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Year 2 Medicine > Endocrine > Flashcards

Endocrine Flashcards

1
Q

Describe the arterial blood supply of the adrenal glands

A
  • Superior suprarenal artery (branch of inferior phrenic artery)
  • Middle suprarenal artery (branch of abdominal aorta)
  • Inferior suprarenal artery (branch of renal artery)
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2
Q

What is the first step in the steroidogenic pathway?

A
  • Conversion of cholesterol to pregnenolone
  • This is catalysed by cholesterol side-chain cleavage enzyme (cytochrome P450 enzyme) in the inner mitochondrial membrane
  • Rate-limiting step is the transport of free cholesterol from the cytoplasm to the mitochondria (carried out by steroidogenic acute regulatory protein or StAR)
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3
Q

Describe the anatomical position of the pituitary gland (include boundaries)

A
  • Anterior: tuberculum sellae
  • Bed: sella turcica (hypophyseal fossa)
  • Inferior: dorsum sellae
  • Superior: diaphragm sella (reflection of dura)
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4
Q

Describe the function of the posterior pituitary gland

A

aka neurohypophysis, direct extension of neurons from hypothalamus

Consists of neurosecretory cells containing non-myelinated axons

Produces 2 hormones

  • ADH (antidiuretic hormone aka arginine vasopressin, AVP)
  • Oxytocin
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5
Q

Explain the actions of the hormones produced by the posterior pituitary gland

A
  • ADH
    Released in response to low plasma volume/high serum osmolality
    Acts on:
    V1 receptors to cause vascular smooth muscle vasoconstriction
    V2 receptors in the kidney to increase water reabsorption via aquaporin insertion
  • Oxytocin
    Promotes uterine contractions & cervical dilatation during labour
    Milk ejection during lactation
    Involved in sexual arousal and romantic relationships
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6
Q

Describe the function of the anterior pituitary gland

A

aka adenohypophysis, glandular tissue

Produces hormones

  • Follicle-stimulating hormone (FSH)
  • Luteinising hormone (LH)
  • Prolactin
  • Growth hormone (GH)
  • Adrenocorticotrophic hormone (ACTH)
  • Melanocyte-stimulating hormone (MSH)
  • Thyroid-stimulating hormone (TSH)
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7
Q

Describe the growth hormone (somatotroph) axis

A

Growth hormone is produced by somatotrophs in the anterior pituitary

The hypothalamus produces:

  • Growth hormone-releasing hormone (GHRH) which stimulates GH
  • Somatostatin which inhibits GH

GH effects are either direct or mediated by IGF-1 (insulin-like growth factor 1) produced by the liver

Increases metabolic growth, protein synthesis, cartilage growth, fatty acid production & insulin resistance

Secretion is pulsatile, mainly overnight - regulated by a negative feedback loop

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8
Q

Describe the hypothalamic-pituitary-adrenal (HPA) axis

A

Hypothalamus produces corticotrophin-releasing hormone (CRH)

Stimulates production of ACTH and MSH in anterior pituitary

Acts on adrenal cortex to increase the production of cortisol and androgens

Regulated by a negative feedback loop

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9
Q

Describe the mechanism of action of ACTH

A
  • Binds to a 7-transmembrane domain (7TMD) G-protein receptor
  • Conformational changes in receptor stimulate adenylyl cyclase > increase in cAMP > activation of PKA and calcium influx
  • Stimulates cholesterol delivery to the mitochondria
  • Increased transcription of genes including steroidogenic enzymes
  • Increased cortisol (androgen) production
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10
Q

Describe the location and function of the hypothalamus

A

Located in the diencephalon, anterior and inferior to thalamus; part of limbic system

Links nervous system to endocrine system - the hypothalamic-pituitary axis is the command centre of the endocrine system

Controls homeostasis (hunger, thirst, sleep, body temperature…)

Connected to the pituitary via the infundibulum (pituitary stalk)

The hypothalamo-hypophyseal portal system allows a connection between the 2 systems

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11
Q

Describe the actions of glucocorticoids

A
  • Anti-inflammatory: inhibit transcription of genes of pro-inflammatory cytokines
  • Reduced T lymphocytes
  • Counter-regulatory metabolic effects: gluconeogenesis, increased adiposity
  • Regulate circadian rhythm
  • Mineralocorticoid effect
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12
Q

Describe the hypothalamic-pituitary-thyroid (HPT) axis

A

Hypothalamus produces thyroid releasing hormone (TRH)

Anterior pituitary produces TSH

Thyroid produces T3 & T4 (regulate metabolism, growth & development)

Once levels are sufficient, negative feedback loop is initiated

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13
Q

Describe the lactotroph axis

A

Anterior pituitary gland produces prolactin

Required for mammary gland development and milk production

Also has roles in steroidogenesis and renal sodium & water reabsorption

Oestrogen stimulates prolactin production

Dopamine from the hypothalamus inhibits prolactin production

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14
Q

Describe the clinical features and causes of diabetes insipidus

A

Clinical features (due to a lack of ADH):

  • Passage of large volumes of dilute urine (>3L/day)
  • Polyuria, polydipsia, nocturia
  • Must exclude hyperglycaemia and hypercalcaemia
Causes
- Cranial: ADH deficiency
Idiopathic
Genetic (mutation in ADH gene)
Trauma, tumours, infection, inflammation
- Nephrogenic: ADH resistance
Genetic (AVPR2 mutation)
Secondary to
- Drugs (e.g. lithium)
- Metabolic upset (hypercalcaemia or hypokalaemia)
- Renal disease
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15
Q

Discuss the diagnosis of diabetes insipidus

A

Water deprivation test

Deprive patient of water for 8h
Measure plasma and urea every 2-4h

In diabetes insipidus, starting plasma osmolality is high, final urine osmolality is low

Then give synthetic ADH (desmopressin, aka ddAVP) and reassess urine osmolality

Cranial diabetes insipidus will respond to ddAVP (increased urine osmolality)
Nephrogenic diabetes insipidus will not respond to ddAVP

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16
Q

Discuss treatments for diabetes insipidus

A
  • Cranial
    Give desmopressin
  • Nephrogenic
    Treat underlying cause
    High dose desmopressin
    Thiazide diuretics
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17
Q

Discuss the clinical features and causes of hyperprolactinaemia

A

Clinical features

  • Galactorrhoea
  • Hypogonadotrophic hypogonadism
  • Menstrual disturbance and subfertility in women
  • Decreased libido and erectile dysfunction in men
Causes
- Secretory pituitary adenoma (prolactinoma)
- Drugs
Antiemetics - metoclopramide, domperidone
Antipsychotics
Antidepressants
Opiates
H2 receptor antagonists
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18
Q

