the patient Flashcards
where is the thyroid gland located
lower part of the neck
in front of the trachea
what is the lumen full of
colloid
( glue like )
what cells surround the lumen
thyroid follicular cells
what do they thyroid follicle cells produce
thyroglobulin protein by exocytosis into the lumen
what does the NIS transporter do and pendrin do?
transports iodide ions from follicular cells into lumen
what does thyroperoxidase do
converts iodide ions to atomic iodine
what is MIT
where 1 iodine is attached to a tyrosine ring on thyroglobulin
what is DIT
two iodines attached to tyrosine on thyroglobulin
di iodo tyrosine
what does DIT + DIT give?
T4
what does MIT + DIT give?
T3
what is T4
thyroxine
tetra iodo thyronine
what do T3 and T4 control
TRH and TSH by negative feedback
what does TRH stimulate the release of
TSH
what does TSH do
Travels to the thyroid gland
stimulating the synthesis and release of thyroid hormones
what do T3 and T4 do
control the secretion if TRH and TSH
where are the adrenal glands
top of the kidney like hats
what are the tree layers of the adrenal glands out to in
makes up the cortex
zona glomerulosa
zona fasciculata
zona reticularis
medulla = middle
remember via GFR
what does the outermost layer produce
aldosterone
what does the fasciculata produce
cortisol
what does the reticularis produce
sex steroids
what does the medulla produce
epinephrine
norepinephrine
what does the medulla do
flight or flight response
what is cortisol
stress signal
why are sex steroids important
reproduction
Why is aldosterone important?
water retention
what caused the release of aldosterone
angiotensin 2
what is the HPA
Hypothalamic, pituitary, adrenal axis
what is a serious issue with transplantation
lack of available organs
immune system - main
when was the first sucessful transplant
1906
when was the opt out scheme introduced
2018
what does rate of rejection depend on 3
- tissue type
Skin rejected faster than kidney, liver well tolerated - number of transplants
Second grafts rejected faster - rejection mechanism
Antibody-mediated rejection can be instant
what are most transplants anf the sources of most transplant
Most transplants are cadaveric (dead donors)
Disadvantage: Long waiting list
Increases in living donor transplants
In the UK- 1 in 4 kidney transplants are now from living
donors
For either source of donated organ, still high risk of rejection
The immune system is just doing its job!
what is an AUTOGRAFT
(generally accepted)
Self-tissue transferred from one body site
to another in the same individual
what is an ISOGRAFT
(generally accepted)
Tissue transferred between genetically
identical individuals (inbred mice or
identical twins)
what is an ALLOGRAFT
(often rejected)
Tissue transferred between genetically
different members of the same species
what is an XENOGRAFT
(vigorously rejected)
Tissue transferred between different
species (e.g. baboon heart into human
recipient)
describe a transplant rejection
when a kidney is gransplanted the recipients T cells attack the transplant
describe graft vs host disease rejection
GvHD
when bone marrow is transplanted, the T cells in the transplant attack the bodys tissues.
Transplantation of immunocompetent
cells
* GvHD can be lethal
describe the Primary immune response
first encounter with
a pathogen
– Longer lag time
– Less specific response
describe the secondary immune response
second and
subsequent infections with the same pathogen
– Faster response
– More specific response
– Principle of vaccination
last two, immunological memory
what does immunological memory lead to
immunological memory results in the more rapid elimination
of pathogens, and more rapid destruction of a second graft
what does the second graft lead to sometimes
a more liekly graft rejection
what is indirect allorecognition
T cells can respond to non-self peptides in self
MHC
what is direct allorecognition
T cells can respond to non-self peptides in non-self MHC
Grafts with no lymphatic
drainage tend to be more
successful
what are the 3 rejection mechanisms
Hyper-acute - antibody mediated
* Acute - T cell mediated
* Chronic - Multiple mechanisms
tell me more about Hyper-acute - antibody mediated
Pre-existing recipient alloantibodies
– sensitised to donor MHC -previous
transplants, blood transfusion
* Rejection occurs in minutes
* Abs bind Ags on graft endothelial cells
Classical complement cascade activated
Neutrophils attracted to site
Blood clotting cascade initiated
Hyper-acute - antibody mediated tell me more about it
Type IV hypersensitivity
* Mediated by activated allospecific effector T cells
* Donor leukocyte involvement -direct allorecognition-
non-self peptide in non-self MHC of donor APC
* This stimulates a strong immune response
In the presence of alloreactive memory T cells
(previous transplants) - much more rapid rejection
tell me more about Chronic graft rejection
Occurs months to years after transplantation
* Gradual reduced blood supply to the graft- loss of function
* This causes failure of over half kidney/heart grafts within
10years
what does Indirect allorecognition drive?
