Module 6 Endocrine Flashcards

1
Q

The neck BORDERS

A

Major conduit for structures passing between head, trunk and limbs

Location of many clinically important structures including pharynx, larynx and trachea, oesophagus, thyroid and parathyroid glands

Boundaries
Anteriorly = inferior border of mandible  manubrium of sternum (suprasternal notch)
Posterior = superior nuchal line of occipital bone to the intervertebral disc between the C7 and T1 vertebrae

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2
Q

Major muscles of the neck region

A

Sternocleidomastoid (CN XI)
Trapezius (CN XI)
Platysma (CN VII)
Infrahyoid and suprahyoid groups

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3
Q

Suprahyoid muscles and action

A

Digastric
Anterior belly (mandibular division of trigeminal nerve CNV3)
Posterior belly (facial nerve CNVII)

Mylohyoid (CNV3)
Geniohyoid (anterior ramus of C1 spinal nerve)
Stylohyoid (CNVII)

All act to elevate the hyoid bone
Mylohyoid helps to support and elevate floor of the mouth
Anterior belly of digastric and geniohyoid can help open the mouth by lowering (depressing) the mandible when the hyoid bone is fixed by other muscles

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4
Q

Infrahyoid muscles and action

A

Sternohyoid
Omohyoid – superior and inferior bellies
Thyrohyoid
Sternothyroid

Innervation = anterior rami of C1 to C3 spinal nerves through the ansa cervicalis
Thyrohyoid is just anterior ramus of C1

All act to depress the hyoid bone and larynx

Thyrohyoid can raise larynx when hyoid bone is fixed in position by other muscles

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5
Q

Cervical fascia

A

Superficial fascia: contains adipose, cutaneous nerves, superficial lymph nodes, superficial veins e.g. external jugular, platysma muscle

Deep cervical fascia
Investing layer: surrounds all structures and encloses the trapezius & SCM

Prevertebral layer: surrounds vertebral column and deep muscles of the back including scalene muscles. Forms axillary sheath to enclose brachial plexus and subclavian artery in axilla

Pretracheal layer: encloses neck viscera i.e. trachea, oesophagus and thyroid gland. Posterior part referred to as buccopharyngeal fascia, which separates pharynx from prevertebral layer

Two carotid sheaths: formed by the other fascial layers and surround the two major neurovascular bundles of the neck (common carotid artery, internal carotid, internal jugular vein and vagus nerve). Extend from base of skull to superior mediastinum

Layers arranged into four compartments: area surrounded by investing layer; vertebral compartment; visceral compartment; vascular compartment

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6
Q

Fascial spaces

A

Retropharyngeal space
Largest and most important fascial space in the neck
Between the pretracheal/buccopharyngeal fascia on the posterior surface of the pharynx and oesophagus and the prevertebral fascia on the anterior surface of the bodies and transverse processes of the cervical vertebrae
Extends from the base of the skull to the upper part of the posterior mediastinum

Pretracheal space
Between investing layer of cervical fascia covering the posterior surface of the infrahyoid muscles and the pretracheal fascia covering anterior surface of thyroid gland and trachea
Passes between neck and anterior part of superior mediastinum

Fascial space within the prevertebral layer covering the anterior surface of the cervical vertebral bodies and transverse processes. Base of skull  posterior mediastinum

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7
Q

Main Triangles of the neck and their boundaries + subdivisions

A

Anterior triangle
Apex = suprasternal notch
Anterior border = midline of the neck
Superior border = inferior edge of mandible
Posterior border = anterior edge of sternocleidomastoid (SCM)

Carotid triangle
Muscular triangle
Submandibular triangle
Submental triangle

Posterior triangle
Apex = occipital bone posterior to mastoid process, between attachments for SCM and trapezius
Anterior border = posterior edge of SCM
Inferior border = superior edge of clavicle
Posterior border = anterior edge of trapezius

Occipital triangle
Subclavian (supraclavicular or omoclavicular) triangle

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8
Q

Carotid triangle

A

Borders
Anterior border = superior belly of omohyoid
Superior border = posterior belly of digastric
Posterior border = anterior edge of sternocleidomastoid (SCM)

Major contents
Common carotid artery, external carotid, internal carotid
Internal jugular vein
Vagus nerve, hypoglossal nerve, ansa cervicalis

Carotid sheath: encloses common carotid, internal carotid, internal jugular and vagus nerve

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9
Q

Muscular triangle (neck)

A

Borders
Anterior border = midline of neck
Superior/posterior border = superior belly of omohyoid
Posterior border = anterior edge of sternocleidomastoid (SCM)

Major contents
Infrahyoids (sternohyoid, omohyoid, thyrohyoid, sternothyroid)
Thyroid gland, parathyroid glands
Pharynx, larynx and trachea

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10
Q

Submandibular triangle

A

Borders
Anterior border = anterior belly of digastric
Superior border = inferior edge of mandible
Posterior border = posterior belly of digastric

Major contents
Submandibular gland
Submandibular lymph nodes
Hypoglossal nerve
Parts of facial artery and vein

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11
Q

Submental triangle

A

Borders
Anterior border = chin and midline of neck
Inferior border = body of hyoid bone
Posterior border = anterior belly of digastric

Major contents
Submental lymph nodes
Tributaries forming anterior jugular vein

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12
Q

Occipital triangle

A

Inferior belly of omohyoid subdivides posterior triangle into: Occipital triangle and Subclavian

Occipital triangle: Contains part of external jugular vein, posterior branches of cervical plexus of nerves, accessory nerve (CN XI), cervicodorsal trunk; cervical lymph nodes

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13
Q

Subclavian triangle

A

Inferior belly of omohyoid subdivides posterior triangle into: Occipital triangle and Subclavian

Subclavian triangle: Contains subclavian artery (third part, trunks of brachial plexus, part of subclavian vein (sometimes), suprascapular artery, supraclavicular lymph nodes

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14
Q

Carotid arteries and branches

A

Common carotid

Internal carotid: Does not branch in neck, Carotid sinus

External carotid: Superior thyroid, Lingual, Facial, Maxillary, Superficial temporal, Occipital, Posterior auricular

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15
Q

Carotid bifurcation

A

Located at superior border of thyroid cartilage (C3/4 level)

Carotid sinus detects pressure changes in arterial blood via baroreceptors
If hypersensitive then external pressure may lead to syncope

