Endocrine Flashcards
What is the function of the thyroid gland?
- Thyroid hormones control the metabolic rate of many tissues.
- Thyroid gland secretes T4 predominantly and only a small amount of biologically active T3
- Most circulating T3 is made by conversion of T4 to T3 in periphery
What is unique about the thyroid amongst endocrine glands?
- There is sufficient iodinated thyroglobulin stored within follicles of the thyroid to provide thyroid hormone for several weeks even in the absence of dietary iodine
- Iodine is therefore an essential requirement for thyroid protection.
What are the thyroid hormones?
T4 - Thyroxine
T3 - Triiodothryonine
Tyrosine + 1 Iodine Molecule -= Monoiodothyrosine
- Drugs and illnesses can alter the concentration of binding proteins or the action of binding so levels may not always be concordant
E.g. oestrogen increases level of thyroid binding globulin and hence total T4
How is thyroid function measured?
Thyroid function (for both hyper and hypo) is measured by
- Serum TSH concentration
- Serum free T4 (or T3) concentration
What is Hyperthyroidism? (Thyrotoxicosis)
Overactivity of the thyroid gland –> overproduction of thyroid hormone
What is Hypothyroidism? (myxoedema)
Underactivity of the thyroid gland –> underproduction of thyroid hormone
- May be due to primary (from disease of the thyroid gland) –> reduced T4 and thus T3
or secondary (pituitary/hypothalamic disease) –> reduced TSH from anterior pituitary - HYPOPITUITARISM
Describe the epidemiology of hyperthyroidism?
- Affects females more than males
- Affects 2-5% of all women at some time
- Presentation mainly between 20-40
What are the causes of Hyperthyroidism?
1) Graves’ disease – most common
2) Toxic multinodular goitre –
3) Toxic thyroid adenoma
4) Pituitary adenoma –> causes more TSH to be produced –> more T3/4
5) De Quervain’s thyroiditis
6) Drug induced
How does drug induced hyperthyroidism occur?
AMIODARONE - anti-arrhythmic drug:
- Can cause both hyperthyroidism (due to the high iodine content of amiodarone) and hypothyroidism (since it also inhibits the conversion of T4 to T3)
• Iodine
• Lithium
How does do toxic multinodular goitre cause hyperthyroidism?
- Nodules that secrete thyroid hormones
- Occurs commonly in older women
- Drug therapy rarely successful in inducing a prolonged remission
How does De Quervain’s thyroiditis cause hyperthyroidism?
- Transient hyperthyroidism sometimes from acute inflammation or the thyroid gland – probably viral
- Usually accompanied by fever, malaise and neck pain
- Treat with aspirin and only give prednisolone for severe
What are the risk factors for hyperthyroidism?
- Female
- Family History/Genetic – association with HLA-B8, DR3 and DR4
- Stress
- Smoking
- Amiodarone
- High iodine intake
- Autoimmune disease
- E.coli and other gram-NEGATIVE organisms contain TSH-binding sites so may initiate pathogenesis via ‘molecular mimicry’
Explain the pathophysiology of Graves’ Disease
- Serum IgG antibodies called TSH receptor stimulating antibodies (TRAb) bind to TSH receptors on the thyroid and stimulate T3/4 production
- This results in excess secretion, hyperplasia of the thyroid follicular cells, hyperthyroidism and goitre
What are the Graves’ specific symptoms?
1) Graves Ophthalmology
- Extra-ocular muscle swelling –> protruding eyes (exophthalamos)
- Eye discomfort
- Lacrimation
- Diplopia – double vision
2) Pretibial myxoedema
- Raised purple-red symmetrical skin lesions over anterolateral aspects of the shins
3) Thyroid Acropachy
- Clubbing – swelling of fingers and toes
4) Goitre
- A swelling of the thyroid gland that causes a lump in the front of the neck.
- The lump will move up and down when you swallow.
What are the common symptoms of hyperthyroidism?
