Endocrine - Hyper and Hypo Thyroidism Flashcards
Thyroid Physiology
- embryology of the thyoroid?
Median ENDODERM downgrowth from BASE OF TONGUE and travels caudally with heart.
Thyroid gland duct breaks down by week 5-6
Enlargement from 4th brachial pouch
Colloid present by week 10
Thyroid functional by week 11-12
Thyroid Physiology
- anatomy of the thyroid?
Isthmus is just in front of trachea, just BELOW CRICOID CARTILAGE
Recurrent laryngeal nerve runs BETWEEN trachea and oesophagus
Pyramidal lobe (in 80%) is remnant of thyroglossal duct
Thyroid Physiology
- How does thyroid hormone provide negative feedback?
Thyroid hormone gives negative feedback via Thyroid Hormone Receptor Beta2
–> inhibits TSH and TRH
Thyroid Physiology
- Other than thyroid hormone what other suppressors of TSH?
Dopamine
Glucocorticoids
Somatostatin
Thyroid Physiology
- How is iodide uptaken?
Iodide uptake on basolateral membrane via NIS on follicular cells.
NIS is ALSO on salivary cells, placenta and lactating breasts
–> NIS is STIMULATED by low iodide levels
–> NIS is INHIBITED by high iodide levels (=Wolf-Chykoff Effect)
Thyroid Physiology
- What is NIS?
NIS is the basolateral channel on follicular thyroid cells via which iodide is uptaken.
NIS is ALSO on salivary cells, placenta and lactating breasts
- -> NIS is STIMULATED by low iodide levels
- -> NIS is INHIBITED by high iodide levels (=Wolf-Chykoff Effect)
Thyroid Physiology
- How does the iodide get into the follicular lumen of follicular thyroid cells?
Via PENDRIN transporter on apical membrane
Thyroid Physiology
- What happens to iodide once the iodide is in the follicular lumen?
Iodide is oxidised by TPO and HYDROGEN PEROXIDE
It is the bound to TYROSINE RESIDUES
Thyroid Physiology
- How does T3 and T4 form?
Iodised Tg is taken back into the cell and processed in lysosomes to form T3 and T4
DIT + DIT = T4
DIT + MIT = T3
Uncoupled tyrosine residues are MIT and DIT and these get recycled
Thyroid Physiology
- What combinations for DIT and MIT for thyroid hormones?
DIT + DIT = T4
DIT + MIT = T3
Uncoupled tyrosine residues are MIT and DIT and these get recycled
Thyroid Physiology
- How is thyroid hormone transported in blood?
Thyroid Binding Globulin (TBG) binds most T3/T4 but ONLY THE FREE HORMONE IS ACTIVE
Thyroid Physiology
- What creates high and low levels of TBG?
High TBG: pregnancy and OCP
Low TBG: liver failure and steroids
What is Pendred Syndrome?
Pendred Syndrome = mutation of pendrin gene (the transporter that transports iodide from follicular cells into follicular lumen in the thyroid)
Features:
- goitre
- sensorineural deafness
Which thyroid hormone is more potent?
T3 is more potent than T4
T4 converts itself to T3 via 5-deiodinase
What are the different types of 5-deiodinase and what do they do?
5-deiodinase Type 1 and Type 2 convert T4 to T3
Type 1: in thyroid, liver and kidneys
Type 2: in pituitary, brain, brown fat and thyroid
Type 3 inactivates T4 and T3, and makes reverse T3
What receptors do thyroid hormones act on?
Nuclear thyroid receptors TRalpha and TRbeta
What are the biochemical markers of thyrotoxicosis?
INCREASED:
- osteocalcin
- ALP
- ANP
- SHBG
- Ferritin
- vWF
DECREASED:
- LDL
- Lipoprotein (a)
What are the biochemical markers of hypothyroidism?