Carotid body chemoreceptors detect changes in composition of arterial blood e.g. pH, partial pressure of arterial O2 or CO2

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16
Q

Palpable facial and neck arteries

A

Superficial temporal artery can be palpated anterior to ear/posterosuperior to TMJ. Anterior branch can be palpated in anterolateral scalp

Facial artery palpated as it crosses the inferior border of mandible, anterior to masseter muscle

Common carotid pulse posterolateral to larynx
External carotid pulse halfway between superior margin of thyroid cartilage and greater horn of hyoid

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17
Q

Jugular veins

A

External jugular veins
Arises near angle of mandible
Formed by posterior branch of retromandibular vein and posterior auricular vein
Passes inferiorly through superficial fascia and crosses SCM before piercing the investing layer of cervical fascia
Travels deep to clavicle and drains into subclavian vein
Injury may result in a venous air embolus

Anterior jugular veins
Arise near hyoid bone from small veins
Descend on either side of midline of neck
Pierces investing layer of cervical fascia to enter subclavian vein
May drain into external jugular instead - variation

Internal jugular veins
Formed by continuation of sigmoid (dural venous) sinus at the jugular foramen of the skull
Contained within carotid sheath and runs deep to SCM
Receives blood from facial vein
Unites with subclavian vein to form brachocephalic vein at T1 vertebral level, superior to sternoclavicular joint and suprasternal (jugular) notch)
Large valve near end of the vein helps to prevent reflux

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18
Q

Lymphatic drainage of the head and neck

A

Superficial lymph nodes of the head
Occipital: occipital area of scalp

Mastoid (posterior auricular): posterior neck, upper part of external ear, lateral scalp, posterior wall of external acoustic meatus

Pre-auricular: superficial areas of face and temporal region

Parotid: nasal cavity, external acoustic meatus, tympanic cavity, lateral borders of orbit, scalp in temporal region, eyes, cheeks

Submandibular: medial canthus, cheeks, lateral aspect of nose, upper and lower lips, gums, anterior teeth

Submental: chin, central lower lip, floor of mouth, apex of tongue

Superficial cervical lymph nodes
Located along external jugular vein and superficial aspect of SCM and receive lymph from posterior and lateral regions of scalp via occipital and mastoid nodes
Drain to deep cervical nodes

Deep cervical nodes
Located along internal jugular vein and receive all lymph from head and neck. Divided into superior and inferior groups
Most superior node is jugulodigastric node – receives lymph from tonsils as well as face, mouth, pharynx
Commonly enlarged in tonsillitis

Jugulo-omohyoid node of inferior group is at tendon of omohyoid and receives lymph from tongue
If enlarged may be a sign of tongue carcinoma

Drain into right and left jugular trunks, then right lymphatic duct/trunk and thoracic duct respectively

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19
Q

Superficial nerves in the neck

A

Cutaneous nerves arise from cervical plexus (anterior rami of C1 – C4)
Transverse cervical (C2 & C3, anterior neck skin)
Great auricular (C2 & C3, skin of ear, mastoid region, parotid region)
Lesser occipital (C2, skin of neck and scalp posterior to ear)
Supraclavicular nerves (C3 & C4, skin over clavicle and shoulder)
Accessory nerve = cranial nerve 11 (CN XI), motor to SCM and trapezius. Crosses posterior triangle

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20
Q

Where would anaesthesia be injected to numb the ear and surrounding neck?

A

Erb’s point or nerve point of the neck: injection site to obtain anaesthesia of the skin around the ear and anterolateral neck

Mid posterior SCM

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21
Q

Deep nerves in the neck

A

Vagus nerve and branches
Glossopharyngeal nerve (CN IX)
Hypoglossal nerve (CNXII)
Phrenic nerve (anterior rami of C3, C4, C5)
Ansa cervicalis (anterior rami of C1, C2, C3)

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22
Q

Thyroid gland location and anatomy

A

Found in visceral compartment of neck and surrounded by pretracheal fascia
Lies lateral and inferior to the thyroid cartilage
Extends between C5 – T1 vertebra

The thyroid gland consists of:
Two lobes which cover anterolateral surfaces of the trachea, the cricoid cartilage, and lower part of the thyroid cartilage. Pair of parathyroid glands on posterior aspect of each lobe
An isthmus in the midline that connects the two lobes and usually covers the anterior surfaces of the second and third tracheal cartilages

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23
Q

Pyramidal lobe of thyroid

A

Present in around ~50% of thyroid glands
Extends superiorly from isthmus although in some cases isthmus may be absent
Remnant of thyroglossal duct from development of thyroid
Thyroglossal duct may sometimes form cysts in anterior neck

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24
Q

Blood supply to the thyroid

A

Superior thyroid artery (from external carotid)
Inferior thyroid artery (from subclavian artery via thyrocervical trunk)
Both arteries can be ligated during thyroidectomy to reduce intraoperative haemorrhaging
Superior laryngeal nerve is at risk of injury when superior thyroid artery ligated
Recurrent laryngeal nerve runs near inferior thyroid artery

Venous drainage is to the superior, middle and inferior thyroid veins
Superior and middle  IJV
Inferior  brachiocephalic vein

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25
Q

Hormones and cells in glucose homeostasis

A

Alpha cells: Glucagon (glucose agonist): hyperglycaemic effect, stimulates glucose production from the liver (glycogenolysis and gluconeogenesis; other functions on energy homeostasis and appetite.

Beta cells: Insulin released with high blood glucose, stimulates glycogen production via hypoglycaemia (increased glucose uptake); inhibits glucagon production.

Delta cells: ~5% of the cells; secrete Somatostatin, a paracrine inhibitor of glucagon and insulin release. Somatostatin release also regulated by β-cells providing a feedback mechanism.

PP cells: F-cells or pancreatic polypeptide (PP) cells, located in the periphery of islets, secrete PP – released post-prandially and has effects on metabolism, GI motility, and appetite.

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26
Q

What causes type I - Insulin deficiency diabetes?

A

Autoimmune disease in which pancreatic beta cells are destroyed and thus not enough insulin is produced
Incidence ~ 3 in 1000

Often develops before age 15 and seldom after 40

May be triggered by viruses and/or toxins

Tendency toward ketosis (developing keto-acidosis) – Why?
Patient requires insulin supplement (exercise and diet are key)

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27
Q

What causes type II - Insulin resistant diabetes?

