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Endocrinology Flashcards

1
Q

How is hypothalamus connected to pituitary?

A

Pituitary stalk

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1
Q

Where is the pituitary located?

A

Between internal carotid arteries, above sphenoid sinus

On top of pituitary is optic chiasm

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2
Q

What structure surrounds the pituitary at the base of the skull?

A

Sella turcica

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3
Q

What structure allows the hypothalamus and pituitary to communicate?

A

Portal vessels

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4
Q

Describe the pituitary gland structure

A 
Two lobes (bilobed gland)
-lies below the brain in the Sella Turcica.

The anterior lobe (adenohypophysis) is derived from an invagination of the roof of the embryonic oropharynx = Rathke’s pouch.

The posterior is formed from a notochordal projection which forms the pituitary stalk, which connects the gland to the brain and also the posterior lobe of the pituitary (neurohypophysis).

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5
Q

Why is the posterior pituitary known as neurohypophysis?

A

Axons from hypothalamus project down towards pituitary and then synapse onto blood vessels rather than nerves, so posterior pituitary releases hormones into bloodstream = neurohypophysis

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6
Q

Where are the cell bodies for the posterior pituitary?

A

In brain (no hormonal production in brain, just released there

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7
Q

What are the cells in the anterior pituitary?

A

Glandular, nuclei within anterior pituitary

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8
Q

What is the pituitary gland’s blood supply?

A

The pituitary gland has a dual blood supply.
– The first is via the long and short pituitary arteries (bring oxygenated blood)
–The second is from the hypophyseal portal circulation (hypothalamus to pituitary). This begins as a capillary plexus around the Arc

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9
Q

How were pituitary cell types originally classified?

A

Staining characteristics- acidic (orange G) and basic (aldehyde fusion) dyes

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10
Q 
What hormones are produced by cell types:
Gonadotroph
Lactotroph
Somatotroph
Corticotroph
Thyrotroph
A

LH + FSH

Prolactin

GH

ACTH

TSH

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11
Q

What are the anterior pituitary hormones and what do they regulate?

A

ACTH- regulates adrenal cortex

TSH- thyroid hormone regulation

GH- growth increase

LH/FSH- reproductive control

PRL- breast milk production

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12
Q

What are the posterior pituitary hormones and what do they regulate?

A

ADH- governs water release from kidney and fluid balance

Oxytocin- breast milk expression and parturition (contractions to expel foetus)

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13
Q

Describe the endocrine system and what happens in the three layers

A

Primary layer- end organ
Secondary layer- pituitary
Tertiary layer- hypothalamus

Hypothalamus role = takes input from brainstem (HR, BP etc) and senses (surroundings) and makes sense of these neural electrical signals into hormones to give the right state for the situation

Eg, stress response = increase in cortisol, GH, PRL, NA, adrenaline and thyroid hormone + repro function inhibited

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14
Q

What is the hypothalamus’s hormonal output?

A

Hypophyseal portal blood vessel (goes from hypothalamus to pituitary)

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15
Q

When hormones are sent to pituitary from hypothalamus what is its role now?

A

Amplification of signal

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16
Q

What is negative feedback?

A

Hormone production and release are primarily controlled by negative feedback. In negative feedback systems, a stimulus elicits the release of a substance; once the substance reaches a certain level, it sends a signal that stops further release of the substance.

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17
Q

Clinical presentation of pituitary tumours

A

Hormone hypersecretion

Space occupying lesion (can compress structures like pituitary):

  • Headaches
  • Visual loss (field defect)
  • Cavernous Sinus Invasion

Hormone deficiency states:
Interference with surrounding normal pituitary

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18
Q

Excess GH secretion

A

Acromegaly- adult

Gigantism- child

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19
Q

Excess ACTH secretion

A

Cushing’s

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20
Q

Excess TSH secretion

A

Secondary thyrotoxicosis

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21
Q

Excess LH/FSH secretion

A

no symptoms, seen in non-functional pituitary tumour

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22
Q

Excess prolactin secretion

A

Prolactinoma

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23
Q

What inhibits growth hormone?

A

Somatostatin

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24
Q

Action of growth hormone

A

Growth hormone stimulates liver to produce IGF-1 which acts on chondrocytes of long bones to cause linear growth

Direct act of Growth Hormone is on fat and muscle tissue so glucose trapped in cells so decrease in glucose metabolsim

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25
Q

Systemic affects of GH/IGF-! excess

A

Acral enlargement

  1. spade like hands rings too small
  2. Inc shoe size
  3. macroglossia
  4. carpal tunnel syndrome

Increased skin thickness

Increased sweating

Skin tags and acanthosis nigricans

Change appearance
- inter-dental spacing

Visceral enlargement

Metabolic Changes

Impaired fasting glucose

Impaired glucose tolerance

Diabetes mellitus

Insulin resistance

Reduced total cholesterol

Increased triglycerides

Increased nitrogen retention

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26
Q

Subtle changes due to acromegaly in face

A

Coarsening of facial features (nose, lips, orbital arches increasing in size over time)