INCREASED:
- CK
- LDL
- Prolactin
- Lipoprotein (a)
- Noradrenaline
DECREASED:
- vasopressin
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
Osteocalcin
INCREASED in THYROTOXICOSIS
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
CK
INCREASED in HYPOTHYROIDISM
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
Noradrenaline
INCREASED in HYPOTHYROIDISM
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
Vasopressin
DECREASED in HYPOTHYROIDISM
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
ALP
INCREASED in THYROTOXICOSIS
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
LDL
DECREASED in THYROTOXICOSIS
INCREASED in HYPOTHYROIDISM
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
SHBG
INCREASED in THYROTOXICOSIS
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
vWF
INCREASED in THYROTOXICOSIS
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
Lipoprotein (a)
DECREASED in THYROTOXICOSIS
INCREASED in HYPOTHYROIDISM
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
ANP
INCREASED in THYROTOXICOSIS
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
Prolactin
INCREASED in HYPOTHYROIDISM
Is _____ a biochemical marker of thyrotoxicosis or hypothyroidism?
Ferritin
INCREASED in THYROTOXICOSIS
What are the two types of Primary Autoimmune Hypothyroidism?
Hashimotos
Atrophic Thyroiditis
What risk factors (non-genetic) are associated with Primary Autoimmune Hypothyroidism?
Female
Older age
What conditions are associated with Primary Autoimmune Hypothyroidism (ie Hashimotos or Atrophic Thyroiditis)
- Pernicious anaemia
- Type 1 Diabetes
- Addisons
- Vitiligo
- Myasthenia Gravis
- Pituitary autoimmunity
What genetic associations are with Primary Autoimmune Hypothyroidism?
HLA -DR3, -DR4, -DR5
CTLA-4
What is the pathogenesis of Primary Autoimmune Hypothyroidism?
Lymphocytic infiltration of thyroid with CD4+ and CD8+
- germinal centre formation
- atrophy of follicles
- absence of colloid
- mild-mod fibrosis
What diagnostic tests would you do for Primary Autoimmune Hypothyroidism?
Anti-TPO (90-95% spec and sensitivity)
Anti-TSH receptor antibody (20%)
How do you treat Primary Autoimmune Hypothyroidism?
L thyroxine (aim for TSH ~1) Start low if ischaemic heart disease
T3 not needed
PREGNANCY: increase dose by 50%
What must you be cautious of when treating Primary Autoimmune Hypothyroidism? What can be unmasked?
In pituitary disease you can unmask the HPA axis with hypoadrenalism and diabetes mellitus
What lab markers would you expect for subclinical hypothyroidism?
Raised TSH with NORMAL T4/T3
40% have anti-TPO
What risk factors for subclinical hypothyroidism?
Older patients
Type 1 diabetes
Downs Syndrome
What is the progression to hypothyroidism in subclinical hypothyroidism?
If the TSH >=1 then 100% progression
When do you treat subclinical hypothyroidism?
Treat if symptoms or TSH >=10
If PREGNANCY: treat if TSH >=2.5
Consider if:
- age <65yrs
- heart failure
- dyslipidaemia
- anti-TPO or anti-Tg positive
What are the clinical features of Myxoedema Coma?
- dry coarse skin (yellow from carotene)
- delayed reflexes
- pericardial and pleural effusions
+/- goitre - myopathy and cardiomyopathy
- elevated CK
- central hypothermia / bradycardia
- seizures
What precipitates myxoedema coma?
Trauma or major illness
What lab findings do you expect in myxoedema coma?
TSH VERY high (>50!!!)
Hyponatraemia
Elevated creatinine
Elevated CO2
How do you manage myxoedema coma?
HDU/ICU
Passive rewarming
Fluid resus +/- inotropes
IV hydrocortisone
T4 loading
VTE prophylaxis
REMEMBER reduced renal clearance
What demographics are patients who present with Graves Disease?
Women predominant
Aged 20 - 50 years old
What two organisms have been proposed to contribute to a molecular mimicry as part of pathogenesis of Graves Disease?
- H pylori
- yersinia enterocolitis
What immune modulating therapies have been associated with developing Graves Disease?
- IFNalpha and IFNbeta
- ipilumumab
- HAART therapy
- Alemtuzumab
- lymphocyte depletion treatments
What genetic associations are with Graves Disease?