A

Impaired b-cell function and/or resistance of tissues to Insulin

~ 3% of population (many undiagnosed), roughly 90% of cases

Onset usually > 40 years

Associated with lack of physical activity and/or obesity

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28
Q

Complications of diabetes

A

kidney damage, defined by proteinuria (microalbuminuria) and reduced GFR.

Peripheral nerve dysfunction, sensory, focal/multifocal, autonomic neuropathies.

Macrovascular complications of diabetes

microvascular complications; diabetic retinopathy

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29
Q

Pathogenesis of arterial damage

A

Damage to vessels and cells reflects the glucose concentration and duration of exposure.
Glucose can be converted to sorbitol which is an osmotic stresser.
Production of advanced glycation endproducts (AGEs). Glycation is a non-enzymatic adduction of targets by glucose. Not the same as glycosylation.

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30
Q

Diabetes symptoms

A

Thirst
Polyuria/nocturia/ incontinence in the elderly
Tiredness
Blurred vision (lens changes shape and size)
Recurrent thrush
Recurrent infections
Feeling of unwell/poor concentration
Weight loss – yes in Type 1, not always Type 2
Mood changes
Micro or macro-vascular problems

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31
Q

Diagnosis of Diabetes State

A

FPG  7 mmol
No food or drink for at least 8 hours
2 hour glucose  11.1mmol during an glucose tolerance test
A1C  48mmol/mol (6.5%)
Using an accepted and standardized laboratory test
If classic symptoms of high glucose = any glucose  11.1 mmol

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32
Q

Symptoms : Type 1 vs Type 2

A

More acute onset in Type 1
Type 2 progressive disease and symptoms more gradual
Symptoms might be not realised and put down to other things
Type 2 diabetes takes on average 10 years to present
IF IN DOUBT – TREAT AS TYPE 1 !

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33
Q
  1. Peptide hormone Biosynthesis
A

Peptide hormones are translated on the RER as a pre-prohormone.

This initial translational product is then cleaved to a prohormone which then undergoes further post-translational processing to produce the hormone which is then stored in secretory vesicles of the endocrine gland.

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34
Q
  1. Phenylalanine/tyrosine derived hormones
A

Hormone or neurotransmitter
Preganglionic fibres stimulate a mixture of epinephrine and norepinephrine into bloodstream.
(80% epinephrine and 20% norepinephrine).

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35
Q
  1. Fatty acid or Arachidonic acid derived hormone biosynthesis
A

Arachidonic acid derived hormones are involved in a number of processes involved in the regulation and control of inflammatory responses.

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36
Q
  1. Hormones derived from Cholesterol
A

The precursor for all steroid hormones is CHOLESTEROL
Cholesterol can be synthesised de novo but usually comes from diet (LDL) and is stored as cholesterol ester.

There are 4 families of lipid soluble steroid hormones
Corticoids
Progestins
Androgens
Estrogens-

Secreted by:
Adrenal cortex- cortisol & aldosterone
Ovaries- oestrogen & progesterone
Testes- Testosterone

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37
Q

Storage of Steroid hormones

A

Unlike peptide hormones, most steroid secreting cells do not store hormone but synthesize them as required

Slower time for steroid hormone to act

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38
Q

Water vs fat soluble hormone Signalling methods

A

Water soluble hormones
e.g. peptide hormones and those derived from phenylalanine and arachidonic acid
Signal via cell membrane receptors and activation of enzymes and other molecules via G protein coupled receptors or Tyrosine kinase coupled receptors

Lipid soluble hormones
e.g. Steroid or thyroid hormones readily cross cell membranes
Signal via intracellular cytoplasmic or nuclear receptors and modulation of gene expression

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39
Q

Short loop negative feedback

A

inhibition of hypothalamic tropic hormones by the anterior pituitary tropic hormone.

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40
Q

Long loop negative feedback

A

the hormone whose secretion is stimulated by the tropic hormone generally feeds back to the hypothalamus (and often the anterior pituitary as well) to inhibit secretion of the tropic hormone.

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41
Q

General adaptation syndrome stages

A

Initial fight or flight

A slower resistance response

Exhaustion

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42
Q

Action of Glucocorticoids – Cortisol (the stress hormone)

A

Increase in bone resorption and decreases collagen formation

EPO is increased, which stimulated RBC, it decreases NO, and increases constriction, decreases permeability It also increases effectiveness of catecholamines and so increases BP

Immunosuppressive and anti-inflammatory actions

Decreases calcium absorption from kidney

Cortisol stimulates the release of amino acids from muscle. Liver utilises these to make glucose. The increase in glucose stimulates insulin release. Cortisol inhibits the insulin-stimulated uptake of glucose in muscle via GLUT4 transporter.

Many effects on fetus. Required for lung development at correct stage

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43
Q

Adrenal axis disorders

A

Cushing’s Disease: Increased ACTH due to pituitary defect/pituitary tumour

Cushing’s Syndrome: Increased glucocorticoid due to ectopic sources of ACTH (small cell lung cancer) or Adenoma of adrenal gland

Ectopic ACTH syndrome

Addison’s Disease (primary adrenal insufficiency): Adrenals cannot produce sufficient steroids - poor BP control ,Increased ACTH- hyper pigmentation, refer to actions of cortisol

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44
Q

Dexamethasone suppression tests:Low and High dose tests

A

Low Dose test (1mg)
Injection (or take orally) low dose of Dexamethasone.
The normal situation would result in suppression of cortisol levels
In patient with excess production (e.g. Cushing’s disease) cortisol suppression is limited with this test

If cortisol remains high after low-dose DEX test, is raised in the urine 24 hr test and shows loss of diurnal variation – Diagnose Cushing’s

High dose test (2mg):
2mg Dex 6 hourly for 48 h; 0900h plasma cortisol measurements taken.

In Cushing’s disease, the cortisol level will decrease to <50% of pre-test value
(in CD, tumour doesn’t produce as much ACTH as ectopic ones and so some of the feedback is retained in response to this dose of dex)

If suppression is less than 50% then ACTH source is outside of pituitary
e.g. Adrenal tumour or ectopic ACTH secretion (as these tumours usually result in greater levels of ACTH than pit tumours)

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45
Q

Suspected pituitary hypofunction

A

Start with measurement of pituitary and target organ hormone in blood taken at 0900h.