Discuss the management of hyperprolactinaemia

A

Dopamine (D2) agonists

  • Cabergoline
  • Quinagolide
  • Bromocriptine

Surgery if large tumour with visual field effects

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19
Q

Discuss the clinical features and complications of acromegaly

A

Acromegaly is usually caused by secretory pituitary adenomas

Characterised by an excess of growth hormone and IGF-1
In children, can lead to gigantism

Clinical features:

  • Sweats, headaches, tiredness
  • Increase in ring/shoe size
  • Joint pains
  • Coarse facial appearance
  • Enlarged tongue, hands/feet
  • Visual field loss

Complications

  • Hypertension, heart failure
  • Diabetes/impaired glucose tolerance
  • Increased risk of bowel cancer
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20
Q

Discuss the diagnosis of acromegaly

A
  • Glucose tolerance test
    Glucose load fails to suppress GH
  • IGF-1 levels
  • Pituitary adenoma
    Tumour usually large (macroadenoma) & extends into surrounding structures
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21
Q

Discuss the management of acromegaly

A

Surgery (transsphenoidal route)

Medical therapies: aim to normalise IGF-1

  • Somatostatin analogues e.g. ocreotide, lanreotide
  • Growth hormone receptor antagonists e.g. pegvisomant
  • Dopamine agonists

Pituitary radiotherapy

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22
Q

Discuss the causes and management of hypopituitarism

A

Failure of anterior pituitary function

Can affect a single hormonal axis (usually FSH/LH) or all hormones (panhypopituitarism)

Leads to secondary adrenal, gonadal and thyroid failure

Management consists of multiple hormone replacement, most importantly cortisol (hydrocortisone)

Causes

  • Radiotherapy
  • Infarction (if post-partum, Sheehan’s syndrome)
  • Infiltrations (sarcoid)
  • Trauma
  • Congenital
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23
Q

Describe the embryological development of the pituitary gland

A
  • Rathke’s pouch + floor of diencephalon
  • Derived from ectoderm (developing oral cavity)
  • Rathke’s pouch forms part of the hard palate
  • Infundibulum develops in the floor of the 3rd ventricle and grows down towards future mouth
  • Thickening of future mouth space (Rathke’s space) invaginates and grows towards infundibulum
  • Forms a discrete sac which differentiates into anterior pituitary while infundibulum differentiates into posterior pituitary
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24
Q

Anterior pituitary gland histology - name the different cell types

A
  • Chromophils
  • Acidophils:
    Stain red
    Lactotrophs, somatotrophs
  • Basophils
    Stain purple
    Gonadotrophs, thyrotrophs, corticotrophs
  • Chromophobes: exhausted secretory cells
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25
Q

Describe the causes of hypocalcaemia

A
  • PTH deficiency
    Hypoparathyroidism: surgery, autoimmune, Mg deficiency
  • PTH excess
    Vitamin D deficiency: malabsorption, lack of sunlight, genetic syndromes, cirrhosis (defective 25-hydroxylation)
    Chronic renal failure: defective 1-alpha-hydroxylation
    Loss of calcium
  • Drugs: PPIs
  • Hypomagnesaemia (PTH resistance)
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26
Q

Describe the symptoms of hypocalcaemia

A 
- Tetany
Increased neuromuscular excitability
Peri-oral numbness
Muscle cramps, tingling of hands & feet
Severe: carpopedal spasm, laryngospasm, seizures
  • Cardiac complications
    Dysrhythmia
    Hypotension
    ECG changes: prolonged QTc interval
- Chronic features
Basal ganglia calcification
Cataracts
Poor dentition
Parkinsonism and dementia
Skin changes
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27
Q

Discuss the management of hypocalcaemia

A
  • IV calcium replacement if tetany/cardiac manifestations
  • May need magnesium infusion
  • Chronic management: vitamin D + oral calcium salts
  • Treat underlying cause
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28
Q

Discuss the differential diagnosis of hypercalcaemia

A
  • PTH high
    Primary hyperparathyroidism:
    Adenoma of parathyroid gland
    Increased bone resorption and GI absorption

Familial hypocalciuric hypercalcaemia (FHH)

Tertiary hyperparathyroidism (renal failure)

  • PTH normal/low
    PTHrP: malignancy
    Vitamin D excess: overuse of supplements, sarcoidosis, lymphoma, TB
    Thiazide diuretics
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29
Q

Describe the symptoms of hypercalcaemia

A

Moans (neurological)

  • Depression, lethargy, fatigue, psychosis
  • Memory loss

Bones (musculoskeletal)

  • Bone pain
  • Osteoporosis
  • Muscle weakness

Stones (kidneys)

  • Polyuria, polydipsia
  • Nephrocalcinosis
  • Nephrogenic diabetes insipidus
  • Nephrolithiasis
  • Distal renal tubular acidosis
  • Chronic and acute renal insufficiency

Groans (GI)

  • Nausea, vomiting, anorexia
  • Bowel hypomotility and constipation
  • Peptic ulcer disease, pancreatitis
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30
Q

Discuss the management of hypercalcaemia

A

Depends on severity; address underlying cause

  • Rehydration - isotonic 0.9% NaCl, patients often hypovolaemic
  • Bisphosphonates - zolendronic acid; inhibits osteoclasts & bone resorption
  • Calcimimetics - cinacalcet; activate parathyroid calcium receptor to produce less PTH
  • Calcitonin: increases renal calcium excretion & reduces bone resorption
  • Glucocorticoids: inhibit vitamin D production
  • Parathyroidectomy: if resistant to treatment
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31
Q

Explain the regulation of calcium homeostasis

A
  • PTH
    Released by chief cells in response to low ionised calcium levels
    Activates vitamin D in the kidney
    Increases bone resorption to release calcium into the bloodstream
    Increases renal reabsorption of calcium
    Controlled by a negative feedback loop (PTH suppressed when ionised calcium levels rise)
  • Active vitamin D (1,25-dihydroxycholecalciferol)
    Increases GI absorption of calcium
    Increases bone resorption
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32
Q

Explain how sodium is regulated and the roles of angiotensin II, aldosterone and ADH in this process

A

Osmoreceptors in macula densa detect low sodium levels > PGE2 > juxtaglomerular cells produce renin which converts angiotensinogen to angiotensin I, the converted to angiotensin II via ACE