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27
Q

Actions of cortisol on glucose

A

Increases plasma glucose levels

  • Inc gluconeogenesis
  • Dec glucose utilisation
  • Increases glycogenesis
  • Inc glycogen storage
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28
Q

Actions of cortisol on lipolysis, proteins

A

Increases lipolysis

Proteins are catabolised

Releases Amino Acids

Na+ and H2O Retention
- Maintains BP

Anti inflammatory

Increased gastric acid production

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29
Q

Cushing’s syndrome

A
  1. Changes in protein and fat metabolism:
Change in body shape
Central obesity
Moon face
Buffalo hump 
Thin skin, easy bruising
Osteoporosis (brittle bones
Diabetes
  1. Changes in sex hormones:

Excess hair growth
Irregular periods
Problems conceiving
Impotence

  1. Salt and water retention:

High blood pressure
Fluid retention

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30
Q

Prolactin mechanism

A

Excess prolactin -> prolactinomas (common)

PRL different control to all other anterior pituitary hormones

  • -> PRL high intrinsic production of it in pituitary, so Tonic release of dopamine inhibits PRL release
  • -> controlled by Positive Feedback

NORMALLY during lactation, mechanical stimulation of nipple sends neural signal to brain to stop production of DA so surge in PRL to produce milk for baby- terminated by removing baby from breast

PRL inhibits LH/FSH so that during lactation another bbay is not produced. bc who wants more of these bitches

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31
Q

What drugs interfere with dopamine and PRL secretion?

A

Antiemetics
Antipsychotics
OCP/HRT

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32
Q

What are features of PRL excess (hypogonadism)?

A

Infertility - Oligoamenorrhoea
Amenorrhoea - Galactorrhoea
Reduced libido - Impotence

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33
Q

Treatment of prolactinomas

A

Dopamine antagonists

bromocriptine,
cabergoline
not surgery

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34
Q

Non-functioning pituitary tumours

A

30% of all pituitary tumours
No syndrome of hormone excess produced

Cause symptoms due to space occupation

  • headache
  • visual field defects
  • nerve palsies
  • interfere with rest of pituitary function - deficiency of hormones
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35
Q

Treatment for non-functioning pituitary tumours

A

surgery (transsphenoidal approach) ± radiotherapy

no effective medical therapy

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36
Q

Why do pituitary tumours affect vision?

A

Eyes at front of head so both eyes look at an object at the same time- each eye sees slightly different image, both together gives depth perception

Images joined from nasal and temporal retinas- neurons from nasal side of one retina line up with neurons on temporal side of other retina, cross over and signal sent to brain

Area of crossing over = OPTIC CHIASM sits directly above pituitary, so if tumour compresses this area you get BITEMPORAL HEMIANOPIA (places lesion at optic chiasm exactly)

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37
Q

If a patient with a tumour suffers from bitemporal hemianopia where must the tumour be?

A

Optic chiasm

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38
Q

In which order are pituitary hormones lost due to expanding tumour?

A 
LH/FSH - sex
GH - growth
TSH - metabolism
ACTH - survival
increased PRL - stalk compression
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39
Q

Treatment of pituitary adenomas

A

SURGERY
Transsphenoidal
(Adrenalectomy - Nelson’s syndrome)

RADIOTHERAPY
Slow

DRUGS
Block hormone production
Stop Hormone Release

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40
Q

Trans sphenoidal surgery

A

Done with telescope -> enter through side of nose/top of jaw to see pituitary tumour and remove it

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41
Q

Causes of pituitary failure

A

Tumour

  1. Benign
  2. (Malignant)

Trauma

Infection

Inflammation

  1. Sarcoidosis - general
  2. Histiocytosis - affects pituitary specifically

Iatrogenic

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42
Q

Low thyroid hormone levels lead to:

A 
Bradycardia
Weight gain
Cold intolerance 
Hypothermia
Constipation
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43
Q

Low sex steroid hormones lead to:

A

Oligomenorrhoea
Reduced libido
Hot flushes
Reduced body hair

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44
Q

Low cortisol levels lead to:

A

Reduced Cortisol:

Tiredness
Weakness
Anorexia
Postural hypotension
Myalgia
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45
Q

Low GH levels lead to:

A

Fatigue + central weight gain

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46
Q

Treatment for low thyroid

A

Thyroxine

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47
Q

Treatment for low sex steroids

A

Testosterone

Oestrogen

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48
Q

Treatment for low cortisol

A

Hydrocortisone

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49
Q

Treatment for low GH

A

GH

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50
Q

What does Vasopressin (antidiuretic hormone) do and what stimulates its release?