In HPA axis
Normal plasma ACTH at 0900h is <50ng/L
Normal cortisol at 0900h is 140-690 nmol/L

If abnormal need to do dynamic testing using stimulation test

ACTH Stimulation Test for Adrenal Insufficiency (synacthen test):
The ACTH stimulation test is very specific for HPA axis.

Blood cortisol and/or urine cortisol are measured before and after an injection with synthetic form of ACTH.

After an injection of ACTH blood and urine cortisol levels rise.

Patients with adrenal insufficiency respond poorly or not all.

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46
Q

CRH Stimulation Test - adrenal insufficiency

A

To perform when the synacthen test is abnormal in order to establish possible cause of adrenal insufficiency (secondary/pituitary or tertiary/hypothalamic).

Blood cortisol levels are measured before and after (30, 60, 90, and 120 minutes after) synthetic CRH injection (i.v.).

Patients with Primary Adrenal insufficiency (Addison’s) : high ACTH, but not cortisol production.
Patients with Secondary adrenal insufficiency deficient cortisol responses and absent or delayed ACTH responses- (Absent ACTH response points to the pituitary; a delayed ACTH response points to the hypothalamus)

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47
Q

Hypothalamus: function

A

The main function of the hypothalamus is to maintain homeostasis by:
Autonomic Function Control
Endocrine Function Control
Motor Function Control
Food and Water Intake Regulation
Sleep-Wake Cycle Regulation
Circadian rhythm
Temperature regulation
Emotional and behavioural responses

Different hypothalamic regions or nuclei are involved

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48
Q

Neurohypophysis: The posterior pituitary gland

A

An extension of the hypothalamus, containing neural tissue consisting of the axon terminals of neurons originating in the hypothalamus which extend downwards as a large bundle behind the anterior pituitary.

Composed of:
The pars nervosa(neural lobe)
Infundibular stalk
Median eminence

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49
Q

Adenohypophysis: The anterior pituitary gland

A

The adenohypophysis can be subdivided into three distinct lobes:
Pars distalis (anterior lobe)
Pars intermedia (intermediate lobe)
Pars tuberalis

50
Q

Hypothalamus - Pituitary relationship

A

Neurons with cell bodies in the supra and paraventricular nuclei of hypothalamus project into posterior pituitary
Directly releasing hormones into venous drainage

Neurons with cell bodies in medial hypothalamic nuclei projecting into median eminence releasing tropic hormones into pituitary portal veins
Tropic hormones influence cells in anterior pituitary to produce hormones circulating in the body

51
Q

Hypothalamic hormones

A

Tropic hormones: regulate the secretion of other hormones into the anterior pituitary, travelling from the median eminence via a unique system of portal veins.

Neurohormones: synthesised in specialised neurons in the supraoptic and paraventricular nuclei of the hypothalamus. They pass down the axons and are stored in the distended parts of the axons in the posterior pituitary.

52
Q

Hypothalamic tropic hormones

A

Thyrotrophin-releasing hormone (TRH)
Gonadotrophin-releasing hormone (GnRH)
Corticotrophin-releasing hormone (CRH)
Growth hormone-releasing hormone (GHRH)
Somatostatin (GHIH)
Prolactin-releasing hormone (PRH)
Dopamine (also referred to as PIH)

53
Q

Posterior pituitary hormones

A

Following synthesis, the peptides are packaged into secretory vesicles, which are transported to the axon terminals in the posterior pituitary.

They are released by exocytosis upon a neuronal signal (neuroendocrine reflexes).

Antidiuretic hormone (ADH; also called vasopressin)
Kidneys are the target cells. Hormone released by increasing water reabsorption.

Oxytocin
Uterus and Breast are the target cells.
Hormone released by pressure in the uterus of pregnant woman.

54
Q

Role of Antidiuretic Hormone ADH + stimulants and inhibitors

A

ADH acts to promote water conservation by the kidney by increasing the permeability of the distal tubular epithelium to water.

The main stimulus for ADH release is increased osmotic pressure of water in the body, which is sensed by osmoreceptors in the hypothalamus.

The other major stimulus is volume depletion, which is sensed by baroreceptors.

Other stimulants for ADH release include pain, stress, emesis, hypoxia, exercise, hypoglycaemia, cholinergic agonists, β-blockers, angiotensin, and prostaglandins.

Inhibitors of ADH release include alcohol, α-blockers, and glucocorticoids.

55
Q

ADH associated pathology

A

A lack of ADH produces central Diabetes Insipidus.

An inability of the kidneys to respond normally to ADH causes nephrogenic Diabetes Insipidus.

In the absence of ADH, urine output increases more than 10 fold.

Removal of the pituitary gland usually does not result in permanent Diabetes Insipidus because some of the remaining hypothalamic neurons produce small amounts of ADH.

56
Q

Oxytocin

A

Two major targets:
The myoepithelial cells of the breast
The smooth muscle cells of the uterus

Major functions:
Milk ejection reflex
Uterine smooth muscle contraction
Both examples of positive feedback regulation

57
Q

Oxytocin and milk ejection

A

The release ofoxytocinfrom theposterior pituitary is stimulated by tactilesensory inputsfrom the nipple
The binding to oxytocin receptors on the myoepithelial cells, cause the myoepithelial cells to contract, and resulting in increased intra-lumenal (intramammary) pressure and ejection of milk from the alveolar lumen.

58
Q

Oxytocin deficiency leads to

A

Failure to progress in labour and difficulty breast feeding

59
Q

Hypothalamic Disorders

A

Primary disorders are extremely rare
Often hypothalamic disorders mimic pituitary disorders
Usually results in decreased secretion of hormones
Exception being prolactin (as prolactin is under inhibitory control by the hypothalamus)

Causes of Hypothalamic disorders
Trauma/surgery
Radiotherapy
Hormone excess: (SIADH), disconnection hyperprolactinaemia
Hormone deficiency: Cranial DI, congenital GnRH deficiency
Primary glial tumours of the hypothalamus

60
Q

Pituitary basophils and acidophils

A

Basophils:
Corticotroph
15-20%
Thyrotroph
Gonadotroph

Acidophils:Somatotroph
40-50%
Lactotroph

61
Q

Corticotrophs

A

ACTH is peptide synthesized as part of a larger prohormone,proopiomelanocortin (POMC) trough a translational processing mediated by different enzymes called prohormone convertases.