Stimulates synthesis and secretion of aldosterone in glomerulosa cells of adrenal cortex

Angiotensin II - stimulates Na+/H+ exchange, increasing Na reabsorption

Aldosterone - Na reabsorption in principal cells of distal tubule, collecting duct

ADH - stimulated by low blood volume, increased serum osmolality and angiotensin II

ADH increases water reabsorption by insertion of aquaporins into cortical collecting duct, decreases serum osmolality

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33
Q

Discuss the causes of hyponatraemia by ECF volume status

A
  • Hypovolaemia (Na and water deficit)
    Renal losses: diuretic excess, mineralocorticoid deficiency, salt-losing nephritis
    Extrarenal losses: burns, vomiting, diarrhoea
  • Euvolaemia (Na normal and excess water)
    SIADH, drugs, pain, psychiatric disorders, hypothyroidism, glucocorticoid deficiency
  • Hypervolaemia (Na and water excess)
    Nephrotic syndrome, cardiac failure, cirrhosis, acute & chronic renal failure
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34
Q

Discuss the clinical features and causes of SIADH (syndrome of inappropriate anti-diuretic hormone)

A

Excessive ADH secretion
Low plasma osmolality, normal total body sodium, excess water
Kidney inappropriately retains water so urine osmolality is high

Clinical features (mild to severe)

  • often asymptomatic
  • mild confusion
  • gait instability
  • marked confusion, drowsiness
  • seizures

Causes
- Infective: esp respiratory tract infection, pneumonia

  • Primary brain injury: meningitis, brain surgery
  • Drugs: amitriptyline, SSRIs, carbamazepine, morphine, PPIs
  • Malignancy: small cell lung cancer
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35
Q

Discuss the diagnosis and management of SIADH

A

Diagnosis

  • Hyponatraemia with inappropriately low plasma osmolality
  • Urine osmolality > plasma osmolality
  • Absence of adrenal, thyroid, pituitary or renal insufficiency
  • No recent diuretic use

Management
- Severe and acute (unconscious or seizures)
Infusion of hypertonic 3% saline: can increase serum sodium quickly

  • Less severe or chronic
    Treat underlying cause
    Fluid restriction, increase slowly
    Consider AVPR2 antagonists (controversial)
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36
Q

Describe how the brain adapts to hyponatraemia

A
  • Acute (sudden drop)
    Cerebral oedema
    Increased intracranial pressure
    Interstitial sodium and water forced out into CSF
  • Chronic (48h)
    Astrocytes lose intracellular solutes e.g. protein, phosphates
    Achieve same osmolality as plasma and decrease brain swelling

Readaption during treatment: sudden rise in Na can cause osmotic demyelination syndrome

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37
Q

Discuss the causes and management of hypernatraemia

A 
Causes:
Unreplaced water loss:
Diabetes insipidus
Very high blood glucose (HHS - osmotic diuresis)
GI and insensible losses

Other: seizures/exercise, excess sodium ingestion (rare, usually in hospitals due to aggressive fluid resuscitation)

Management:

  • Treat underlying cause & estimate total body water deficit
  • Avoid overly rapid correction (concern of cerebral oedema)
  • Use combination of saline and 5% dextrose
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38
Q

Name the symptoms of hypernatraemia

A

Mnemonic: FRIED SALT

Fever (low)
Restless (irritable)
Increased fluid retention, increased blood pressure
Edema
Decreased urinary output, dry mouth

Skin flushed
Agitated
Lethargy
Thirst

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39
Q

Describe the anatomical and functional zonation of the adrenal cortex

A

Outer to inner
- Zona glomerulosa: small cells in rounded clusters
Production of mineralocorticoids: aldosterone, deoxycorticosterone

  • Zona fasciculata: large cells in parallel cords
    Production of glucocorticoids e.g. cortisol, corticosterone
  • Zona reticulata: closely packed cells in haphazard arrangement
    Production of androgenic steroids e.g. DHEA, DHEA sulphate, androstenedione
    Produce a small amount of glucocorticoids
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40
Q

List the physiological effects of cortisol and name the enzyme which catalyses the terminal stage in its production

A

Terminal stages are catalysed by 11-beta hydroxylase

Effects:

  • Stimulates gluconeogenesis in the liver
  • Stimulates lipolysis in adipose tissue
  • Insulin antagonist
  • Increases breakdown of skeletal muscle protein
  • Memory, learning, mood
  • Immune suppression
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41
Q

Describe the physiological effects of aldosterone and name the enzyme which catalyses the terminal stages in its production

A
  • Catalysed by aldosterone synthase
  • Effects:
    Acts on principal cells in distal tubule and collecting duct
    Upregulates ENaC increasing apical membrane permeability for Na
    Stimulates K secretion into lumen
    Stimulates H+ secretion via H+ ATPase in intercalated cells in collecting duct
    Stimulates water and sodium reabsorption from gut, sweat, saliva in exchange for potassium
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42
Q

List causes of primary adrenal insufficiency

A
  • Addison’s disease
  • Congenital adrenal hyperplasia
  • Adrenal TB
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43
Q

Outline the pathophysiology and clinical features of Addison’s disease as well as “Addisonian crisis”

A

Autoimmune destruction of the adrenal cortex
Associated with other autoimmune diseases like type I diabetes

Clinical features:
Anorexia, weight loss
Hypotension, dizziness
Abdominal pain, vomiting, diarrhoea
Skin pigmentation
Addisonian crisis - acute adrenal insufficiency
Fatigue, weakness
Abdominal pain, nausea, vomiting
Hypotension, syncope
Metabolic encephalopathy, shock
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44
Q

Briefly describe the pathophysiology of congenital adrenal hyperplasia (CAH)

A
  • 21-hydroxylase deficiency
  • Autosomal recessive
  • Lacking enzyme for steroid hormone synthesis
  • Accumulation of androgens but lack of cortisol & aldosterone
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45
Q

Discuss the diagnosis of Addison’s disease

A
  • Short synacthen test: measure plasma cortisol before & 30 mins after ACTH injection
  • Low sodium, increased potassium with increased renin
  • Adrenal autoantibodies
  • Hypoglycaemia
  • ACTH levels
    Should be increased
    Causes skin pigmentation as it is derived from pro-opiomelanocortin (POMC), which also produces melanocyte-stimulating hormone
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46
Q