• Weight loss
• Irritability
• Heat intolerance
• Insomnia
• Diarrhoea
• Sweats
• Palpitations
• Anxiety
• Menstrual disturbance (oligomenorrhoea and amenorrhoea)
What are the common signs of hyperthyroidism?
• Tachycardia/AF
• Goitre
• Tremor
• Hyperkinesia – increase in muscle activity
• Lid lag
• Lid retraction
• Thin hair and hair loss
• Onycholysis – painless separation of the nail from the nail bed
• Exophthalmos – bulging of the eye out of the orbit
Explain the differential diagnosis of symptoms in patients
1) Elderly:
- Atrial fibrillation
- Other tachycardias and/or heart failure
2) Children:
- Excessive height or excessive growth rate
- Behavioural problems like hyperactivity
- Usually is clinically obvious
Differentiation of mild cases from anxiety can be difficult, look for:
- Eye signs e.g lid lag and stare
- Diffuse goitre
- Proximal myopathy and wasting
What investigations should take place to diagnose hyperthyroidism?
1) Thyroid Function tests
- Primary (negative feedback due to hyperthyroidism) – low TSH, high T3/T4
- Secondary (e.g. pituitary secreting adenoma) – high TSH, high T3/T4
2) Thyroid autoantibodies
- Thyroid peroxidase antibodies – more often seen in hypothyroidism
- Thyroglobulin antibodies
- TSH receptor antibody (TRAb) – Graves only
3) Thyroid ultrasound
- Helps to differentiate Graves’ from toxic adenoma
4) Radioactive iodine isotope uptake scan
– Much greater uptake in Graves’ Disease
Note – if it is drug induced, everything will be normal except for raised thyroid hormones.
What is the treatment for hyperthyroidism?
1) BETA BLOCKERS for rapid system control in attacks
- Decreases CNS activation (HR + BP)
2) CARBIMAZOLE – anti-thyroid drug
- Blocks thyroid hormone synthesis and also has immunosuppressive effects which affects Graves’ disease
Two strategies:
- Titration – oral Carbimazole for 4 weeks then reduce according to TFTs
- Block and replace – oral Carbimazole and thyroxine (less risk of going hypo)
- Aim is to maintain normal free T4 and TSH levels
- Severe side effect is agranulocytosis –> neutropenia
3) RADIOIODINE THERAPY
- Contraindicated in pregnancy and breast feeding
- Iodine taken up and local irradiation and tissue damage causes return to normal function
- Could potentially lead to hypothyroidism
4) THYROIDECTOMY – removal of the thyroid gland leaving a small remnant in order to maintain thyroid function - indicated for those with large goitre, poor response to drugs and have drug side-effects
- Anti-thyroid drugs are stopped 10-14 days prior and replaced with oral potassium iodide
Complications:
- Bleeding
- Post-op infection
- Hypocalcaemia
- Hypothyroidism
- Hypoparathyroidism
- Recurrent laryngeal palsy – due to laceration
- Recurrent hyperthyroidism
What are the complications of hyperthyroidism?
- Congestive HF
- Atrial Fibrillation
- Osteoporosis
- Graves ophthalmopathy complications
- Graves dermopathy - elephantitis
What is a thyroid crisis (storm)?
- Rare life-threatening condition in which there is a rapid deterioration of thyrotoxicosis with
- Hyperpyrexia
- Tachycardia
- Extreme restlessness
- Even delirium, coma and death
What is a thyroid storm usually precipitated by?
- Infection
- Stress
- Surgery
- Radioactive iodine therapy
What is the treatment for a thyroid storm?
- Large doses of Carbimazole
- Propranolol
- Potassium iodide – to acutely block release of thyroid hormone from gland
- Hydrocortisone – to inhibit peripheral conversion of T4 to T3
Describe the pathophysiology of hypothyroidism
Under-activity of the thyroid gland.
May be primary (from disease of the thyroid gland) or less commonly secondary to pituitary or hypothalamic disease (secondary hypothyroidism) resulting in reduced TSH drive.