MSH (melanocyte-stimulating hormones) exist in three forms:α,β, andγand they are products primarily of the intermediate lobe of thepituitary gland.
MSH is well known for its ability to stimulate melanogenesis and is involved in the energy balance.

62
Q

POMC

A

POMC harbours the peptide sequence for ACTH,α- andβ-MSH, endorphins (endogenous opioids), and enkephalins

63
Q

ACTH

A

Circulates as an unbound hormone with a short half-life up to 10 min
ACTH secretion exhibits a diurnal variation pattern (highest in early morning)
ACTH binds to the melanocortin-2 receptor (MC2R) on cells in the adrenal cortex and can also bind malanocortin-1 receptor (MC1R) on melanocytes
Cleavage of POMC to generate ACTH is important in appetite pathways as failure is thought to cause monogenic obesity

Binding to MC2Rs in the adrenal cortex:
Stimulates hydrolysis of stored cholesterol ester to provide cholesterol for steroid synthesis.
Increase the expression of enzyme Desmolase important for cholesterol conversion to pregnenolone
Stimulates glucocorticoid (cortisol) release from the zona fasciculata of the adrenal cortex
Promotes, in the long term, growth and survival of two zones of adrenal cortex.

64
Q

Circadian rhythms of ACTH and steroid production

A

ACTH secretion happen in a pulsatile manner and shows a pronounced diurnal pattern, with a peak in early morning and again in late afternoon

During sleep steroid demand is low so levels of these are at their lowest.

ACTH levels increase early before awakening, stimulating cortisol production –This is known as the cortisol awakening response (CAR).

65
Q

MSH (melanocyte stimulating hormone)

A

MSH decreases appetite
Increases skin pigmentation (MSH and beta lipotropin stimulate release of melanin by melanocytes).
Responsible for tanning (UV activates p53 which switches on transcription of POMC gene)
May be involved in sexual arousal
CRH stimulates its release and dopamine inhibits its release
MSH is increased in Cushing’s and Addison’s disease
In Addison’s increased skin pigmentation is mostly due to excess ACTH (ACTH can bind to MSH receptors)

66
Q

Thyrotropes

A

TSH is a pituitary glycoprotein hormonecomposed of anα-subunit, called theα-glycoprotein subunit (α-GSU), and aβ-subunit(β-TSH).

The half-life is around 60 min.

Essential for normal growth and development, stimulates every aspect of thyroid function. Also strong tropic effect, stimulating hypertrophy, hyperplasia, and survival of thyroid epithelial cells.

The production is stimulated by the thyrotropin-releasing hormone (TRH), which isreleased according to a diurnal rhythm (highest during overnight hours, lowest around dinnertime).

67
Q

Gonadotrophs

A

Thegonadotrophis a dual hormone producer in that the same cell secretesFSHandLH (also called gonadotropins
Gonadotropins are involved in the control of sexual differentiation, steroid hormone synthesis and gametogenesis

In males, LH and FSH involved in spermatogenesis; LH stimulates the testosterone synthesis pathway; FSH stimulates the maturation of spermatozoa in the Sertoli cells.

In females, LH and FSH stimulates estrogen biosynthesis and regulate hormones involved in the menstrual cycle; FSH stimulates follicle development

68
Q

Lactotrophs

A

Thelactotrophproduces prolactin (PRL).

The lactotrope differs from the other endocrine cell types of the adenohypophysis :

The lactotrope is not part of an endocrine axis, therefore PRL acts directly on non-endocrine cells to induce physiologic changes.

The production and secretion of PRL is predominantly under inhibitory control by the hypothalamus through the neurotransmitter,dopamine.
The disruption of the pituitary stalk and the hypothalamo-hypophyseal portal vessels results in an increase in PRL levels, but a decrease in ACTH, TSH, FSH, LH, and GH.

69
Q

Somatotrophs

A

Most abundant pituitary cell type - Produce Growth Hormone GH (also called Somatotropin).

About 50% is bound to GH-binding protein (GHBP) which increases the half-life of GH (max 20 min)

secretion is under dual control by thehypothalamus:

Growth hormone releasing hormone (GHRH) from the arcuate nucleus of the hypothalamus stimulates synthesis and secretion of GH.

GHRH is released in a pulsatile fashion and causes a similar pulsatile release of GH

Somatostatin (GHIH) from the periventricular nucleus of the hypothalamus inhibits synthesis and secretion of GH.

Somatostatin inhibits the effect of GHRH on the somatotrophs​

70
Q

Somatotrophs: Growth hormone actions

A

Acts as a hormone & a trophic factor
Promotes synthesis & secretion of insulin-like growth factors (IGFs and somatomedins) from the liver to promote mitosis & cellular differentiation for growth.

Anabolic & growth effects
Increases bone length & width prior to epiphyseal closure
IGFs stimulate both bone & cartilage growth
anti-insulin-like
synergises with cortisol

71
Q

Normal growth and development hormones

A

GH is not the only hormone necessary for normal development:

Thyroid hormone
Growth severely stunted in hypothyroid children
Hypersecretion does not cause excessive growth

Insulin
Deficiency often blokes growth
Hyperinsulinism often stimulates excessive growth

Androgens
Play role in pubertal growth surge, stimulates protein synthesis in many organs

Oestrogens
Effect on growth prior to bone maturation are not well understood

72
Q

Somatotrophs: Growth hormone associated disorders

A

Gigantism: Excessive GH production before Puberty.
Pituitary dwarfism: insufficient of GH production.
Laron Syndrome: Growth Hormone resistance due to a genetic defect in the expression of GH receptors.