Discuss the management of Addison’s disease

A
  • Do not delay treatment to confirm the diagnosis
  • Replace cortisol with hydrocortisone
    15-30mg tablets daily
    Try to mimic circadian rhythm (higher dose in the morning)
  • Replace aldosterone with fludrocortisone
  • Patient education
    Sick day rules (double dose)
    Steroid warning card
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47
Q

Describe causes of secondary adrenal insufficiency

A

Hypothalamic/pituitary problem: lack of CRH/ACTH

  • Iatrogenic
    Exogenous steroid use e.g. high dose prednisolone, dexamethasone, inhaled corticosteroid

Anterior pituitary switches off ACTH production & cortisol is not produced

Clinical features: same as primary adrenal insufficiency but no skin pigmentation (no increase in ACTH) and aldosterone production is intact (regulated by RAAS)

Manage with hydrocortisone replacement

  • Tumours
  • Surgery/radiotherapy
  • Abscess
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48
Q

Discuss the clinical features of Cushing’s syndrome

A
  • Excess cortisol secretion

Characterised by

  • Central obesity with proximal myopathy
  • Hypertension
  • Hyperglycaemia/diabetes
  • Depression/euphoria
  • Deep red striae
  • Buffalo hump
  • Easy bruising
  • Facial plethora
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49
Q

Discuss the causes of Cushing’s syndrome

A

ACTH-dependent

  • Pituitary adenoma (Cushing’s disease)
  • Ectopic ACTH (carcinoid, carcinoma)
  • Ectopic CRH

ACTH-independent

  • Adrenal carcinoma/adenoma
  • Nodular hyperplasia

Iatrogenic

  • Due to prolonged high dose steroid therapy
  • Chronic suppression of ACTH and adrenal atrophy, low plasma cortisol level
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50
Q

Discuss the diagnosis of Cushing’s syndrome

A
  • Establish cortisol excess: dexamethasone suppression testing, failure to suppress cortisol
    also 24h urinary free cortisol, late night salivary cortisol - both elevated
  • Establish source of cortisol excess

Measure ACTH
- Normal/high ACTH

CRH stimulation test

  • No increase in ACTH: ectopic source of ACTH
  • Exaggerated increase in ACTH: pituitary adenoma (Cushing’s disease)
  • Undetectable ACTH: adrenal tumour
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51
Q

Discuss the management of Cushing’s syndrome

A
  • Surgical
    Transsphenoidal pituitary surgery
    Laparoscopic adrenalectomy
    Removal of ACTH source
  • Medical
    Metyrapone/ketoconazole: inhibit cortisol production in the short-term
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52
Q

Discuss the pathophysiology and clinical features of primary hyperaldosteronism (Conn’s syndrome)

A

Autonomous production of aldosterone independent of its regulators (angiotensin II/potassium)

Due to either single adrenal adenoma or bilateral adrenal nodules

Commonest cause of secondary hypertension

Clinical features

  • Significant hypertension
  • Alkalosis
  • Hypokalaemia
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53
Q

Discuss the diagnosis and management of Conn’s syndrome

A

Diagnosis:

  • Biochemistry: raised sodium, low potassium, low renin
  • Suppression testing with IV saline load (fails to suppress aldosterone)
  • Adrenal CT scan

Management:
Surgical - if adenoma
Unilateral laparoscopic adrenalectomy

Medical
MR antagonists: spironolactone or eplerenone
Amiloride: blocks Na reabsorption by blocking ENaC in kidney

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54
Q

Discuss the clinical features, diagnosis and management of a phaeochromocytoma

A

Catecholamine-secreting tumour of the adrenal medulla
Hypertension and episodes of headaches, pallor, sweating and palpitations

Diagnosis

  • Adrenal CT
  • Measure urinary catecholamines and metabolites

Management
- Adrenalectomy (pre-op prep with alpha 1 and beta 1 antagonists to block effects of catecholamine surge)

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55
Q

Describe the histological features and functions of the adrenal medulla

A

Made up of chromaffin cells

  • Pale stain, granular cytoplasm (secretory vesicles)
  • Cells are polyhedral and arranged in clumps, surrounded by rich vasculature
  • Secrete catecholamine hormones: adrenaline and noradrenaline

Central adrenomedullary vein found here

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56
Q

Outline the pathophysiology of type I diabetes

A
  • Autoimmune destruction of beta cells of the pancreas; insulin deficient
  • Usually early onset w/ severe presentation
- Autoantibodies include
IA2: insulinoma-associated antigen-2
GAD65: glutamic acid decarboxylase 65
ZnT8: zinc transporter
IAA: insulin auto-antibody
ICA: islet cell antibody
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57
Q

Outline the pathophysiology of type II diabetes

A
  • Later onset, characterised by insulin resistance, associated with obesity and adipokines
  • Genetic predisposition combined with weight gain predisposes to dyslipidaemia
  • Insulin resistance causes beta cells to increase production of insulin > hyperinsulinemia (pre-diabetes & early diabetes)
  • This can result in hypertension, impaired glucose tolerance & fasting glucose
  • Eventually hyperglycaemia arises due to beta cell exhaustion and decreased insulin production (early and then late diabetes)
    Associated with advanced age & microvascular complications
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58
Q

Briefly describe the functions of adipokines

A

Adiponectin: protective, reduces levels of free fatty acids

Leptin: informs hypothalamus about amount of fat

TNF-alpha: insulin receptor signalling interference

IL-6: insulin receptor signalling interference

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59
Q

Which mutations are associated with monogenic diabetes (MODY)?

A
  • Autosomal dominant
  • HNF-1-alpha: reduction in insulin production
  • Glucokinase: higher levels of glucose
  • HNF-4-alpha: reduction in insulin production
  • HNF-1-beta: reduction in insulin production
  • Neonatal: mutation affecting potassium channel
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60
Q

Name conditions which can lead to the development of secondary diabetes

A
  • Pancreatitis
  • Haemochromatosis
  • Cystic fibrosis
  • Steroid-induced
  • Acromegaly
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61
Q

Name the clinical features of diabetes mellitus which could be identified in a medical history

A

Symptoms

  • Polydipsia, polyuria, nocturia
  • Weight loss
  • Fatigue
  • Loss of muscle bulk

Family history
- Suscepibility genes e.g. HLA DR3/4-DR2/8

Precipitating events
- Bacteria, viruses (esp Coxsackie), cow’s milk, wheat proteins, vitamin D deficiency…