chronic rejection
Indirect allorecognition of transplanted
tissue
* Allogeneic (non-self) HLA Class I are
processed and presented by self APC
* This activates self TH
* These will help activate naïve B cells –
release of anti-alloHLA alloantibodies
* Endothelial cells in the graft express
alloHLA antigens
* Binding of the anti-alloHLA antibodies
to the alloHLA antigens results in
impairment of function (autoimmune
mechanisms)
Also- Non-immunological rejection processes
Graft injury
disease
drug toxicity
what is graft injury chronic graft rejection
at time of transplantation or during
transit from donor to recipient
e.g. ischaemia-reperfusion injury
what is disease chronic graft rejection
Recurrence of the problem that
necessitated the transplant
e.g. lung infection in CF
what is drug toxicity chronic graft rejection
immunosuppressants can be
damaging
e.g. cyclosporin A is toxic to kidneys
The options to minimise rejection of allogeneic grafts are:
- HLA matching (tissue typing)
- Immunosuppressant therapy
- Induce tolerance (experimental)
ABO and Rh antigen matching prevents type
II hypersensitivity in blood transfusions testing
Cross match testing of matched blood prior to transfusion
will then reveal whether any other antibodies in the patient
serum react with the donor red cells
what is HLA expression analysis
Mix blood with a panel of antibodies to different HLA
antigens
Agglutination reaction (blue) indicates antigen expression
what is The mixed lymphocyte reaction that measures T cell responses
Incubate irradiated donor
cells (yellow) with recipient
lymphocytes (blue)
This test indicates the
presence of alloreactive T
cells- acute/chronic rejection
Three kinds of immunosuppressant:
– Corticosteroids
– Cytotoxic compounds
– T cell modifiers
The majority of patients receive mismatched organs
* We need to use drugs to suppress alloreactions and
prevent rejection
Corticosteroids
Steroids have many adverse side effects
– Use acutely, not long-term
Cytotoxic drugs 3
Azathioprine- pro-drug
* Inhibits DNA replication
* Prevents replication of
alloantigen-stimulated T
cells
Cyclophosphamide-
chemical weapon from WWI-
many toxic effects!
Methotrexate – inhibits
replication, useful in
inhibiting GVHD in bone
marrow transplants
what are T cell modifiers
Inhibit T cell activation but also
suppress B cell/granulocyte
activation
No effects on proliferating cells
(good news for the intestines)
BUT fairly toxic to the kidneys
* COMBINATION THERAPY
what can HLA do
minimise rejection
what does sucessful transplantation require
lifelong therapy on a cocktail of
immunosuppressant drugs
what is HYPERSECRETION
too much
Hyperthyroidism
what is HYPOSECRETION
hypothyroidism
too little
what is graves disease
Hyperthyroidism (Graves disease)
more common in men
Autoimmune disease
Causes overproduction of thyroid hormones
Result from generalised over activity of thyroid gland:
– Hot, flushed, heat intolerant
– Enlarged thyroid gland (goitre)
– Exopthalmos
– Weight loss
– Muscle weakness, tremor
– Pulse rate ⇑, palpitations, sweating
– Hair loss, menstrual changes
diagnosis for hyperthyroidism
- Physical examination
- Family history
- Blood tests
– Thyroid hormones (T3, T4 ⇑)
– TSH levels (⇓)
– Thyroid antibodies - Thyroid scan (iodine uptake)
Hyperthyroidism: Drug Treatment
Anti-thyroid drugs: ⇓ T3/4 secretion
Anti-thyroid Drugs
Drugs which inhibit organic binding of iodine:
Carbimazole
* FIRST LINE IN UK
* Thought to act by inhibiting the thyroperoxidase enzyme
Propylthiouracil
T4 pro-hormone, less active, more abundant)
* In UK kept for people unable to take carbimazole
prescribing carbimazole
- Give in high doses unitl euthyroid
- Reduce to maintenance dose
- Withdraw after 1-2 years and monitor
Clinical effect note:
Rapid action to inhibit organic binding BUT large stores of T3 and T4 must be
“used up” before therapeutic effect
Drugs which reduce the uptake of iodine:
– Thiocyanate
– Perchlorate
hyperthyroidism symptom relief drug
propanolol
B blocker
Used to reduce symptoms of over activity of the sympathTaken up by active transport &
concentrated in gland
how to track radioactive iodine
Taken up by active transport &
concentrated in gland
* Local tissue destruction by x ray &
β-particle emission
tell me more about radioactive iodine
may produce
hypothyroidism (need
replacement therapy).