73
Q

Pituitary relations

A

Anatomical relations:
Anterior = sphenoid sinus, tuberculum sellae
Posterior = dorsum sellae, basilar artery, pons
Superior = diaphragma sellae (dura mater), optic chiasm
Inferior = sphenoid bone (hypophyseal fossa)
Lateral = cavernous sinus (venous blood)

74
Q

Pituitary structure - adenohypophysis

A

Anterior lobe of pituitary (adenohypophysis)

Pars distalis makes up most of adenohypophysis - contains chromophil cells
Acidophils and basophils containing various pituitary hormones in secretory granules (see other pituitary endocrine lectures)

Pars tuberalis surrounds stalk

Pars intermedia is region between two lobes

75
Q

Pituitary structure - neurohypophysis

A

Posterior pituitary (neurohypophysis)

Consists of pars nervosa and communicating pituitary stalk (infundibulum)

Does not contain hormone-synthesising cells
Instead contains long axons of secretory neurons from the hypothalamus. The cell bodies of these neurons are located in hypothalamic nuclei e.g. supraoptic nucleus

These neurons secrete two hormones:
Anti-diuretic hormone (ADH) AKA vasopressin
Oxytocin

76
Q

Hypothalamo-hypophyseal portal system

A

Superior hypophyseal artery (from internal carotid) helps to supply blood to hypothalamus and forms the primary capillary bed (plexus)

Neuropeptides released from hypothalamus enter the primary capillary bed and then long hypophyseal portal veins that descend further into the anterior lobe of the pituitary

Hypophyseal portal veins then form a secondary capillary bed (plexus) within anterior pituitary

Anterior pituitary hormones are released into the secondary capillary bed before draining into hypophyseal veins and the cavernous sinuses

77
Q

Hypothalamo-hypophyseal tract

A

Paraventricular nucleus and supraoptic nucleus of hypothalamus

These hypothalamic neurons have long unmyelinated axons which descend into the posterior lobe of the pituitary gland

Hypothalamic nuclei are neurosecretory: hormones are synthesised inside the neurons and transported through their axons into the posterior lobe of the pituitary

Herring bodies: dilated endings of neurons for temporary storage of hormones

ADH and oxytocin released into capillary beds and drain into hypophyseal veins and the cavernous sinus

78
Q

Cavernous sinus

A

An intracranial dural venous sinus on either side of the pituitary gland, lateral to the sella turcica and the body of the sphenoid bone

The cavernous sinus will receive venous blood from the
Cerebral veins
Ophthalmic veins
Emissary veins via the pterygoid plexus
Hypophyseal veins from the pituitary gland

Venous anastomoses between the facial vein and the ophthalmic veins are a potential route whereby infection can spread from an extracranial site (the face) to the intracranial space around the brain

Contents of each side of the cavernous sinus:
Superior  inferior
O culomotor nerve
T rochlear nerve
O phthalmic branch of trigeminal nerve
M axillary branch of trigeminal nerve

Medial to lateral
C arotid artery (internal carotid)
A bducens nerve
T rochlear nerve

79
Q

Infection where may result in a cavernous sinus thrombosis

A

Danger triangle” of the face (nose, upper lip) where an infection can spread via venous anastomoses to the cavernous sinus

80
Q

Pituitary tumours are intracranial space-occupying-lesions (SOL) with potential to cause:

A

Endocrine disturbances – may lead to overproduction of anterior pituitary hormones e.g. growth hormone (gigantism or acromegaly)
Optic chiasm compression (bitemporal hemianopia)

81
Q

Development of the pituitary gland

A

Anterior lobe (adenohypophysis)
Derived from surface ectoderm from developing oral cavity (Rathke’s pouch)
Starts growing from week 4
Loses connection to oral cavity by week 8

Posterior lobe (neurohypophysis)
Derived from neuroectoderm (neural tube ectoderm) arising from the floor of the future diencephalon of the brain
Still connected to hypothalamus via infundibulum

82
Q

Ectopic pituitary gland tissue

A

Pharyngeal hypophysis (aberrant hypophysis)
Ectopic anterior pituitary tissue located in the roof of the nasopharynx

Ectopic pituitary tissue can also be found within the sphenoid bone (intraosseous) or in the hypophyseal fossa inferior to the pituitary gland (suprasellar/intracranial)

Craniopharyngioma
Tumour of persistent embryonic tissue associated with Rathke’s pouch (surface ectoderm)

May be non-functional (benign) or functional (secretory)

Often associated with visual disturbances, headache and pituitary dysfunction

83
Q

Congenital adrenal hyperplasia (CAH)

A

inherited defect in an enzyme involved in the production of cortisol and aldosterone

Several possible types
>90% of CAH due to deficiency of 21b-hydroxylase

Decreased negative feedback inhibition result in excess ACTH release
- prolonged ACTH hyperstimulation results in hyperplasia of the adrenals (hence, the name of the condition)

84
Q

Secondary adrenal insufficiency

A

Secondary insufficiency:
Lack of ACTH production
tumour/damaged pituitary
Adrenal suppression / atrophy
long-term, high-dose glucocorticoid use

85
Q

Conn’s syndrome

A

hyperaldosteronism
Abnormally large amount of aldosterone produced
common cause = tumour
Results in the retention of Na+, and hence increased water retention, increased K+ elimination - polyuria, hypokalaemia, weakness
The main clinical finding in Conn’s is hypertension
Treatment:
Surgery, aldosterone receptor antagonist e.g. spironolactone

86
Q

Adrenal Glands SHAPE

A

The right adrenal gland is triangular shaped

The left adrenal gland is semilunar shaped

87
Q

What is the embryological origin of the cortex and the medulla?

A

Different embryological origins:
Cortex from mesoderm (epithelial tissue)
Medulla from neural crest

Cortex: 5th week proliferation of mesothelium cells, penetrate mesenchyme - second wave encloses cortex

Medulla: neural crest cells form medially and are then enclosed

88
Q

Histological appearance of the adrenal medulla

A

Closely packed clumps of secretory cellsarranged in ovoid clusters near capillaries (chromaffin) that have a strongly basophilic cytoplasm. The cells have secretory granules which contain either epinephrine or norepinephrine.

When fixed in potassium bichromate, the medullary cells become brown. Therefore, they are calledchromaffin cells.The color is the result of a reaction between chromate and epinephrine or norepinephrine.
With the typical H&E stain, the cells appear as somewhat stellate-shaped cells containing a rather prominent, round nucleus.

A fine network of capillaries branch throughout the medulla and numerous larger venules draining blood from the sinusoids of the cortex into the central medullary vein.

89
Q

Adrenal glands structure and function: summary

A

Zona Glomerulosa ZG: cells arranged in clusters (glomeruli) Mineralocorticoids

Zona Fasciculata ZF: rows of lipid-laden cells arranged radially in bundles of parallel cords (fasces) Glucocorticoids

Zona Reticularis ZR: tangled network of cells androgens

Medulla: chromaffin cells arranged in ovoid clusters near capillaries. cetecholamines

90
Q

Physiological functions : Mineralocorticoids

A

1) Activation of the renin-angiotensin system related to
a decrease in Na+ and decrease in Blood Pressure.