Describe the epidemiology of hypothyroidism
- Affects females more than males
- Affects 0.1-2% of the population
- Autoimmune hypothyroidism is associated with other autoimmune disease e.g. DMT1, Addisons’, pernicious anaemia
- In general hypothyroidism is associated with Turner’s (only affects females, only have one X chromosome as opposed to the normal XX) & Down’s (trisomy 21) syndrome, cystic fibrosis, primary biliary cirrhosis and ovarian hyper-stimulation
What are the causes of hypothyroidism?
1) Post-partum thyroiditis – following child birth
- Usually transient phenomenon observed following pregnancy
- If conventional antibodies are present, there is a high chance of proceeding to permanent hypothyroidism
2) Autoimmune thyroiditis – may be associated with a goitre (Hashimoto’s thyroiditis or thyroid atrophy)
3) Iodine deficiency – occurs particularly in mountainous areas
4) Drug-induced
o Carbimazole
o Lithium
o Amiodarone
Amiodarone can cause hyperthyroidism due to high iodine content
Can cause hypothyroidism as it inhibits the conversion of T4 to T3
5) Latrogenic – caused by treatment or examination
- Thyroidectomy – for treatment of hyperthyroidism or goitre
- Radioactive iodine treatment or external neck irradiation for head and neck cancer
6) Congenital hypothyroidism:
–> Related to thyroid aplasia or dysplasia or defective synthesis of thyroid hormones
What is autoimmune thyroiditis? (Hashimoto’s thyroiditis)
- Autoimmune thyroiditis may be associated with a goitre (Hashimoto’s thyroiditis or thyroid atrophy)
- Associated with anti-thyroid autoantibodies leading to lymphocytic infiltration of the gland and eventual atrophy and fibrosis of normal follicles
- Thyroid peroxidase is an enzyme essential for the production and
storage of thyroid hormone - Thyroid peroxidase antibodies (TPO-Ab) are present in HIGH TITRES
- Since there is atrophy, there is NO GOITRE
- Almost all patients have serum antibodies to thyroglobulin and thyroid peroxidase (TPO)
- Associated with other autoimmune conditions e.g. pernicious anaemia and Addison’s disease
- CD8 mediated
What are the symptoms of hypothyroidism?
• Hoarse voice
• Goitre
• Weight gain
• Constipation
• Cold intolerance
• Menorrhagia – heavy periods
• Tiredness
• Lethargy
• Poor memory
• Puffy eyes
• Arthralgia/myalgia
What are the signs of hypothyroidism?
BRADYCARDIC
• Bradycardia
• Reflexes relax slowly
• Ataxia
• Dry thin hair/skin
• Yawning
• Cold hands
• Ascites
• Round puffy face
• Defeated demeanour
• Immobile – ileus (temporary arrest of intestinal peristalsis)
• Congestive HF
Note – young women should always have hypothyroidism excluded in any period problems
What investigations should be undertaken to diagnose hypothyroidism?
1) Thyroid function test
- Primary - High TSH, low free T4
- Secondary – inappropriately low TSH, low T3/T4 (since issue is in pituitary)
2) Thyroid antibodies
- Thyroid antibodies (TPO) in Hashimoto’s
3) Other
FBC
- Normocytic and normochromic anaemia
- May be macrocytic in women due to menorrhagia
- May be microcytic due to pernicious anaemia
o Hyperlipidaemia
o Hyponatraemia (due to increased ADH and impaired clearance of free water)
o Increased serum creatine kinase levels with associated myopathy
Describe the management of hypothyroidism
Lifelong oral Levothyroxine (T4)
o Start 25mcg and increase incrementally every 3-6 weeks
o Aim is to get TSH to >0.5
o Primary – titrate dose until TSH normalises
o Secondary – TSH will always be low, T4 monitored
What are the complications of hypothyroidism?
Myxoedema coma:
- Severe hypothyroidism (REDUCED T4) that may rarely present
with confusion and coma - particularly in elderly
- Typical features include hypothermia, cardiac failure,
hypoventilation, hypoglycaemia and hyponatraemia
- MEDICAL EMERGENCY and given IV/ORAL T3 & glucose infusion
as well as gradual rewarming
What are the differential diagnoses in hypothyroidism?