Associated with other autoimmune conditions e.g. thyroid, coeliac

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62
Q

Describe diagnostic tests for diabetes mellitus

A
  • Fasting blood glucose
    Normal: <=6mmol/L
    Impaired: 6.1-6.9mmol/L
    Diabetes: >=7mmol/L
  • Oral glucose tolerance test
    Normal:<=7.7mmol/L
    Impaired:7.8-11mmol/L
    Diabetes:>=11.1mmol/L
  • Glycosylated haemoglobin (HbA1c): average blood glucose over previous 2-3 months
    Pre-diabetes: 42-47mmol/mol
    Diabetes:>=48mmol/mol
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63
Q

Outline the mechanism of action and side-effects of metformin

A
  • Inhibition of hepatic gluconeogenesis via inhibition of hepatic mitochondrial function
  • Side-effects
    Anorexia, nausea
    Diarrhoea
    Lactic acidosis
64
Q

Outline the mechanism of action and side-effects of sulphonylureas (give examples)

A

E.g. glibenclamide, gliclazide, glimepiride…

Inhibit the ATP-sensitive potassium channel to increase insulin secretion

Side-effects
Weight gain
Hypoglycaemia

65
Q

Outline the mechanism of action of thiazolidinediones & side effects (give examples)

A

E.g. pioglitazone

Ligand for PPAR-gamma (peroxisome proliferator activated receptor gamma)

PPAR-gamma is a transcription factor for triglyceride storage

Thiazolidinediones stop inappropriate deposition of lipids in non-adipose tissues (which leads to insulin resistance)

Side-effects
Weight gain
Anaemia
Osteoporosis

66
Q

Outline the mechanism of action and side-effects of alpha-glucosidase inhibitors

A

E.g. acarbose

Prevents hyperglycaemic peaks following a meal
Prevents the cleavage of alpha glycosidic bonds in starch, slowing digestion

Side-effects
Flatulence
Abdominal distension
Diarrhoea

67
Q

What are the actions of incretins and where are they found?

A

Incretins are gastrointestinal hormones that potentiate insulin secretion

  • Glucagon-like peptide 1 (GLP-1)
    Brain - promote satiety and reduces appetite
    Beta cells - enhances glucose-dependent insulin secretion in the pancreas
    Alpha cells - suppresses post-prandial glucagon secretion
    Liver - reduces hepatic glucose output
    Stomach - slows rate of gastric emptying
  • Gastric inhibitory peptide

Rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4)

68
Q

Explain the mechanism of action of GLP-1 receptor agonists and give examples

A

E.g. exenatide, liraglutide

Mimic incretins but are not cleaved by DPP-4
Improve insulin secretion

69
Q

Explain the mechanism of action and side-effects of DPP-4 inhibitors and give examples

A

E.g. sidagliptin, vildagliptin

Inhibit DPP-endogenous incretin-mediated increase in insulin

Side-effects: nausea and increased risk of heart failure

70
Q

Explain the mechanism of action and side-effects of SGLT2 inhibitors, giving examples

A

E.g. canagliflozin, empagliflozin, dapagliflozin

Inhibit SGLT2 in PCT, increasing excretion of glucose in the urine (glycosuria), reducing hyperglycaemia

Also reduces BP; cardioprotective

Side-effects
Genital candidiasis
Dehydration
DKA

71
Q

Outline methods of glucose measurement

A
  • Flash glucose measuring (FGM)-FreeStyle Libre device
    Measures interstitial glucose every minute
    Doesn’t interrupt insulin flow
    Best for trends; high and low blood glucose alarms
  • Continuous glucose monitoring (CGM)
    Measures interstitial glucose every 5 minutes & communicates w/ insulin pump to adjust dose
72
Q

Outline the types of injection regimes for insulin delivery

A
  • Conventional regime
    Injection 2x day
    No flexibility - same type of food at same time + no exercise
    mixed insulin (1/3 fast-acting, 2/3 long-acting)
  • Basal-bolus regime
    Intensive regime injections 4x day
    Long-acting insulin at night & fast-acting bolus with each meal
    Resembles physiological insulin release
73
Q

Outline the role of insulin pumps in insulin delivery

A
  • Insulin pump aka CSII (continuous subcutaneous insulin infusion)
    Only rapid-acting insulin (Novorapid)
    Delivers multiple basal rates, microboluses + correction doses
    Disadvantages: commitment, regular testing, CHO counting skills
  • Sensor augmented pump
    Sensor on the abdomen sends information to pump so it can adjust settings
    Predicted low glucose suspend - if the algorithm detects that the person will become hypoglycaemic, it suspends insulin
74
Q

Explain the pathophysiology of diabetic ketoacidosis (DKA)

A
  • Insulin deficiency blocks glucose uptake in peripheral tissues
    Proteolysis provides amino acids for gluconeogenesis
    Lipolysis leads to an increase in fatty acids delivered to hepatocytes; converted to acetyl CoA > acetoacetate > ketone bodies (ketosis)
  • Results in metabolic acidosis (pH < 7.3) as acidic ketone bodies reduce plasma pH
  • Increased renal excretion of H+ initially, then loss of bicarbonate ions (<15mmol/L)
  • Increased respiratory rate + later Kussmaul breathing (low pCO2 due to respiratory compensation)
  • Impaired renal compensation with worsening acidosis & renal hypoperfusion
  • Hyperglycaemia, osmotic diuresis and counterregulatory hormones
75
Q

Explain what is meant by “osmotic diuresis” in the context of DKA

A
  • Glucose and ketones freely filtered at the glomerulus
  • Maximum reabsorption threshold for glucose is exceeded
  • Increased solute concentration in tubular lumen causes osmotic gradient
  • Increased water loss in urine - profound dehydration (vomiting contributes to this)
  • Hyperaldosteronism arises as a result: increased potassium loss due to lack of GI and renal absorption
  • Serum potassium may be normal or high despite the depletion (lack of insulin prevents potassium from moving into cells)
76
Q

Describe the actions of counter-regulatory hormones in DKA

A

Adrenaline

  • Glycogenolysis
  • Gluconeogenesis
  • Lipolysis

Cortisol and growth hormone

  • Gluconeogenesis
  • Lipolysis
  • Inhibition of peripheral glucose uptake
77
Q

Describe the management of diabetic ketoacidosis (DKA)

A
  • Hypovolaemia: IV fluids
  • Hyperglycaemia: IV insulin (after fluids), add 10% dextrose
    Start when plasma glucose is stable as fluids can make glucose fall
  • Potassium depletion: IV potassium chloride
  • Supportive
    NG tube
    Antiemetics
    Treat underlying cause
78
Q