HLA-DR CTLA-4 CD25 PTPN22 FCRL3 CD226
What are the Graves-Specific features which present in addition to thyrotoxicosis features with Graves Disease?
Goitre Ophthalmopathy Pretibial myxoedema Thyroid acropachy Myopathy Onycholysis Psychosis / aesthenia Osteoporosis AF with HIGH EMBOLISM RISK Heart failure and IHD exacerbation Neutropenia, lymphocytosis and thrombocytopenia
What are the Graves-Specific musculoskeletal features of Graves Disease?
Myopathy
Osteoporosis
What are the Graves-Specific cardiac features of Graves Disease?
AF with HIGH EMBOLISM RISK
Heart failure and IHD exacerbation
What gender distribution is seen in Graves Ophthalmopathy?
Male > Female
What are the eye features of Graves Ophthalmopathy?
Exophthalmos Proptosis and lid lag Periorbital lid swelling and chemosis Diplopia and poor convergence Limited upward gaze Reduced visual acuity
What causes the proptosis and lid lag seen in Graves Opthalmopathy?
What causes the reduced visual acuity seen in Graves Ophthalmopathy?
Proptosis and lid lag is due to overactivity of sympathetic stimulation in levator
Reduced visual acuity is due to retinal and optic nerve oedema
What are the risk factors for progression of Graves Ophthalmopathy?
Smoking (STRONGEST)
Hypothyroidism
Iodine 131
What is Hypokalaemic Periodic Paralysis
Transient hypokalaemia often post carbohydrates and exercise
Seen in Asian males
Acquired forms are seen in hyperthyroidism during THYROTOXIC phases
What is the natural history of Graves Disease?
25% of untreated will spontaneously remit
If conservated treatmetn: 50% will remit
Once remission:
25% recur
25% become hypothyroid
How do you manage the symptoms of Graves Disease?
Beta blockers
How do you treat Graves Disease?
Symptom management with beta blockers
Antithyroid drugs: avoid permanent ablation (propylthiouracil and carbimazole) FAVOURED IF: - age <40yrs with small goitre - during pregnancy - low titre TR-Abs
Mechanism of Propylthiouracil?
Use in pregnancy?
Side effects?
Propylthiouracil (PTU)
- shorter half life than carbimazole
Action:
At Thyroid: inhibits thyroperoxidase to inhibit oxidation of iodide to iodine
At peripheries: inhibits 5-deiodinase to inhibit conversion of T4 to T3
PREGNANCY:
- safer than carbimazole in 1st trimester
- safe in breast milk at doses <300mg/day
S/E:
- (rare) fulminant hepatitis
- ANCA positive vasculitis
Mechanism of Carbimazole?
Use in pregnancy?
Side effects?
Carbimazole (CBZ)
- 1st line in treatment due to risk for hepatitis with PTU
Action:
Carbimazole is a pro drug, later converted to methimazole which inhibits thyroperoxidase to inhibit oxidation of iodide to iodine
PREGNANCY:
- in 1st trimester causes foetal damage
S/E:
- rash
- mild neutropenia
- agranulocytosis (0.4%)
Use of Iodine 131 in treatment of Graves Disease?
Safe but causes hypothyroidism
Can EXACERBATE ophthalmopathy
Use in adults >40yrs who have failed other treatments
Use of surgery in treatment of Graves Disease?
Most RAPIDLY effective
BEST for obstructive goitre
S/E:
- hypothyroidsim
- hypoparathyroidsim
- laryngeal nerve damage
TSHr mutation mediated hyperthyroidism presents similarly to, and is treated similarly as, Graves Disease.
What three risk factors for TSHr mutation mediated hyperthyroidsim?
Older
Women
Iron deficiency
What are the two types of Amiodarone Induced Thyrotoxicosis (AIT) and how do you differentiate them?
AIT Type 1: Increased thyroid hormone due to iodine load
AID Type 2: thyrocyte toxicity
To differentiate:
- Scan uptake is LOW in both
- IL-6 is ELEVATED in Type 2
- Tg is ELEVATED in Type 2
- Vascularity: REDUCED in type 2, INCREASED/NORMAL in type 1
What is, and when do you treat, subclinical hyperthyroidism?