* First line treatment
* sometimes
* OR after failure of anti
thyroid drugs
* OR after failure of
thyroidectomy
* OR as standard
procedure for some
thyroid cancers
what is Thyroidectomy
surgery
For patients where 131I and drugs have failed
– Patients with large goitre: cosmetic effects, swallowing or breathing
difficulties
* Ideally: sub-total thyroidectomy leaving patient with enough gland to
be euthyroid
– BUT possibility of recurrent thyrotoxicosis or developing hypothyroidism is a
risk
* Hypothyroidism: need thyroid replacement therapy (see later)
what is Hypothyroidism
Syndrome caused by deficiency of thyroid hormones
* Possible causes
* Congenital
* Autoimmune disease: Abs to thyroglobulin
* Inflammation of thyroid (Hashimotos thyroiditis)
* Dietary iodine deficiency
Hashimotos thyroiditis what is it
hypothyroidism
Inflammation, fibrosis and decreased function of thyroid gland. Goitre evident.
what is Myxoedema
hypothyroidism
– Hypothyroidism developing in adult life
– Adult onset slow and insidious, confused with normal aging process. ⇑ women
– In rare cases, becomes medical emergency, requires treatment by T3.
Cretinism: affects children from birth what is it
hypothyroidism
– Poor mental development, pot belly, dwarfism
– Prevented by RAPID treatment with T4 at birth
* Maternal iodine deficiency
* Congenital dysfunction in hormone biosynthesis
clinical features / symptoms of hypothyroidism
– Weakness, fatigue
– Cold intolerance
– Weight gain (but may have decreased appetite)
– Constipation
– Dry skin, thickened skin
– Brittle hair, alopecia
– Intellectual deterioration, mental and physical lethargy
– Goitre (TSH⇑)
diagnosis for hypothyroidism
- Physical examination
- Family history
- Blood tests
– Thyroid hormones (T4 ⇓)
– TSH levels (⇑) - Overt hypothyroidism
– TSH > 10mU/L and FT4 below reference range - Consider subclinical hypothyroidism
– TSH is raised but FT4 within reference range - Consider secondary hypothyroidism
– T4 is low without raised TSH and clinical features
Thyroid Replacement Therapy
hypothyroidism
- Thyroxine (T4) used to replace deficiency
- Aim of therapy:
– Replace thyroid hormone function
– ⇒ normal physical & mental development
– Reduce goitre (suppress raised TSH levels) - Optimum dose determined individually
– Single dose, before breakfast
– Important counselling points!
Life-long therapy, monitor effect
Non-compliance leading to increased doses:
Drugs for Thyroid Replacement Therapy
Levothyroxine sodium
– Synthetic T4
– Treatment of choice for
maintenance
– Once daily dose
possible
* Liothyronine sodium
– Similar action but more rapidly
metabolised
– May be used in severe
hypothyroid states
– Used IV as part of supportive
treatment of thyroid coma
Monitor TSH levels when…
– Within 8 weeks of starting levothyroxine
– After a dose change
– Annually once established
Monitoring of Replacement Therapy
what is Cushing’s syndrome
which is a disorder caused by prolonged exposure to high levels of cortisol, a hormone produced by the adrenal glands
-Pituitary adenoma
Secretes excess ACTH
Benign (mainly), women 5:1 men
Ectopic ACTH tumour
– Malignant or benign, men 3:1 women
* Adrenal tumours
– Secrete excess cortisol & other adrenal hormones
– Non-malignant adenomas, onset>40 years, uncommon, rapid onset of symptoms:
women>men
Clinical Features / symptoms of crushings syndrome
Weight gain
– Increase in body fat
– Rounded face, flushed, prominent cheeks
* Easily bruised skin
* Violaceous striae
* Hypertension
* Glucose intolerance
* Depression or psychosis
* Osteoporosis
diagnosis of crushing syndrome
Patient history, physical examination, biochemical tests, scan for tumours
* Saliva cortisol test
* 24 hour free cortisol in the urine
Dexamethasone (steroid) suppression test (DST) – blood
– Low dose – presence of Cushing’s
– High dose - distinguishes between pituitary and ectopic ACTH-secreting
tumours
– Only PITUITARY ACTH suppressed by dexamethasone
with a normal pituitary, normal cortisol levels,
when you introduce dexamethaone what happens to ACTH and Cortisol
both decrease due to negative feedback
in pituitary adenoma
high cortisol and high ACTH
what happens when you introduce dexamethasone
both still decrease
describe the mngement of crushings syndrome
HPA axis is used to having high levels of steroids, you need to ween the patient off this.