2) Direct stimulation of the adrenal cortex by increase in blood K+ concentration

Primary site of action is the distal tubules of thekidney nephron where it promotes Na+retention into the blood andenhances K+ elimination into the urine filtrate

91
Q

Glucocorticoids action

A

Increased:
Appetite
Blood pressure
Insulin resistance
Gluconeogenesis, lipolysis

Decreased: Fibroblast activity (wound healing)
Immune and inflammatory activity
Bone formation

92
Q

Pheochromocytoma

A

Tumour of Adrenal medulla that release excessive catecholamine form the chromaffin cells.
The tumours can manifest with highly variable presentations
From rare and progressive hyper-catecholaminergic episodes, through relatively sustained hypertension, to severe and clinically malignant disease, complicated by hypertensive crises, stroke, acute myocardial infarction and numerous other conditions.

The “rule of tens” for pheochromocytomas:

10% are bilateral,
10% are extra-adrenal,
10% are malignant.

93
Q

S%S pheocytochroma

A

Episodic pounding headache
Palpitations and Tachycardia
Diaphoresis

94
Q

Thyroid hormones and metabolism rate

A

Lipid metabolism:
T3 stimulates fat mobilization, leading to increased concentrations of fatty acids in plasma.
T3 also enhance oxidation of fatty acids.

Carbohydrate metabolism:
Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose.

Growth & Development:
Thyroid hormones essential for normal growth in children.
Normal levels of thyroid hormone are essential to the development of the foetal and neonatal brain.

Cardiovascular system:
Increases heart rate, cardiac contractility and cardiac output.
Promote vasodilation, which leads to enhanced blood flow to many organs.

Central nervous system:
Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state.
Too little thyroid hormone, and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness.

Reproductive system:
Normal reproductive behaviour and physiology is dependent on having essentially normal levels of thyroid hormone.
Hypothyroidism is associated with infertility

95
Q

Functions of Thyroid Hormone on cells

A

Cell membrane - Stimulates the Na+/K+ATPase pump - Increased demand for metabloites e.g. glucose

Mitochondria - Stimulates growth, replication & activity; basal metabolic rate is raised. - Increased heat production, oxygen demand, HR and stroke volume

Nucleus - Increases the expression of enzymes for energy production - Lipolysis, glycolysis & gluconeogenesis increased to raise blood metabolite levels and cellular metabolite levels

Neonatal cells - Cell division & maturation - Essential for development of CNS & skeleton

96
Q

What is needed to make TH?

A

Synthesis of TH requires:
Tyrosine
Iodine
Thyroglobulin (Tgb)

Body stores adequate tyrosine
Iodine dietary intake necessary
Inadequate intake  goitre
Iodination of salt in UK and USA
Rice iodine enrichment
Normal intake 150 micrograms/day of which 125 micrograms taken up by the thyroid

97
Q

TH formation storage and release

A

1) Iodide (I-) trapping by follicular cells against electrochemical gradient (rate limiting step!)
Na+/K+ATPase-dependent Na+/I- symporter-basal surface of follicular cell

2 & 3) A pendrin channel (specialized Cl-/I- cotransported) transports the I- at the apical membrane

Synthesis of thyroglobulin in vesicles (TGB) & its release via exocytosis into colloid. The TGB vesicles express thyroid peroxidase (TPO) which is released upon fusion with the membrane and immediately results in
Oxidation of two iodides (I-) to I2 by thyroperoxidase (TPO)

4) Iodination of tyrosine residues in TGB to T1 then T2 by TPO

5) Coupling/ conjugation of T1 & T2 to form T3 & T4 (ratio about 1:13) also by TPO

6) Uptake (pinocytosis) & lysosomal digestion of TGB to release thyroid hormones by follicle cells (stimulated by TSH and megalin receptors). Other degradation products are recycled by the pendrin transporter

7 & 8) Secretion of T3 & T4 into blood & transportation by primarily thyroxine-binding globulin (TBG)

98
Q

At the target tissue - Thyroid hormones

A

T3 (biologically active)
Formed from T4 by 5’-deiodination in thyroid (20%) and peripheral tissues.

Deiodinases maintain cellular and serum concentrations of T3 and the expression of these enzymes changes according to thyroid hormone status.

T3 binds to nuclear thyroid receptors that complex with retinoid X receptor (RXR)

The receptor complex binds to the thyroid response elements for initiation of transcription

T4
50X more in plasma that T3
80% is metabolised to T3 & rT3.
20% is conjugated and excreted.

T4 is tightly bound to plasma proteins compared to T3

99
Q

Drugs, hormones and effect on the Thyroid

A

Inhibit TSH: Corticosteroids, Dopaminergic drugs
Inhibits T3 +T4 production: Lithium, Carbimazole
Inhibit TBG: Corticosteroids, Androgens
Decrease conversion of T4 to T3: Beta blockers
Increase TBG and TSH: Oestrogens

100
Q

Two overall categories of Hyper hypoothyroid symptoms

A

Those due to excess of hormones (hyperthyroidism or thyrotoxicosis)
Tachycardia, heat intolerance warm moist skin, goitre increased appetite and weight loss, anxiety and tremor

Those related to deficiency of hormones (hypothyroidism)
Bradycardia, cold intolerance, dry thin hair and skin, goitre, fatigue and depression

101
Q

Recap on basic thyroid hormone synthesis control

A

Thyroid hormones - T3 and T4

Produced in thyroid glands under control by TSH

TSH released by thyrotropic endocrine cells in anterior pituitary gland upon stimulation by TRH produced by hypothalamus

T3 / T4 suppress TSH at pituitary level and TRH at hypothalamus level

102
Q

Energy levels and thyroid hormone synthesis (leptin)

A

Fasting leads to reduced leptin production

Leptin control thyroid hormone synthesis at hypothalamus level

PVN (direct) – reduced TRH release
ARC (indirect) - reduced POMC. Increased AgRP / NPY. All suppress PVN TRH release

Reduced TRH leads to reduction in TSH level – low T3 and T4

103
Q

T4 Deiodination at target tissue

A

Transport: Binding to Thyroid binding globulin (70%), transthyretin (10%), 20% ablumin

Tissue deiodinase
Activity modulated by many factors: diet, disease, stress, drugs…..etc

Presents an extra HPT axis level of control on thyroid hormone effects on body functions

T3 internalised then translocates to nucleus,
binds to Thyroid hormone receptor acting as transcription factor on Transcription Response Element (TRE), initiating metabolic gene transcription.