Explain the pathophysiology of hyperosmolar hyperglycaemic state (HHS)

A
  • Insulin deficiency, but sufficient to suppress lipolysis
  • Blockage of glucose uptake in peripheral tissues leads to hyperglycaemia
  • This drives osmotic diuresis & dehydration
  • Chronic renal impairment is common
  • Longer onset so more profound hypovolemia
  • Impaired thirst mechanism leads to lack of water replacement
  • Risk of central pontine myelinolysis and cerebral oedema due to large fluid shifts
79
Q

Compare DKA and HHS

A

DKA

  • Short history
  • Patient < 65 y/o, usually type I DM
  • No residual insulin
  • Hyperglycaemia & dehydration
  • Acidosis
  • Patient usually alert

HHS

  • Insidious history
  • Patient > 65 y/o, usually type II DM
  • Residual insulin
  • Profound hyperglycaemia, dehydration and hypernatraemia
  • No acidosis
  • Patient often drowsy
80
Q

Outline the causes and symptoms of hypoglycaemia

A
  • Causes
    Diabetes & drug-induced (diabetes medication)
    Insulinoma
    Excessive alcohol consumption
    Severe liver disorders e.g. cirrhosis, hepatitis
    Hormone deficiencies (adrenal and pituitary tumours)
  • Symptoms
    Initial - autonomic
    Tremor and sweating (mediated by adrenaline)
    Hunger (mediated by ACh and noradrenaline)
    Palpitations and anxiety

Late - neuroglycopaenic
Confusion and impaired consciousness level

81
Q

Discuss the management of hypoglycaemia

A
  • Mild (BM < 4mmol)
    15-20g of fast-acting carbohydrate
- Severe
15-20g of fast-acting carbohydrate
If reduced consciousness level:
IM glucagon (associated w/ nausea, vomiting)
IV dextrose
82
Q

Explain what is meant by “hypoglycaemia unawareness”

A

Associated with frequent episodes of hypoglycaemia
Unclear mechanism

Autonomic dysfunction: no longer present with autonomic hypoglycaemic symptoms

Complications:
Nocturnal hypoglycaemia
Driving restrictions

83
Q

Describe the pathophysiology of diabetic microvascular complications

A
  • Capillary damage
    Hyperglycaemia leads to structurally and functionally abnormal vessels
    > Increased capillary pressure
    > Thickened and damaged vessels
    > Endothelial damage w/ leakage of albumin & other proteins
  • Metabolic damage
    Most tissues need insulin to take up glucose but kidneys, retina and nerves don’t
    Glucose is absorbed and metabolised to sorbitol by aldose reductase
    Excessive glucose enters polyol pathway
    Sorbitol accumulates > less NADPH for cell metabolism > buildup of ROS and oxidative stress > cell damage
84
Q

Describe the stages of diabetic retinopathy

A
  • Early (non-proliferative)
    Hyperglycaemia causes damage to small vessel wall & microaneurysms
    When vessel wall is breached, dot haemorrhages appear
    Protein and fluid left behind lead to hard exudates
    Micro-infarcts result in cotton wool spots
  • Later
    Damage to veins leads to venous budding and blockage of blood supply
    Proliferative retinopathy: ischaemia stimulates the production of VEGF
    > Neovascularisation and vitreous haemorrhage
    Fluid not cleared from macula results in macular oedema
85
Q

Describe the prevention and treatment of diabetic retinopathy

A
  • Prevention
    Stop smoking
    Good blood pressure control, good glycaemic control
- Treatment
Address risk factors
Ophthalmic review
> Laser
> VEGF inhibitors (bevacizumab)
> Vitrectomy
86
Q

Outline the different types of diabetic neuropathy

A
  • Peripheral (sensory) neuropathy: most common
    Capillary damage including occlusion in the vasa nervorum
    Reduced blood supply to neural tissue leads to impairment in nerve signalling
    Affects sensory & motor function
  • Autonomic neuropathy
    > Cardiovascular: postural hypotension
    > Genitourinary: erectile dysfunction
    > Gastrointestinal: gastroparesis, gustatory sweating
  • Mononeuritis multiplex
    Painful, asymmetrical, asynchronous sensory & motor peripheral neuropathy
    Isolated damage to at least 2 separate nerve areas
  • Diabetic amyotrophy
    Pain & muscle wasting in thighs, hips, buttocks & legs
87
Q

Describe the signs and symptoms of diabetic neuropathy

A
  • Signs
    Diminished vibratory perception
    Decreased knee & ankle reflexes
    Reduced protective sensation e.g. heat, pain, pressure
    Diminished ability to sense position of toes and feet
- Symptoms
Numbness
Prickling/tingling
Aching/burning/lancinating pain
Allodynia (unusual sensitivity to non-painful stimuli) esp in feet
88
Q

Describe the stages of diabetic nephropathy

A
  • Renal hypertrophy and increased GFR
    Afferent arteriole vasodilates
    > increased glomerular pressure & thickening of basement membrane
    > capillary damage, shear stress on endothelial cells
  • Microalbuminuria
    Leakage of protein into urine (tiny traces of albumin)
    Calculate ACR (albumin:creatinine ratio)
    If present, treat with ACE inhibitor or ARB (angiotensin receptor blocker) to prevent progression to macroalbuminuria
  • Macroalbuminuria
  • End-stage renal failure
89
Q

Explain what is meant by “diabetic foot” and how it is treated

A
  • Combination of neuropathy and peripheral vascular disease
    > Ulcers
    > Infection
    > Ischaemia

Treatment

  • Debride (chiropodist)
  • Pressure relief (orthotist)
  • Treat infection
  • Circulation
90
Q

Explain what is meant by “Charcot foot” and how it is treated

A
  • Numb foot
    Repetitive microtrauma
    Stress fractures
  • Dysregulated blood flow
    Increased bone turnover; fragile bone

Treatment
- Immediate immobilisation in plaster cast

91
Q

List macrovascular complications of diabetes

A
  • Coronary heart disease
  • Ischaemic heart disease
  • Congestive heart failure
  • Peripheral arterial disease
92
Q

List non-vascular complications of diabetes

A
  • Infections: fungal infection, influenza, pneumonia
  • Degenerative diseases
  • Depression
  • Cognitive disorders
  • Cirrhosis
  • Colon cancer
93
Q

