longer half-life (longer acting)

• At target organs,

• De-iodination converts T4- T3

• about 80% circulating T4 converted to T3/reverse T3 (rT3) in the periphery

• Reverse T3: A very weak agonist (1% activity of T3) that is made in relatively large amounts in,
chronic disease, in carbohydrate starvation and in fetus
Thyroid Hormone
• T3 is 3-8X more active than T4

• Thyroid Gland produces 10X T4 to T3

• 5’-deiodinase
• Converts T4 to T3 in Target Tissues

• Primarily responsible for circulating levels of T 3

• T4 probably a pro-hormone

• T3 less tightly bound to plasma proteins

• T3 binds more avidly to thyroid hormone receptors

Physiological effects of thyroid hormone
• Increases oxygen consumption and heat production

• Positive chronotropic and inotropic effects on heart

• Increase sensitivity to adrenergic effectors

• Up-regulates -adrenergic receptors

• Increase gut motility

• Increase bone turnover

Physiological effects of thyroid hormone

• Increases reflex response

• Increase hepatic glycogenolysis and gluconeogenesis

• Stimulates lipolysis

• Developmental effects
• Growth

• Brain development
 HIGHER BRAIN
REGULATION OF THE THYROID GLAND
CENTERS

BODY
SHORT-LOOP
TEMP.
FEEDBACK LONG-LOOP
STARVATION
HYPOTHALAMUS FEEDBACK

TRH
EXPOSURE GOITROGENS
TO COLD TSH
ANTERIOR
PITUITARY
T4
TSH- TSH
RECEPTOR
ANTIBODIES
THYROID HIGH
GLAND SERUM
THYROID AUTO IODIDE
REGULATION T3 & T4
Hypothyroidism

• Lower production and release of thyroid hormones by the thyroid gland

resulting in low serum levels
 Classification of Hypothyroidism
• Primary hypothyroidism(90%) is characterized by a high serum thyrotropin (TSH) concentration and a
low serum free thyroxine (T4) concentration.

• Iodine deficiency – most common cause

• • Hashimoto’s thyroiditis – where iodine is sufficient

• • Diagnosis based on measurement of TSH and fT4

• Subclinical hypothyroidism is defined biochemically as a normal free T4 concentration in the presence

of an elevated TSH concentration. Other terms for this condition are mild hypothyroidism, early thyroid
failure, preclinical hypothyroidism, and decreased thyroid reserve.

• 
• Secondary (central) hypothyroidism is characterized by a low serum T4 concentration
and a serum TSH concentration that is not appropriately elevated.

• Transient or temporary hypothyroidism can be observed as a phase of subacute

thyroiditis.

• Consumptive hypothyroidism, identified in an increasing number of clinical settings, is

the result of accelerated inactivation of thyroid hormone by the type 3 iodothyronine
deiodinase (D3).
GOITROGENS DRUGS

• Anti-thyroid

• Cough medicines

• Sulfonamides

• Lithium

• Phenylbutazone

• PAS (para-amino salisylic acid)

• Oral hypoglycemic agents

Goitrogen Food

• Soybeans – Lobiya type

• Millet - Bajra

• Cassava - shakargandi

• Cabbage
Progression of Thyroid Failure
 Causes
• Autoimmune disease. The most common cause of hypothyroidism is an autoimmune disorder known as Hashimoto's

thyroiditis.

• Autoimmune disorders occur when your immune system produces antibodies that attack your own tissues.

• Sometimes this process involves your thyroid gland.

• Scientists aren't sure why this happens, but it's likely a combination of factors, such as your genes and an environmental

trigger.

• Over-response to hyperthyroidism treatment. People who produce too much thyroid hormone (hyperthyroidism) are often

treated with radioactive iodine or anti-thyroid medications. The goal of these treatments is to get thyroid function back to

normal.

• Sometimes, correcting hyperthyroidism can end up lowering thyroid hormone production too much, resulting in permanent

hypothyroidism.
• Thyroid surgery. Removing all or a large portion of your thyroid gland can diminish or halt hormone production.

• In that case, you'll need to take thyroid hormone for life.

• Radiation therapy. Radiation used to treat cancers of the head and neck can affect your thyroid gland and may
lead to hypothyroidism.