normalisation of cortisol levels or actions
tell me about Metyrapone
not commonly comissioned
££££
individual patient request
black triangle drug
Inhibits 11β-hydroxylation in the adrenal cortex
Inhibition of cortisol production
what is Osilodrostat
Licensed for endogenous Cushing’s syndrome
– Steroidogenesis inhibitor that inhibits 11-beta-hydroxylase
– Not routinely commissioned by NHS England
what is addisons disease
Chronic adrenal insufficiency:
effets men and women equally
HYPOcorticolism
– Insidious worsening of symptoms
* Often undiagnosed, sometimes until an ADDISONIAN CRISIS
occurs
primary causes of addisons disease
Destruction of the adrenal cortex
* Cortisol AND aldosterone levels⇓⇓⇓
– Immune mediated, strong link with TB
– Adrenal insufficiency when 90%+ cortex destroyed
– Also associated with fungal infections, metastasis, amyloid and
surgical removal of adrenals
secondary causes of addisons disease
due to lack of ACTH
– Pituitary or hypothalamic in origin
– ACTH stimulation⇓ therefore Cortisol ⇓
Temporary
– Due to sudden stoppage of chronic exogenous glucocorticoid therapy
Permanent
– Surgical removal of ACTH-secreting tumours of pituitary (causing
Cushing’s)
– Piuitary atrophy, or lack of ACTH production (tumours, infections, radiation,
other damage)
aldosterone levels are normal due to asrenal cortex being normal !!!
Temporary Drug Induced Addison’s Disease
HPA takes a long time to reset after prolonged suppression with steroids
* Therefore, when chronic exogenous glucocorticoid therapy is stopped, the body
will no longer have sufficient endogenous cortisol secretion to respond to any
stress
eg COPD patients, have to be weened off steroids
clinical features of addisons disease
Anorexia
* Weight loss
* Weakness and fatigue
* GI disturbances
* Hypotension
* Salt cravings
* Increased thirst
* Postural dizziness
* Muscle or joint pain
* Skin hyperpigmentation
what is Addisonian Crisis, medical emergency
Acute response to stress in a compromised patient
– Sudden penetrating pain in lower back, abdomen or legs
– Severe vomiting, diarrhoea, dehydration
– Blood pressure decreases, loss of consciousness
– FATAL if untreated
Caused by body’s inability to respond to stress because of adrenal insufficiency.
treatment: steroid we can give via IV, emergency, eg hydrocortisone
how to diagnose addisons disease
Morning serum cortisol taken (exclusion test)
Synacthen test (ACTH stimulation test)
– Serum cortisol levels checked before and 30 mins after giving synthetic
analogue of ACTH (tetracosactide)
Does the adrenal gland respond to ACTH?
If the answer is NO: primary insufficiency most likely
Treatment of Addison’s Disease
Replacement of glucocorticoid and mineralocorticoid
* Glucocorticoid
– Usually hydrocortisone
* Mineralocorticoid
– Fludrocortisone
Sick day rules
* Emergency treatment pack
– IM hydrocortisone for self administration
(emergency, vomiting or diahorrea, cannot absorb steroid orally, switch to IV/IM hydrocortisone)
what is hypercorticolism
crushings disease
what is hypocorticolism
addisons disease
what is the adrenal glad composed of
two tissues
both of different origin
what two tissues are the adrenal cortex’ made up of
adrenal cortex
adrenal medulla
what is the adrenal cortex
Surrounds the medulla
Three zones – secreting glucocorticoids and mineralocorticoids and
androgens
what is the adrenal medulla
Chromaffin tissue
Secretes adrenaline and noradrenaline
what are glucocorticoids
Glucocorticoids are a class of steroid hormones produced by the adrenal cortex, specifically by the zona fasciculata. They play a crucial role in regulating various physiological processes in the body, including metabolism, immune response, and stress response. The primary glucocorticoid in humans is cortisol, also known as hydrocortisone.
where are glucocorticoids produced
Produced by cells of zona fasciculata
Controlled by pituitary ACTH
in the adrenal cortex
roles of glucocorticoids
Intermediary metabolism: carbohydrate, lipid and protein
* Anabolic effects on liver, catabolic effects on skeletal muscle and adipose tissue
Permissive actions
* Required for functioning of sympathoadrenal system
* Necessary for catecholamine synthesis and uptake and action
Enable body to respond to stress