1) Children with hypothyroidism:
• May not show the classic features but often have a slow growth velocity,
poor school performance and sometimes an arrest in puberty
2) Young women with hypothyroidism:
• May not show obvious signs
• Hypothyroidism should be excluded in all people with oligomenorrhea/
amenorrhoea, menorrhagia, infertility or hyperprolactinaemia -
3) Hypothyroidism in the elderly:
• Hard to differentiate clinical features from normal ageing - should exclude hypothyroidism in those with cognitive impairment
Explain the pathpphysiology of thyroid cancer
- Thyroid cancer is uncommon and most present as asymptomatic thyroid nodules.
- Minimally active hormonally
- Over 90% secrete thyroglobulin which can be used as a tumour marker after thyroid ablation
- Carcinomas derived from thyroid epithelium may be:
- Differentiated - papillary or follicular
- Undifferentiated - anaplastic
What are the different types of thyroid carcinoma?
Papillary (70%)
- Young people
- Local
- Good
Follicular (20%)
- Middle age
Lung/bone
Usually good
Medullary cell (5%)
Often familial
Local and metastases
Poor
Lymphoma (2%)
Variable
Usually poor
Anaplastic (<5%)
Aggressive
Local
Very poor
What are the symptoms of thyroid carcinoma?
• Thyroid nodules – increased size, hardness and irregularity
• Dysphagia
• Hoarseness of voice – tumour pressing on recurrent laryngeal nerve
What are the signs of thyroid carcinoma?
• Lymph node metastases
• Lung or bone metastases (rare)
• Thyroid nodule with history of progressive increase in size
• Hard and irregular nodule
• Enlarged lymph nodes
What is the differential diagnosis of thyroid carcinoma?
Goitre
What are the investigations for thyroid carcinoma?
• Fine needle aspiration cytology biopsy best for distinguishing between benign and malignant thyroid nodules
• Thyroid ultrasound
• TFTs – hyper/hypothyroidism needs to be treated before surgery
What is the treatment for thyroid carcinoma?
+ Follicular and papillary cancers
-Total thyroidectomy with neck dissection for local nodal spread
- Ablative radioiodine subsequently given – taken up by remaining thyroid tissue or metastatic lesions
+ Anaplastic and lymphoma
- External radiotherapy may produce brief respite
- Otherwise treatment is largely palliative
What does the adrenal gland consist of?
• Adrenal glands consist of:
Outer cortex – steroids (aldosterone, cortisol and androgens):
1) Zona glomerulosa (G) – Mineralocorticoids e.g. aldosterone
2) Zona fasciculata (F) – Glucocorticoids e.g. cortisol
3) Zona reticularis (R) – Androgens (sex hormones)
- GFR – Makes Good Sex
• Inner medulla:
Catecholamines –> Under sympathetic control and secretes catecholamines e.g. adrenaline and noradrenaline
What is Cushing’s Syndrome?
- Abnormalities resulting from a chronic excess of glucocorticoids (CORTISOL) whatever the cause
- Loss of hypothalamic
pituitary axis feedback - Loss of circadian rhythm
- Most cases result from administration of synthetic steroids or ACTH for medical treatment
Syndrome = Steroid use
What is Cushing’s disease?
Cushing’s disease specifically refers to excess glucocorticoids resulting from inappropriate ACTH secretion from the pituitary - (typically a pituitary adenoma)
Disease = aDenoma
Describe the epidemiology of Cushing’s.
• Most common cause is oral steroids i.e. glucocorticoid therapy
• Spontaneous endogenous causes are rare – of these, 80% are due to raised ACTH (with pituitary adenoma most common cause)
What are the causes of Cushing’s?
ACTH Independent causes
o Oral steroid use (iatrogenic) – most common
o Adrenal adenomas/carcinomas – tumour of adrenal gland that releases cortisol
ACTH dependent causes
o Cushing’s disease
- Bilateral adrenal hyperplasia due to ACTH hypersecretion by pituitary adenoma
o Ectopic Cushing’s Syndrome – coming from elsewhere
- Due to paraneoplastic syndrome e.g. small cell lung cancer producing ACTH
What is the pathology of excess cortisol?