A

Acts on collecting ducts increasing their permeability to water -> allows water to return to body from urine -> decreases amount of urine produced (antidiuretic)

Causes vasoconstriction and increasing blood pressure - produced in response to dehydration -> plasma osmolality increase leads to increased production of vasopressin

Produced when blood pressure low - sensed by baroreceptors in atria and arch of aorta

Also produced due to low oxygen and high CO2 in bloodstream - signals to brain circulating volume is reduced (cortisol, sex steroids and angiotensin 2 stimulate vasopressin release here)

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51
Q

Syndrome of inappropriate ADH (SIADH)

A

Too much ADH

Brain injury/infection

Lung cancer/infection asthma IPPV

Metabolic

  • Hypothyroidism
  • Addison’s
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52
Q

What would determine a diagnosis of SIADH?

A
  1. Plasma Na+ (low sodium bc osmolality reduced)
    (<130mmol/l)
  2. Plasma osmolality - reduced
    (>285mOsm/kg)
  3. Urine osmolality (very concentrated)
    (>100mOsm/kg)
  4. Urine Sodium
    (>30mmol/l)
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53
Q

Treatment of SIADH

A

Fluid restriction

Demeclocyline - stops ADH in kidney

ADH Antagonist (Tolvaptan)

Treat underlying cause tho- usually chest infection

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54
Q

Diabetes insipidus

A

Underproduction ADH
- Cranial issue eg damage to hypothalamus or injection causing Lack of Production

Nephrogenic
- Receptor resistance (ADH is being produced by brain but damage to kidney)

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55
Q

What would confirm a diagnosis of diabetes insipidus?

A

Too much urine being produced

Polyuria (>3l)
but could be Polydipsia (drinking large amounts of fluid)
- Plasma Na+
- Plasma osmolality increased (> 295 mosmol/kg)
- Urine osmolality - too diluted (< 700 mosmol/kg)
- Urine Na+

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56
Q

How to confirm between diabetes insipidus and polydipsia?

A

Water deprivation test

Patient not allowed any access to water for 8 hours - body weight measured at start of test and weighed after and look for signs of dehydration

Then given ADH injection

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57
Q

How would a normal person vs diabetes insipidus patient respond to water deprivation test?

A

Normal person: maintain plasma osmolality and urine concentrated and low volume (osmolality of urine 3x of plasma)

Cranial Diabetes insipidus: continue to pass urine so plasma concentrated, but urine not concentrated and LESS 3x upper limit of normal and ADH injection makes it normal (so DI confirmed because can’t maintain normal plasma osmolality but respond to ADH, so body not making any ADH as they can respond)

Nephrogenic DI: plasma concentrated and urine too dilute, person dehydrated and things do NOT get better after ADH injection because they can’t respond to ADH, telling us its nephrogenic

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58
Q

Treatment for diabetes insipidus

A

ADH injection/tablet/nasal spray

for CRANIAL- low dose
for NEPHROGENIC - high dose bc receptor resistance

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59
Q

How does the thyroid develop in embryo?

A

Develops from Tongue root (foramen cecum)
Descends into the neck as the Thyroglossal duct
Formed by 5th-6th week of development

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60
Q

Where are C cells derived from?

A

Ultimobranchial body (arch V(

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61
Q

What do C cells secrete?

A

Calcitonin

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62
Q

What happens if thyroid fails to descend?

A

Lingual thyroid sits at back of tongue, root of thyroid down to hyoid bone

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63
Q

What happens if the thyroglossal duct fills with fluid?

A

Thyroglossal cyst

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64
Q

Blood supply of thyroid gland

A

Inferior thyroid artery from SUBCLAVIAN

Superior thyroid artery from CAROTID

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65
Q
A
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66
Q

Location of thyroid gland

A

Isthmus sits between 2nd + 3rd tracheal ring just below larynx

67
Q
A
68
Q

Thyroid hormone pathway

A

TRH release from hypothalamus
Stimulates anterior pituitary to release TSH -> TSH stimulates thyroid
TSH causes release of Triiodothryonine and thyroxine from thyroid gland

69
Q

Thyroid stimulating hormone TSH (thyrotropin)

A

Produced by the Thyrotroph cells of the anterior pituitary

Acts on the thyroid follicular cell

Increases iodine uptake

  • Increases thyroid colloid production
  • Increases thyroid hormone secretion
  • Increase thyrotroph growth

Act via G coupled protein receptor

70
Q

What are the plasma thyroid hormones?

A

3,5,3,5-tetraiodo L-thyronine (thyroxine T4)

3,5,3`-triiodo L-thyronine (triiodothyronine T3)

71
Q

T4 and T3 receptor types

A

Receptor is nuclear (type2) forms heterodimer

72
Q

What proteins do thyroid hormones bind to in circulation?

A
  • Thyroid Binding Globulin
  • Albumin
  • Prealbumin
73
Q

Half life of thyroid hormones

A

Plasma half life
T3 (1-3 days)
T4 (4-7 days)

74
Q

Daily iodine requirement

A

50ug/day

75
Q

How is thyroglobulin protein produced?