Describe the transport of glucose into tissues

A
  • Down a concentration gradient via facilitated diffusion using transporters (GLUT1-4)
  • Against a concentration gradient using energy provided by co-transport with sodium (SGLT1 & 2)
    > Absorbs glucose from gut lumen & reabsorbs glucose in kidney
    > Requires ATP for Na/K-ATPase to maintain electrochemical gradient
94
Q

Describe glucose transporters GLUT1-4 including molecules transported and site of expression (mention the function of GLUT5)

A

GLUT1: ubiquitous
Molecules: glucose & galactose

GLUT2: liver, pancreatic beta cell, kidney, small intestine
Molecules: glucose, galactose, fructose

GLUT3: brain, placenta, testes
Molecules: glucose and galactose

GLUT4: skeletal and cardiac muscle; adipocytes
Molecules: insulin-responsive; high affinity for glucose

GLUT5: in small intestine & sperm
Molecules: fructose

95
Q

Describe the purpose of the pentose phosphate pathway

A

Synthesis of

  • Fatty acids: generation of NADPH for reductive biosynthesis
  • Nucleotides (RNA, DNA): formation of ribose-5-phosphate

Dehydrogenation of glucose-6-phosphate is the committed step

96
Q

Describe the process of glycogenesis

A
  • Glucose converted to G6P via glucokinase
  • G6P converted to G1P via phosphoglucomutase
  • G1P converted to UDP-glucose using glucose-1-phosphate uridiyltransferase
  • UDP-glucose converted to glycogen using glycogen synthase (highly regulated)
97
Q

Describe the process of glycogenolysis

A
  • Glycogen converted to G1P using glycogen phosphorylase (highly regulated)
  • G1P converted to G6P via phosphoglucomutase
98
Q

Discuss the hormonal regulation of glycogen synthesis

A
  • Noradrenaline: liver and muscle
    Inhibits glycogen synthase and stimulates glycogen phosphorylase
  • Insulin: liver and muscle
    Secreted in response to high glucose
    Increase glucokinase, PFK, glycogen synthase
    Decrease G6Pase, F1,6bPase, PEPCK, glycogen synthase
  • Glucagon: liver
    Secreted in response to low glucose
    Decrease glucokinase, PFK, pyruvate kinase & glycogen synthase
    Increase G6Pase, PEPCK, F1,6bPase & glycogen phosphorylase
99
Q

Name the substrates used for gluconeogenesis

A

Synthesis of glucose from a non-carbohydrate source, occurs in the liver

  • Lactate: converted to pyruvate first
  • Pyruvate
  • Glycerol: converted to DHAP, intermediate in glycolysis
  • Certain amino acids: converted into pyruvate or various TCA cycle intermediates
100
Q

Describe the process of gluconeogenesis

A

Pyruvate converted to oxaloacetate using pyruvate carboxylase (PCOX)

Oxaloacetate converted to phosphoenolpyruvate using phosphoenolpyruvate carboxykinase (PEPCK)

Phosphoenolpyruvate converted to Fructose-1 6-bisphosphate using Fructose-1 6-bisphosphatase (F1, 6bPase)

Fructose-1 6-bisphosphatase converted to fructose-6-phosphate

Fructose-6-phosphate converted to glucose-6-phosphate

Glucose-6-phosphate converted to glucose using glucose-6-phosphatase (G6Pase)

101
Q

Describe the synthesis of insulin in pancreatic beta cells

A
  • First synthesised as a long polypeptide (preproinsulin)
  • Signal sequence is lost, forming proinsulin
  • Covalent links are formed between sulphydryl groups on cysteine residues
  • C-peptide chain is cleaved to form mature insulin
    > 2 polypeptide chains linked by sulphur bridges
102
Q

Describe the synthesis of glucagon in pancreatic alpha cells

A

Long precursor - proglucagon

Alpha cell cleaves proglucagon into glucagon and other products

Intestinal L cells and some neurons will cleave it differentially leading to the production of GLP-1 and GLP-2

103
Q

Explain the mechanism of insulin signalling

A

Insulin binds to the insulin receptor (tyrosine kinase) found primarily in liver, striated muscle & adipocytes; receptor dimer autophosphorylates

Phosphorylated tyrosine residues on the insulin receptor act as binding sites for other proteins (insulin receptor substrates)

IRSs become phosphorylated by the insulin receptor, starting the signal transduction cascade

Phosphatidylinositol-3’-kinase (PI3K) is activated
Activates protein kinase B (Akt/PKB)

Results in GLUT4 translocation to the cell membrane & transport of glucose into the cell

104
Q

Explain the mechanism of glucagon signalling

A

Glucagon binds to a G-protein coupled receptor (GPCR) found in hepatocytes

Activates adenylyl cyclase

Increases cyclic AMP

cAMP stimulates cAMP-dependent protein kinase A (PKA)

105
Q

Describe the role of insulin in the suppression of lipolysis

A

Insulin stimulates fatty acid and triglyceride synthesis

  • Increases expression of fatty acid synthase, acetyl CoA carboxylase
  • Increases activity of lipoprotein lipase in adipocytes

Also stimulates breakdown of cAMP: noradrenaline no longer able to stimulate lipolysis

106
Q

Describe the process of glycolysis up until the commitment step

A
  • Glucose (6C) is broken down into glucose-6-phosphate via glucokinase
  • Glucose-6-phosphate is converted to fructose-6-phosphate using phosphoglucose isomerase
  • Fructose-6-phosphate is metabolised to fructose-1 6-bisphosphate via phosphofructokinase-1 (commitment step)
107
Q

Describe the process of glycolysis after the commitment step

A

Fructose-1 6-bisphosphate is metabolised by aldolase into 2x 3C sugars:

  • Dihydroxyacetone phosphate: metabolised to glyceraldehyde-3-phosphate by triose phosphate isomerase
  • Glyceraldehyde-3-phosphate

Glyceraldehyde-3-phosphate converted to 1,3-bisphosphoglycerate by glyceraldehyde-3-phosphate dehydrogenase

1,3-bisphosphoglycerate is converted to 3-phosphoglycerate using phosphoglycerate kinase

> converted to 2-phosphoglycerate (phosphoglyceromutase)
converted to phosphoenolpyruvate (enolase)
converted to pyruvate (pyruvate kinase)

108
Q

Discuss the 2 paths glycolysis can take depending on the presence of oxygen

A

Not present: anaerobic glycolysis
- Pyruvate converted to lactate using lactate dehydrogenase
Regenerates NAD+ to keep glycolysis going
2x ATP generated