Excess can result from:
1) Excess ACTH which in turn stimulates excess cortisol production
2) Neoplasms in adrenals which stimulate zona reticularis to produce more cortisol
- Ingesting excess glucocorticoids itself e.g. prednisolone
What are the symptoms of Cushing’s?
• CUSHING
o Cataracts
o Ulcers
o Striae – purple strokes on skin
o Hypertension and hyperglycaemia (due to impaired glucose tolerance)
o Increased risk of infection – dampening of inflammatory response
o Necrosis
o Glucosuria
• Amenorrhoea
What are the signs of Cushings?
• Truncal/central obesity
• Moon face
• Buffalo hump – fatty hump on upper back
• Acne
• Hirsutism – unwanted male pattern hair growth in women
• Thin skin/bruising
• Osteoporosis
What is the differential diagnosis for Cushing’s?
• Pseudo-Cushing’s syndrome
o Caused by alcohol excess
o Resolves after 1-3 weeks of alcohol abstinence
What investigations would you do to diagnose Cushings? (1st line)
• Random cortisol – if high then proceed to first line test (may mislead as cortisol varies throughout the day)
• 1st line – overnight dexamethasone suppression test
o Dexamethasone usually suppresses cortisol level
o Failure to suppress over 24-hour period is diagnostic of Cushing’s syndrome
o Low dose dexamethasone
- Most reliable screening tests
- Normal individuals suppress cortisol to <50 nmol 2 hours after last dose of dexamethasone
o High dose dexamethasone
- Most patients with pituitary-dependent Cushing’s disease suppress plasma cortisol by 48 hours
- Failure of suppression suggests an ectopic source of ACTH or an adrenal tumour
• Check 24-hour urinary free cortisol measurement – normal levels mean Cushing’s is unlikely
What investigations would you do to diagnose Cushings? (2nd line)
• 2nd line - If no suppression, then 48hr dexamethasone test
• Plasma ACTH
o Low –> adrenal imaging (CT/MRI to detect adenoma or carcinoma)
o High –> distinguish pituitary and ectopic cause
- Suppression by high dose dexamethasone = pituitary adenoma followed by pituitary MRI to find lesion
- No suppression by high dose = look for ectopic
• IV contract CT chest, abdomen and pelvis
• MRI of neck, thorax and abdomen
• CXR to look at lungs for small cell lung cancer - Or do CRH test
• If cortisol increases = pituitary disease
• If cortisol doesn’t increase = ectopic
• CT or MRI
o To detect adrenal carcinomas and adenomas
o To detect pituitary
Describe the treatment of Cushing’s.
• If iatrogenic – stop steroids
• Cushing’s Disease – transphenoidal removal of pituitary adenoma
• Adrenal adenoma – adrenalectomy*, radiotherapy
o *May cause Nelson’s syndrome
- If you remove the adrenal glands, then no cortisol will be produced in response to ACTH produced by the pituitary gland.
- If no cortisol is produced, then there is no negative feedback on ACTH levels which can cause ACTH to build up in the body tissues.
- This can cause a bronze pigmentation of the skin, visual disturbances and headache
- Adrenal carcinoma – adrenalectomy + RT and adrenolytic drugs e.g. mitotane
- Ectopic ACTH – surgery to remove tumour if location known and it hasn’t spread
What is Acromegaly?
• Acromegaly = excessive production of growth hormone occurring in adults after fusion of the epiphyseal plates
• Gigantism = excessive production of growth hormone occurring in children before fusion of the epiphyses of long bones
How is GH secreted?
Pituitary GH is secreted in a pulsatile fashion under the control of GHRH (stimulates GH production) and somatostatin (inhibits GH production).
Hypothalamus –> GHRH –> Anterior Pituitary –> GH –> Liver –> IGF-1 –> Protein synthesis + cell division
GH is Inhibited by somatostatin and high glucose.