A

TSH circulates through blood and binds onto receptor outside cell (peptide hormone) activating intracellular pathway to produce thyroglobulin protein:

  • G stimulatory protein bound to GDP -> converted to GTP active form
    • Activates effector enzyme adenylate cyclase, reacts with G protein
    • Converts ATP -> cyclic AMP
    • Activates PKA
    • PKA phosphorylates transcription factor in nucleus
    o Stimulates genes to make a specific protein
    o Transcription produces mRNA -> goes to ribosomes on rough ER and produces proteins
    o Proteins modified etc
    o Sent to golgi and packaged/modified in vesicles
    o Protein in vesicle fuses with cell membrane
    o Exocytosis
    o Releases protein into luminal space (colloid)
76
Q

What residues are on thyroglobulin?

A

Thyroglobulin has tyrosine residues which are iodinated by thyroid peroxidase

77
Q

Thyroid peroxidase

A

THYROID PEROXIDASE enzyme converts iodide into IODINE (iodide oxidation- loss of electrons) kicks iodide so hard the electrons get knocked off him (I- to I2)

It then ADDS IODINE to tyrosine amino acids on thyroglobulin IODINATION of the protein

(o MIT- monoiodotyrosine (one iodine on tyrosine) T1
o DIT- diiodotyrosine (2 iodine on tyrosine) T2)

78
Q

How are T3 and T4 produced?

A

o Iodide circulating in bloodstream
 In ion form with negative charge IODIDE
 Concentrated in follicular cells, low concentration outside
 Sodium high conc outside cell, low in cell so moves passive transport from high to low into cell, co-transporting iodide
• Symporter moves iodide into the cell with sodium SECONDARY ACTIVE TRANSPORT
• PENDRIN protein pumps iodide out from cell into luminal space
• THYROID PEROXIDASE enzyme converts iodide into IODINE (iodide oxidation- loss of electrons) kicks iodide so hard the electrons get knocked off him (I- to I2)
• Iodines then added to tyrosine amino acids on thyroglobulin protein so IODINATION of the protein via thyroid peroxidase
Leads to:
o MIT- monoiodotyrosine (one iodine on tyrosine) T1
o DIT- diiodotyrosine (2 iodine on tyrosine) T2
o MIT and DIT are coupled by TPO

  • DIT + DIT = T4 or THYROXINE
  • MIT + DIT = T3 or TRIODOTHYRONINE
79
Q

How do T3 and T4 get into the bloodstream?

A

So thyroglobulin has T3 and T4 in it post iodination, whole protein brought into cell

  • Done via lysosomes
  • Endocytosis of protein into cell

T3 and T4 need to be isolated to be secreted

  • Lysosomes fuse with vesicle
  • Cleavage enzymes enter and cut and isolate T3 and T4
  • So only thyroid hormones remain in vesicle
  • Vesicle fuses with follicular cell membrane to release T3 and T4 into bloodstream
  • Act as steroid hormones (not water soluble) so need to be transported through blood via transport protein produced by liver THYROXINE BINDING GLOBULIN → Transports T3 and T4
80
Q

Actions of thyroid hormones

A 
Increases Basal Metabolic Rate
Increase thermogenesis
Increases sympathetic nerve activity
Increase protein synthesis
Chronotropic
81
Q

Hyperthyroidism

A 
Over production:
Thyrotoxicosis
Graves disease
Multinodular Goitre
Toxic Solitary Nodule
Thyroiditis
82
Q

Tests for hyperthyroidism

A

Thyroid Function
Autoantibodies
Technesium Scanning
ESR

83
Q

Thyrotoxicosis symptoms

A

Sympathetic overactivity

Poor appetite 
Myopathy
Increased Growth
Diarrhoea
 In the elderly
Minimal symptoms
Anorexia
CCF or AF
Grave’s:
Pretibial Myxodema
Exopthalmos
Chemosis
Acropachy
84
Q

Investigation for thyrotoxicosis

A
  1. Thyroid Function tests
  2. Autoantibodies
  3. Technesium Scanning
    - Lack of uptake in thyroiditis and iodine ingestion
    - In MNG it serves to define the functional characteristics of the gland
85
Q

Treatment for hyperthyroidism

A 
Carbimazole (side effects: agranulocytosis eg white cell drops, rash, aplasia cutis)
Propylthiouracil
Beta Blockers
(Lugol’s Iodine)
DXT
Surgery (Subtotal thyroidectomy)
86
Q

Complications of thyroidectomy

A

Bleeding
Hypocalcaemia
Hypothryoidism
Recurrent laryngeal nerve damage

87
Q

Thyrotoxicosis and pregnancy

A

Drugs are safe in pregnancy

Possible association of carbimazole with foetal aplasia cutis

Some physicians may substitute PTU for CMZ in pregnancy

No contraindication to breast feeding

PTU is excreted less in breast milk

Patients receiving CMZ in the dose of 20mg or less need not be changed to PTU

88
Q

Outcome of hyperthyroid treatment

A 
Long term remission can be achieved in 50-60% of cases 
Large goitre
Positive TSH receptor antibodies
F/H of thyroid disease
Opthalmopathy
Smoking
Male Gender
89
Q