Subclinical hyperthyroidism = subnormal TSH but normal T4 and T3
WHEN TO TREAT?
- TSH <0.1
- Multinodular goitre
- Coexisting AF or osteoporosis
How do you treat subclinical hyperthyroidism?
Thionamides for young patients with subclinical Graves
Radioiodine if older or multinodular goitre
Surgery if LARGE multinodular goitre
What are the features of a thyroid storm?
Fever (usually >40) and diaphoretic Tachycardic and AF CCF and APO Proximal myopathy Dehydration and shock
What are precipitants of a thyroid storm?
Infection/trauma
Radioiodine
Noncompliance
What is the management of thyroid storm?
HDU/ICU
Beta Blocker: IV propranolol to aim for HR 90bpm then oral 40-80mg TDS
PTU preferred to CBZ as it is more rapid
Lugol’s drops (BUT if used >=4 days then will worsen the thyrotoxicosis)
Cholestyramine will increase T4 clearance
Hydrocortisone will block thyroid output and T4–>T3 conversion
Plasmapheresis
What medication must you AVOID in a thyroid storm?
Aspirin
Avoid it to prevent decreased protein binding and subsequent increases in free T3 and T4 levels
What demographic tend to get thyroiditis?
Females
Aged 30 - 50yrs
What is the implied pathogenic trigger for thyroiditis?
Viral infection
What genetic association with thyroiditis?
HLAB35 in 75%
What clinical features for thyroiditis?
PAINFUL goitre
Jaw pain and hoarse voice
Constitutional symptoms and fevers
Symptoms of thyrotoxicosis for 2-6 weeks
What lab findings are expected with thyroiditis?
Elevated ESR and CRP
Elevated T3/T4 with REDUCED TSH
hypothyroid phase happens post thyrotoxic phase
What treatment for thyroiditis?
What complications of thyroiditis?
Aspirin and NSAIDs
Prednisolone
Thyroxine if a prolonged hypothyroid phase
10% get permanent hypothyroidism
What are the clinical features for Lymphocytic and Post Partum Thyroiditis?
PAINLESS goitre
NORMAL ESR
What lab findings are expected for Lymphocytic and Post Partum Thyroiditis? What biopsy findings?
Anti-TPO Ab (ESPECIALLY IF POST PARTUM!)
Low-zero uptake on US
Biopsy: lymphocytic infiltration
What is the clinical course of Lymphocytic and Post Partum Thyroiditis?
Hyperthyroid for 2-4 weeks
Hypothyroid from 4-12 weeks
How do you treat Lymphocytic and Post Partum Thyroiditis?
Symptoms management with beta blocker
Treat with thyroxine if prolonged hypothyroidism
Presentation and treatment of Riedel’s Thyroiditis?
RARE
Occurs in middle aged women
? part of IgG4 Systemic Disease
Usually presents with fixed painless thyroid mass
Treat with surgery, steroids and TAMOXIFEN
What associated features are with Riedel’s Thyroiditis?
Horners
Carotid stenosis
Hypoparathyroidism
THROID & DRUGS:
Lithium?
Lithium can cause both hypothyroidims and thyroiditis
THROID & DRUGS:
Immune checkpoint inhibitor antibodies?
Ipilumumab & Tremilimumab (anti-CTLA4)
- central hypothyroidism (5%)
- thyroiditis (2%)
Nivolumumab & Pembrolizumab (anti-PD1)
- thyroiditis (4%)
- central hypothyroidism (<1%)
THROID & DRUGS:
Alemtuzumab?
Alemtuzumab (anti-CD52)
- Graves (15%)
- Thyroiditis
THROID & DRUGS:
Interferon-Alpha?
Interferon alpha
- anti-TPO and anti-Tg (15%)
- Hypothyroidism (5%)
- Graves
THROID & DRUGS:
Tyrosine kinase inhibitors?
Hypothyroidism (25%)
THROID & DRUGS:
Bexarotene?
Bexarotene (RXR agonist)
- central hypothyroidism (impairs TSH release)
and increases T4 clearance