• Medications. A number of medications can contribute to hypothyroidism.

• One such medication is lithium, which is used to treat certain psychiatric disorders.

• If you're taking medication, ask your doctor about its effect on your thyroid gland.
Hoshimoto’s Thyroiditis

• An autoimmune
phenomenon –
presentation
determined by ratio
of antibodies
Who is at Risk

Patient at routine examination

Lithium carbonate therapy Autoimmune thyroiditis
Psychiatric patients
Autoimmune disease
Elderly patients Previous treatment for thyrotoxicosis
Postpartum women
Patients with sleep apnea Neck radiation therapy
Strong family history
Patients with hypercholesterolemia Amiodarone therapy
Grave’s opthalmopathy
Causes

• Central – insufficient stimulation by TSH

• Primary – inadequate function of the gland itself

• (1000x more common than central)

• Congenital
Congenital Hypothyroidism

• The majority of infants appear normal at birth, and <10% are diagnosed based on
clinical features, which include prolonged jaundice, feeding problems, hypotonia,
enlarged tongue, delayed bone maturation, and umbilical hernia.

• Importantly, permanent neurologic damage results if treatment is delayed.

• Typical features of adult hypothyroidism may also be present.

• Other congenital malformations, especially cardiac, are four times more common in
congenital hypothyroidism
 Diagnosis & Treatment
• Because of the severe neurologic consequences of untreated congenital hypothyroidism, neonatal screening
programs have been established based on measurement of TSH or T4 levels in heel-prick blood specimens.

• When the diagnosis is confirmed, T4 is instituted at a dose of 10–15 μg/kg per day, and the dose is adjusted by
close monitoring of TSH levels.

• T4 requirements are relatively great during the first year of life, and a high circulating T4 level is usually needed
to normalize TSH.

• Early treatment with T4 results in normal IQ levels, but subtle neurodevelopmental abnormalities may occur in
those with the most severe hypothyroidism at diagnosis or when treatment is delayed or suboptimal.
• Treatment of hypothyroidism

• • Causative

• • Thyroid hormone replacement - Levothyroxine

• • Iodine

• • Jod-Basedow effect (hyperthyroidism following administration of iodine or iodide)

• • Screening
Dosage Forms & Strengths -
Levothyroxine
• Tablet • Oral solution
• 25mcg, 50mcg, 75mcg, 88mcg, • 13mcg/mL, 25mcg/mL, 50mcg/mL,
100mcg, 112mcg 75mcg/mL, 88mcg/mL
• 125mcg, 137mcg, 150mcg, 175mcg, • 100mcg/mL, 112mcg/mL, 125mcg/mL,
200mcg, 300mcg 137mcg/mL, 150mcg/mL
• 175mcg/mL, 200mcg/mL
• Capsule
• Powder for injection
• 13mcg, 25mcg, 50mcg, 75mcg,
88mcg • 100mcg/vial
• 100mcg, 112 mcg, 125mcg, 137 mcg, • 200mcg/vial
150mcg • 500mcg/vial
Mild Hypothyroidism

• 1.7 mcg/kg or 100-125 mcg PO • >50 years with CV disease

qDay; not to exceed 300 mcg/day • Usual initial dose: 12.5-25 mcg PO qDay

• >50 years (or <50 yr with CV • May adjust dose by 12.5-25 mcg q4-

disease) 6weeks until patient becomes euthyroid

and serum TSH concentration normalized;
• Usual initial dose: 25-50 mcg/day
adjustments q6-8weeks also used
• May adjust dose by 12.5-25 mcg
• Dose range: 100-125 mcg PO qDay
q6-8Week
Severe Hypothyroidism

• Initial: 12.5-25 mcg PO qDay

• Adjust dose by 25 mcg/day q2-4Week PRN

• Subclinical Hypothyroidism

• Initial: 1 mcg/kg PO qDay may be adequate, OR

• If replacement therapy not initiated, monitor patient annually for

clinical status
Levothyroxine treatment

• • TSH response is gradual and should be measured about 2

months after starting treatment

• • Clinical effects of levothyroxine replacement are slow to

appear

• • Patients may not experience full relief from symptoms until 3-

6 months after normal TSH levels are restored