Radioactive iodine

A

Safe and appropriate treatment in nearly all types of hyperthyroidism, especially in elderly

Contraindicated in children, pregnancy and women who are breast feeding

Women of childbearing age should wait for 4 months after 131I before becoming pregnant

Should be used with caution in patients with opthalmopathy

Use prophylactic steroids and avoid hypothyroidism

90
Q

Clinical signs of thyroiditis

A
  • Inflammatory response and gland is painful
  • Investigation High ESR
  • Technesium scan no uptake
91
Q

Treatment for thyroiditis

A
  • beta-blocker is usually sufficient to control the symptoms of hyperthyroidism
  • NSAIDS
  • steroids
92
Q

2 types of amiodarone induced thyroiditis

A

Type 1

  • usually affects patients with latent or preexisting thyroid disorders
  • more common in areas of low iodine intake.
  • Caused iodine-induced excess thyroid hormone synthesis and release (Jod-Basedow phenomenon).

Type 2

  • previously normal thyroid gland
  • caused by a destructive thyroiditis that leads to the release of preformed thyroid hormones from the damaged thyroid follicular cells.

Mixed forms of AIT may occur

93
Q

Hypothyroidism

A

Underproduction:

Congenital

  1. Pendred’s Syndrome
  2. Congenital Hypothyroidism

Iodine deficiency
Hashimoto’s thyroiditis
Gland destruction

94
Q

Tests for hypothyroidism

A

Thyroid Function

Autoantibodies

95
Q

Hypothyroidism symptoms

A

Sympathetic underactivity:

Bradycardia
Mental slowness
Poor memory
Decreased locomotor activity
Weight gain
Cold intolerance
Hypothermia
Poor appetite 
Myopathy
Decreased growth
Constipation
Dry skin and hair
Slow relaxing Reflexes

Hoarse voice
Puffy face
Menstrual Irregularity

96
Q

Features of hypothyroidism on ECG

A

Increased amount of electricity needed in machine to produce ECG

So ECG is small volume

Gap between start of P wave and QRS is increased = FIRST DEGREE HEARTBLOCK

Bradycardia

Small uptick in upstroke of R wave = REVERSE TICK PATTERN

97
Q

Investigations for hypothyroid

A

Underproduction

Thyroid Function

Autoantibodies Thyroid peroxidase antibody

Ultrasound if goitre present

  • Can be associated with
  • High CK
  • Abnormal lipids

Guthrie Test

98
Q

Treatment for hypothyroidism

A

Thyroxine

99
Q

Investigation for thyroid nodule

A 
NODULES:
Thyroid Function
Ultrasound
FNA
(CT/MRI)
GOITRE:
Thyroid Function
Ultrasound
CXR
CT/MRI
Flow Volume Loop - see how gland is affecting breathing by compressing trachea
100
Q

U classification of thyroid nodules

A

U1 + U2 = benign, no biopsy

U3, U4, U5 = biopsy needed, could be malignant

101
Q

Thy Classification

A

Biopsy of thyroid lobe done, looking at cells under microscope- classify them as thy

Thy 2 benign
Thy 3 possible cancer
Thy 4 probably cancer
Thy 5 definitely cancer

102
Q

CASE:

A 39-year-old-woman presents with weight gain, lethargy, headaches and constipation. She is 10 weeks post partum. Examination of the neck is normal but she is found to have papilloedema. Her investigations reveal.

TSH mU/L [0.3-3.2] <0.05 fT4 pmol/l [9-26]4.2 fT3 pmol/l [2.5-5.7]0.8

The most likely diagnosis is:

A

Secondary hypothyroidism

103
Q

A 42-year-old-woman presents with weight gain, lethargy, headaches and constipation. Examination of the neck is reveals a smooth goitre.
Her investigations reveal:

TSH mU/L [0.3-3.2] 50 fT4 pmol/l [9-26]6.2 fT3 pmol/l [2.5-5.7]1.8

The most likely diagnosis is:

A

Primary hypothyroidism

104
Q

Diurnal rhythms

A

Most hormones are pulsatile and vary during the day

105
Q

Insulin tolerance test

A

Gold standard for assessing adrenal reserve

  • Insulin is administered to achieve hypoglycaemia with glucose less than 2.1 mmol/L
  • Hypoglycaemia stimulates the stress response which is mediated by the compensatory hormones for hypoglycaemia
  • Glucagon, catecholamines, growth hormone, prolactin.

The test is contraindicated in

  • Ischemic heart disease.
  • Epilepsy.
  • Severe panhypopituitarism
  • The very old or very young
  • Pregnancy

Where the insulin tolerance test is contraindicated, the glucagon test can be used

106
Q

Radioimmunoassay

A

Uses radiolabeled molecules in a stepwise formation of immune complexes.

A RIA is a very sensitive in vitro assay technique used to measure concentrations of substances, usually measuring antigen concentrations (for example, hormone levels in blood) by use of antibodies.