104
Q

T3 effects

A

Protein, carbohydrate and lipid metabolism
Stimulates protein and triglyceride synthesis
Stimulated production of glucose
Also stimulates catabolism of glucose, proteins, and triglycerides

Calorigenic
BMR  (heart, skeletal muscle, liver and kidneys most sensitive)
O2 consumption 
Sweating 
Increased body temperature

Growth and development
Enhances GH secretion
Production and effectiveness of IGF-I 
Essential for CNS development (Synaptogenesis, axon proliferation)
Essential for normal bone formation
Essential for mammary gland development
Need for normal menstrual cycle

Cardiovascular/respiration
Heart rate 
Force of contraction 
Indirect effects:
Cardiac output ,
Peripheral resistance  ,
O2 delivery to tissues 
β adrenergic receptors ,
Sensitivity to sympathetic stimulation 

105
Q

Graves’ disease

A

Thyroid stimulating hormone (TSH) produced by the anterior pituitary binds to TSH receptor(TSHR)s expressed by thyroid follicular cells to stimulate TH production.

Thyroid Stimulating Immunoglobulins (TSI) are autoantibodies against Thyroid Stimulating Hormone RECEPTOR (TSHR).

When binding to TSHR, TSI crosslinks receptors and initiates intracellular signalling activating thyroid follicular cells, mimicking the stimulation by TSH to instruct the production and release of thyroid hormones.

Hyperactive follicular cells extend into the colloid causing a ‘scalloping’ effect

Extensive vacuoles indicate hyperactivity of thyroid hormones packaging and release

106
Q

Differential diagnosis for hyperthyroidism

A

Abnormal levels of thyroid-stimulating immunoglobulins (Graves’ disease)

Hyper-secreting thyroid tumour
(Toxic multinodular goitre, toxic adenoma)

Secondary to excess hypothalamic or ant. pituitary secretion

Iatrogenic causes (e.g. amiodarone, lithium)- See Marshall’s for details

107
Q

Hashimoto’s Disease

A

CD4 T helpers activate B cells into plasma cells producing autoantibodies

High levels of autoantibodies:

Anti-thyroid peroxidase
Anti-thyroglobulin

Cytotoxic T Lymphocyte (CTL)s also induce thyroid cell death

An autoimmune thyroiditis, thyroid acini are progressively destroyed by immunological processes, and the gland becomes diffusely infiltrated by the lymphocytes.

When thyroid cells are destroyed (apoptosis or necrosis), thyroid hormones released in circulation – initial increase in circulating T4 / T3

Followed by hypothyroidism due to decreased TH production by less thyroid cells

108
Q

Anti-thyroid hormone drugs

A

Goitrogens: agents (drugs and foods) that decrease production of TH by thyroid:

Thionamides: (Inhibit TPO (thyroid peroxidase)) – What does TPO do?
-methimazole (10x more potent)
-propylthiouracil
-carbimazole (formulary drug)

Iodides
Oldest remedy, now used in conjunction with thionamides
Observe effects within 24 hours, Maximum effect: 10 –15 days
Inhibit TH release (paradoxical action), inhibit organification of iodide
Decreased size and vascularity of hyperplastic gland

Radioactive Iodine (131I)

109
Q

Thyroid Gland

A

On each side of trachea is lobe of thyroid
Weighs approx. 25g

Highly vascularised (80-120ml blood/min)
Contains LARGE store of thyroid hormones and iodine

Thyroid gland can readily “trap”/sequester iodine from the blood
Secretes two iodine rich bioactive hormones:
Triiodothyronine (T3) and Thyroxine (T4)

110
Q

Thyroid gland cellular structure

A

Spheres of follicles composed of follicular cells and parafollicular cells

Follicular cells produce thyroid hormone, stored in colloid lumen

Parafollicular cells (C cells) make calcitonin

111
Q

Congenital Hypothyroidism

A

Absence or severe deficient thyroid gland
Primary cause (approx. 75%) – Incomplete development of thyroid gland
Others:
Enzyme deficiency approx. 10%
Hypothalamic – pituitary axis defects approx. 10%

112
Q

Anatomical location - Parathyroid Glands

A

2 pairs: upper and lower parathyroid glands

Situated on the dorsal side of the right and left lobes of thyroid gland.

113
Q

Parathyroid cells and PTH secretion

A

Principal (Chief) cells - Predominant and secrete PTH.

Oxyphil cells - Eosinophilic cells with unidentified function, appearing with age.

114
Q

Primary Hyperparathyroidism

A

Excessive production of PTH caused by a single adenoma confined to one of the glands.

115
Q

Secondary hyperparathyroidism

A

Overproduction ofPTHsecondary to a chronic abnormal stimulus for its production - e.g. vit D insufficiency or hypocalcaemia

116
Q

Is there Maternal transfer of Grave’s disease?

A

Transfer provides natural experimental evidence of the role of TSH autoantibodies.

117
Q

Symptoms of Grave’s disease

A

Graves’ ophthalmopathy: observed in ~20% of patients. Condition affects connective tissue behind the eyes leading to swelling, redness, conjunctivitis, exophthalmos (often bilateral).

Pre-tibial myxedema: ~5% of Graves’ disease patients, infiltrative dermopathy, arises from effects of inflammation on tissue glycosaminoglycans (GAGs) which drives edema.

118
Q

Atrophic Thyroiditis

A

Primary myxedema, dermal inflammation, absence of goitre, can involve TSHR blocking antibodies. Part of the spectrum of thyroid autoimmune diseases.

119
Q

Pernicious anaemia

A

Intrinsic factor (IF) binds Vit B12 to facilitate its update. Blocking antibodies to IF or binding antibodies to the IF-B12 complex reduce/block Vit B12 updake, a cofactor required for nucleotide synthesis of rbcs, hence can cause pernicious anaemia.

120
Q

Goodpasture’s disease (Type II)

A

Autoantibodies bind directly to glomerular basement membranes

121
Q

Pemphigus vulgaris

A

autoantibodies to epidermal cadherin

122
Q

Systemic lupus erythematosus (SLE or ‘lupus’)

A

Immune complexes of DNA/anti-DNA/nucleosomes in the blood.
Skin involvement in SLE: ‘butterfly’ rash.
Can be photosensitive
Vasculitis in SLE.