Ghrelin, which is synthesised in the stomach, also increases GH secretion.
What is the function of GH?
Function of GH:
• Direct – acts on tissues such as liver, muscles, bones and fat to induce metabolic changes
• Indirect – IFG-1
o Stimulate growth by protein synthesis and cell division
o Increases lipolysis and calcium retention
o Decrease blood glucose
o Stimulate hypertrophy and hyperplasia of bone, skeletal muscle etc.
Describe the epidemiology of Acromegaly.
• Rare – 3 per million/year
• Incidence – mean age of diagnosis is 40 years old
• Males and females affected equally
• Associated with multiple endocrine neoplasia-1 (MEN-1)
What are the causes of acromegaly?
•Benign GH-producing pituitary adenoma – very slow insidious onset over many years
•Ectopic GH-releasing hormone from a carcinoid tumour (rare)
Describe the pathology of Acromegaly.
• Increased GH usually due to a pituitary adenoma travels to tissues such as liver where it binds to receptors resulting in an increase in IGF-1
• Stimulates skeletal and soft tissue growth giving rise to “giant-like” appearance and symptoms
• Local tumour expansion in pituitary causes compression of surrounding structures resulting in headaches and visual field loss
Describe the symptoms of Acromegaly.
• Result of local tumour expansion
o Headaches
o Bitemporal hemianopia – visual field loss
o Hypopituitarism
• Metabolic effects of excess GH
o Acroparaesthesia
o Sweating
o Arthralgia
o Decreased libido or impotence
o Amenorrhoea or oligomenorrhea in women
o Galactorrhoea
Describe the symptoms of Acromegaly
• Acral enlargement (massive growth of hands, feet and jaw) – often say they can’t wear their wedding ring, hats, gloves etc. anymore
• Big tongue with widely spaced teeth
• Prominent supraorbital ridge
• Puffy lips, eyelids and skin
• Darkening skin
• Thick skin
• Obstructive sleep apnoea
• Deep voice
• Hypertension
• HF
What investigations would you do to diagnose Acromegaly?
• Oral glucose tolerance test
o Normally a rise in blood glucose will suppress GH levels
o Give glucose and then test GH levels – if they remain high this is diagnostic for acromegaly
• Serum IGF-1 levels – almost always raised in acromegaly and fluctuate less than those of GH
o Normal IGF-1 levels are a strong indicator that the patient does not have acromegaly
• MRI of pituitary fossa – evidence of pituitary adenoma
• Visual field tests for defects – bitemporal hemianopia
• ECG and Echocardiogram
• Serum prolactin – can be raised as a result of the adenoma
- Not a random GH test as GH is a pulsatile protein and levels vary throughout the day
What is the management of Acromegaly?
• 1st line
Transphenoidal surgical resection to remove the adenoma and correct compression of surrounding structures e.g. optic chiasm
o Complications
- Hypopituitary
- Infection
- Diabetes Insipidus
• 2nd line medical therapy
o Somatostatin analogues e.g. IM octreotide/lanreotide – inhibit GH secretion
- Given by s/c or IM injection
o Dopamine agonists e.g. ORAL bromocriptine or ORAL cabergoline – inhibit GH secretion
- Don’t work as well but can be given orally instead of s/c or IM injection
- GH antagonist e.g. pegvisomant – reserved for treatment of patients whose IGF-1 levels cannot be reduced to safe levels with somatostatin analogues alone
- External radiotherapy
What is Conn’s Syndrome?
- Conn’s syndrome refers ONLY to PRIMARY Aldosterone producing adenoma
- 2/3 cases – Conn’s Syndrome: A solitary aldosterone producing adrenal adenoma
- 1/3 cases – Bilateral Adrenocortical hyperplasia (technically NOT Conn’s)
What are the risk factors for Conn’s syndrome?
Hypertension
What is the pathology of Conn’s syndrome?
- Excess production of aldosterone, independent of RAAS causes
- Increased K+ loss, Na+ and water retention + raised BP
- Decreased renin release
- Hypokalaemia