107
Q

What is the problem with total hormone assays?

A

Dependant on binding protein levels
SO
Not always reflective of the free hormone levels

108
Q

Free hormone assays pros and cons

A

PROS:
representative of the active hormone fraction
not binding protein dependant

CONS:
complex and expensive
–> Have a separation step
Can have poor reproducibility

109
Q

Why do peptide hormones need to be measured using an immunometric assay?

A

RIA means that useless peptide fragments will also be measured along with biologically active peptide hormone, making it inaccurate for measuring actual amount of peptide hormone in blood

Immunometric assay washes away fragments leaving only antibodies behind

110
Q

Investigation for thyroid issues

A

Thyroid function- looking at overproduction and underproduction and thyroiditis

Autoantibodies- looking at overproduction and underproduction

Technesium scanning- overproduction and thyroiditis

ESR- thyroiditis

111
Q

If there is thyroiditis present what will technesium scanning show?

A

Quiet and negative bc gland not biologically active

112
Q

Technesium scanning in Grave’s disease

A

Technesium uptake HIGH

112
Q

Technesium scanning in Grave’s disease

A

Technesium uptake HIGH

bc excess thyroid hormone produced (more hormone = higher uptake)

113
Q

What is in this technesium scan?

A
  1. Diffuse uptake throughout gland = Grave’s disease
  2. single toxic nodule
  3. multi nodular goitre
  4. cold nodule - due to cyst
114
Q

Thyroid function tests: what results mean primary/secondary hypo/hyperthyroidism?

A

if T3/T4 high → hyperthyroid
+ TSH detectable
= SECONDARY HYPERTHYROID

if T3/T4 high → hyperthyroid
+ TSH low, suppressed
= PRIMARY HYPERTHYROIDISM

if T3/T4 low → hypothyroid
+ TSH is high
= PRIMARY HYPOTHYROIDISM

if T3/T4 low → hypothyroid
+ TSH low, pituitary not responding normally
= SECONDARY HYPOTHYROIDISM

115
Q

What is sick euthyroid?

A

T4/T3 normal but TSH low
due to stress response -> CRH from pituitary can inhibit TSH/TRH production
= SICK EUTHYROID

116
Q

T3 toxicosis

A

T4 normal, T3 high and TSH low
= T3 toxicosis

seen with toxic nodule

117
Q

Screening and confirmation of Cushing’s

A
  1. Screening
    - Urinary free cortisol
    - Diurnal Rhythm
    - Overnight dexamethasone suppression test
  2. Confirmation of the Diagnosis
    - Low dose Dexamethasone Suppression testing
  3. Differentiation of the Cause
    - High dose Dexamethasone Suppression testing
    - ACTH
    - CRH test
    - Localisation
118
Q

Overnight Low Dose Dexamethasone Suppression Test

A

Cortisol is measured at 8am
Dexamethasone 1mg is given at 11pm
Cortisol is measured at 8am the next morning
Cortisol suppression to <50nmol/l is normal

119
Q

Psuedocushing’s syndrome

A

Depression
Alcoholism
Anorexia Nervosa
Obesity

120
Q

How to tell between True Cushing’s and Pseudocushing’s?

A

LOW DOSE DEX SUPPRESSION TEST
0.5 mg Dexamethasone six-hourly, 48 hrs

Result:
complete suppression (<50nmol/l) in normal subject

If cortisol detectable then patient has CUSHING’S SYNDROME

121
Q

Why is the kidney useful for measuring cortisol?

A

Cortisol: Circadian rhythm

  • highest in morning
  • undetectable at midnight
  • if see cortisol levels high at night and detectable suggests diurnal rhythm disrupted- but difficult so use kidney
  • 24 hour urine collection, use kidney to create peaks- so if large amounts of cortisol throughout day can suggest a problem
122
Q

Why do we use dexamethasone and not cortisol for the suppression test?

A

Instead of giving cortisol for negative feedback, give dexamethesone to actually be able to measure cortisol levels (if you gave cortisol it would appear in the assay)

123
Q

Why would someone with depression/anxiety score above 50 on dexamethasone test?

A

Chronic stress, so cortisol levels higher and seen as pseudocushing’s

124
Q

How to rule out Cushing’s disease?

A

High dexamethasone suppression test

HIGH DOSE
2 mg Dexamethasone six-hourly for 48 hrs

If cortisol suppresses to < 50% of baseline then the patient has Pituitary dependent Cushing’s Disease
If the Cortisol does not suppress then the patient has ectopic ACTH production or an adrenal tumour

only pituitary has cortisol receptors

125
Q

Differential diagnosis if Cushing’s is ruled out

A

Adrenal tumour (low ACTH)

Ectopic ACTH production (high ACTH)

benign or malignant

126
Q

What enzyme reduces cortisone to cortisol

A

11 Beta Hydroxysteroid dehydrogenase type 1 (HSD1)

type 2 does reverse

127
Q

What test is used to differentiate between pituitary dependant Cushing’s and ectopic ACTH?

A

CRH TEST

0.1 µg/kg of human CRH is given
Blood is assayed for ACTH and cortisol at time -15, 0, 15, 30, 60, 90, 120.

An exaggerated response indicates pituitary dependant Cushing’s Disease

A flat response indicates ectopic ACTH production

128
Q

What is the test for adrenal insufficiency?

A

Synacthen test

129
Q

Short vs Long Synacthen test

A

Short Synacthen (250mcg)
Blood taken over 1 hour
Used to diagnose primary adrenal failure

Long Synacthen Test (1mg)
Blood taken over 24 hours
Used to diagnose secondary adrenal failure

130
Q

Why is cortisol level higher on day 2 of synacthen test in secondary adrenal failure?

A

Adrenal gland grows due to high dose of synacthen

131
Q

Short synacthen test

A
132
Q

Long synacthen test

A
133
Q

What is the test for acromegaly?

A

Oral glucose tolerance test

134
Q

Oral Glucose Tolerance test

A

Take blood sample for GH and IGF-1
75 grams oral glucose

Take blood for GH and glucose at t=30, 60, 90 and 120 minutes

A synacthen test can be carried out at the end of this test

samples for cortisol taken at t=120, 150 and 180. Synacthen 250 mcg is administered at t=120

135
Q

What suggests acromegaly in oral glucose tolerance test (vs normal) ?

A

In normal individuals, GH levels fall following oral glucose, and at least one of the samples during the test should have undetectable GH levels.

Failure of suppression or a paradoxical rise in GH suggests acromegaly.

Following treatment safe level of GH < 1.0mU/l (0.4ng/ml)

136
Q

What hormones are produced in the renal cortex?

A

Cortisol, aldosterone, sex steroids

137
Q
A
138
Q

Where is 21 hydroxylase expressed?

A

21 hydroxylase only expressed in adrenals

so only in adrenal is aldosterone and cortisol produced

139
Q

Oestrogen and dihydrotestosterone production

A

Enzymes for testosterone production in both ovary and testis

Production of testosterone in ovary but also production of aromatase enzyme so oestrogen produced

In males testosterone produced but active androgen is actually dihydrotestosterone, so testosterone is reduced by 5 alpha reductase to dihydrotestosterone

140
Q

Why is it important for women that the adrenal cortex produces androgens?

A

For women, androgen production in circulation is 50% from ovary directly and 50% from adrenal synthesis

141
Q

What enzyme is downregulated in 2nd half of menstrual cycle?

A

17 alpha hydroxylase (meaning progesterone reduced)

142
Q

Defects in this pathway can cause what?

A

Congenital adrenal hyperplasia

143
Q

Cushing’s syndrome vs Cushing’s disease

A

Cushing’s Syndrome
Excess cortisol in the blood

Cushing’s Disease
Excess cortisol in the blood due to an ACTH secreting pituitary tumour

144
Q

Clinical features of Cushing’s syndrome

A

Excess hair growth
Irregular periods
Problems conceiving
Impotence

High blood pressure
Fluid retention
(due to salt and water retention)

Depression and anxiety

145
Q

Genes from POMC

A

Gene for ACTH part of POMC (pro opiomelanocortin)

alpha MSH strong appetite suppressor

POMC often activated in cancer - but if in a cell where intracellular machinery for making hormones is not present it will do nothing, but will in one that does

146
Q

Labartpry features of Cushing’s

A

Hypokalaemia

Metabolic alkalosis

Hyperglycaemia

147
Q

Mechanism of hypernatremia, hypokalaemia and metabolic alkalosis in Cushing’s

A

Mineralocorticoid receptor binds aldosterone

Channel retains sodium → need to lose positive charge to bring in sodium so potassium booted out, when potassium runs out H+ used

So when cell overactive = hypernatremia, hypokalaemia and metabolic alkalosis

148
Q

Cortisol to cortisone mechanism

A

Cortisol can also bind to mineralocorticoid receptor to equal affinity to aldosterone so 11 Beta hydroxysteroid dehydrogenase 2 protects receptor by DESTROYING CORTISOL and converting it into cortisone

Catalytic site of enzyme has saturation point higher than cortisol level produced daily, but lower than cortisol level produced in extremis

THUS normally when aldosterone controls BP all cortisol daring to near receptor is demolished so only aldosterone remains victorious controlling BP

But if we are busy dying in extremis cortisol much higher presence in bloodstream so catalytic site saturated and now cortisol can acsess receptor and do its job

149
Q

Treatment for adrenal adenoma

A

SURGERY

Cortisol Production Blockers

  • Metyrapone
  • Ketoconazole

Patients need to have steroid replacement tablets at the time of and following surgery
The adrenal tumour suppresses the function of the normal gland
Many will not need the steroid tablets long term

150
Q

Clinical features of Addison’s disease

A 
Tiredness
Weakness
Anorexia
Weight loss
Postural hypotension
Myalgia
Salt Craving
Nausea Vomiting
Hyperpigmentation
Vitiligo
Hyponatraemia 
Hyperkalaemia
Acidosis
Hypercalcaemia
Hypoglycaemia
Increased urea and creatinine
Eosinophilia
Lymphocytosis
151
Q

Causes of Addison’s syndrome

A
152
Q

Investigations for adrenal insufficiency

A 
9 AM cortisol
ACTH
Electrolytes
FBC
Adrenal imaging
Adrenal anti-bodies

Investigations for other causes of adrenal failure

Infection screen

Imaging for cancer

Biochemical testing for enzyme deficiency

153
Q

Dynamic Tests for adrenal insufficiency

A

Short Synacthen (250mcg)

  • Stimulate adrenal directly
  • Used to diagnose primary adrenal failure (Addison’s disease)

Long Synacthen Test (1mg)

  • Prolonged stimulation of adrenal directly
  • Used to diagnose secondary adrenal failure (due to pituitary failure)

Insulin tolerance test

  • stimulates the hypothalamus directly
  • Gold standard for assessing adrenal axis

Glucagon test

  • stimulates the hypothalamus directly
  • Performed when insulin tolerance test is contraindicated
154
Q

Treatment for Addison’s

A

Hydrocortisone

  • 10mg 5mg 5mg
  • Mimicks the diurnal rhythm
  • Last dose before 6pm

Fludrocortisone
- 50-200mcg o.d.

155
Q

21-hydroxylase Deficiency (Classical) CAH

A

Cortisol can’t be produced = no negative feedback = lots of cholesterol bc lots of ACTH
→ build up of 17 hydroxyprogesterone (intermediate product) needs to be destroyed and only way to do this is production of testosterone bc cortisol pathway blocked

In female causes virilisation of genitalia, hirsutism, premature adrenarche, infertility

Bc no aldosterone also salt losing crisis eg hyperkalaemia and hypotension

156
Q

11β-hydroxylase Deficiency (Non-Classical)

A 
Accounts for approx 5% of reported CAH.
Incidence 0.5:100 000 live births
Autosomal recessive 
Increased in Moroccan Jews (1:6000 live births)
HLA linked - HLA-B14,DR1

Defect here is lower in pathway than classical-

156
Q

11β-hydroxylase Deficiency (Non-Classical)

A 
Accounts for approx 5% of reported CAH.
Incidence 0.5:100 000 live births
Autosomal recessive 
Increased in Moroccan Jews (1:6000 live births)
HLA linked - HLA-B14,DR1

Defect here is lower in pathway than classical- 17 hydroxyprogesterone increases = masculinisation of female via testosterone

Also deoxycorticosterone produced in excess (partial mineralocorticoid receptor agonist) so present with hypertension rather than salt crisis
→ so hypertension and hypokalaemia

Cortisol not produced so lots of cholesterol bc no neg feedback

157
Q

Investigation for congenital adrenal hyperplasia

A

Synacthen Test:

  • No cortisol rise
  • Increased 17OH Progesterone levels

Prednisolone suppression:
-Androgens should fall into normal range

158
Q

Treatment for congenital adrenal hyperplasia

A

Both entities comprise a spectrum of disease – partial deficiencies complicate matters.

Rx of 11b- and 21- hydroxylase deficiency lies mainly in the use of glucocorticoid therapy

  • To replace cortisol
  • To inhibit ACTH production, reducing adrenal testosterone production

Surgery to virilised female genitalia.

Treatment of Mother to prevent foetal Virilisation

159
Q

Aldosterone

A

Produced in the zona glomerulosa of the adrenal cortex
Acts on the kidney via receptor binds glucocorticoids with equal affinity
Intranuclear receptor (type 1)

160
Q

How is aldosterone stimulated?

A

Stimulation of aldosterone:

  • low BP
  • low sodium at macula densa (DCT)
  • SNS activity

causes renin release from juxtaglomerular cells
renin acts on angiotensinogen in liver to release angiotensin 1 → converted by ACE into angiotensin 2
angiotensin 2 acts on adrenal gland to release aldosterone
aldosterone acts to retain sodium, expanding extracellular fluid and reduced potassium

161
Q

Aldosterone neg feedback with renin

A

No aldosterone receptors on kidney but action of it reverses stimuli to renin production = PHYSIOLOGICAL NEGATIVE FEEDBACK

162
Q

Aldosterone syndromes

A
163
Q

What happens in steroid treatable hypertension?

A

Due to defect in 11 beta hydroxylase dehydrogenase 2 enzyme - enzyme doesn’t work so BP controlled by cortisol not aldosterone

Treated by glucocorticoid eg dexamethasone, causes neg feedback to ACTH so cortisol stops being produced so aldosterone can take over BP again
Dexamethasone replaces cortisol

164
Q

Conn’s treatment

A

surgery to remove the gland (tumour)

Spironolactone/Eperelone
Amiloride / Triampterine
Potassium Supplementation
Treatment of the Primary Tumour
Sugery

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