Present: aerobic glycolysis

  • Pyruvate transported into mitochondrion
  • Pyruvate + coenzyme A make acetyl coenzyme A via decarboxylation using pyruvate dehydrogenase
  • Produces 1x CO2 and 1x NADH + H+
  • Requires vitamins as co-factors (thiamine)
  • Acetyl CoA then enters TCA cycle
109
Q

Describe the process of triglyceride synthesis

A
  • Esterification of 3 fatty acids + glycerol
  • Lipoprotein lipase hydrolyses triglycerides in chylomicrons/LDL on cell surface to provide fatty acids
  • Diacylglycerol acyl transferase (DGAT) re-esterifies fatty acids to triglycerides in cell to add to a lipid droplet
  • Glycerol derived from DHAP (glycolysis)
110
Q

Describe the process of lipolysis

A
  • Breakdown of triglyceride into glycerol + 3 fatty acids
  • Performed by hormone sensitive lipase (HSL) in adipose tissue
  • HSL is activated by cAMP-dependent phosphorylation (PKA) in response to noradrenaline in the fasted state
  • Inhibited by insulin
111
Q

Describe the process of lipogenesis

A
  • Fatty acids are built 2 carbons at a time (limit is 16C)
  • Key regulatory enzymes

> Acetyl CoA Carboxylase
Fixes bicarbonate onto acetyl coA (uses ATP & biotin/vitamin B7)
Forms malonyl CoA (Inhibits fatty acid oxidation via carnitine palmitoyl transferase)

> Fatty Acid Synthase (FAS)
7 successive steps by multifunctional FAS
Active in cytoplasm of lipogenic tissues
Requires NADPH

112
Q

Outline the process of beta oxidation

A

To be transported into mitochondria, CoA is added to free fatty acids by acyl CoA synthetase > fatty acyl CoA

To cross the inner mitochondrial membrane, fatty acids are shuttled across using the carnitine shuttle (carnitine palmitoyl transferase)

CoA is replaced with carnitine using CPT I > fatty acyl carnitine

Enters mitochondrial matrix and carnitine is replaced with CoA using CPT II > fatty acyl CoA

In beta oxidation, carbon backbone is cleaved between alpha and beta carbons producing acetyl CoA for TCA cycle & 1x NADH, 1x FADH2

113
Q

Explain how ketone bodies are formed and give examples

A

When fat is oxidised due to glucose unavailability, ketones are formed

Examples: acetoacetate, beta-hydroxybutyrate, acetone

Used by other tissues as a source of acetyl CoA (therefore ATP)

Acetyl CoA + acetyl CoA = acetoacetyl CoA

Acetoacetyl CoA - CoA = acetoacetate (can be converted to acetone & beta-hydroxybutyrate)

114
Q

Describe the different classes of lipoproteins

A
  • Chylomicrons (synthesised in gut after a meal)
    Carry triglycerides from intestines to liver, muscle & adipose tissue
  • VLDL (very low density lipoprotein - synthesised in liver)
    Carry endogenously-synthesised triglycerides from liver to adipose tissue
  • IDL (intermediate density lipoprotein)
  • LDL (low density lipoprotein - synthesised in circulation from VLDL)
    Major cholesterol reservoir; taken up via LDL receptors on cells
  • HDL (high density lipoprotein - synthesised in liver)
    Absorb cholesterol released by dying cells
    “Reverse transport” to return cholesterol to liver; reduces circulating cholesterol
115
Q

Describe the exogenous pathway of cholesterol transport

A
  • Intestine
    Chylomicrons transport large lipids out of intestine via lacteals & drain into thoracic duct
- Circulation
Lipoprotein lipase (LPL) in capillary endothelium removed 3 fatty acids (stored in adipose tissue), leaving a chylomicron remnant (expresses ApoE protein)
  • Liver
    ApoE interacts with counterreceptor on liver & enters
    Chylomicron remnant is broken down & stored as free fatty acids and cholesterol
116
Q

Describe the endogenous pathway of cholesterol transport

A
  • Liver
    If lipids are required, cholesterol and free fatty acids can be made into a VLDL particle
  • Circulation
    VLDL can be acted on by LPL (removes 3 fatty acids for storage in adipose tissue) making IDL
  • Liver
    IDL acted on by hepatic lipase to form LDL
  • Peripheral tissue
    Tissues requiring LDL cholesterol express LDL receptors on their surface
117
Q

Describe the process of phospholipid synthesis

A
  • Same as triglyceride synthesis until diacyl glycerol (DAG) is made
  • Then combined with an alcohol

Examples:

  • Phosphatidylinositol
  • Phosphatidylcholine
  • Phosphatidylserine
118
Q

Explain the requirement for essential fatty acids

A

Essential fatty acids cannot be synthesised; obtained from diet e.g. polyunsaturated omega-3, omega-6

Functions:

  • Cell membrane formation
  • Proper growth & development
  • Brain & nerve function
  • Precursor for eicosanoids - prostanoids & leukotrines - needed in the inflammatory response
119
Q

Describe the embryological development of the pancreas

A
  • Derived from endoderm; develops from 2 buds which emerge from the foregut
  • Ventral pancreatic bud: forms neck, body and tail of pancreas
  • Dorsal pancreatic bud: forms head & uncinate process of pancreas
  • Point of fusion between 2 buds creates pancreatic duct
  • During development, cells of the embryonic pancreas migrate from duct system and aggregate around capillaries

> Create clusters nestled amongst the glandular tissue - islets of Langerhans

120
Q

Describe the different cell types found in the islets of Langerhans

A
  • Alpha cells: produce glucagon
  • Beta cells: produce insulin and amylin (slows gastric emptying, preventing hyperglycaemic peaks)
  • Delta cells: produce somatostatin
  • Epsilon cells: produce ghrelin, which stimulates hunger
  • Gamma cells: produce pancreatic polypeptide, which regulates exocrine & endocrine pancreatic secretion
  • VIP (vasoactive intestinal polypeptide) cells
121
Q

Describe the anatomical relationship of the pancreas with local blood vessels & nearby organs

A
  • Head
  • Uncinate process: posterior to superior mesenteric artery + vein
  • Neck: sits on superior mesenteric artery + vein; behind neck, superior mesenteric vein + splenic vein join to form the hepatic portal vein
  • Body:
  • Tail: makes contact with the spleen & lies in splenorenal ligament
122
Q

State the blood supply to the pancreas

A
  • Splenic artery: travels behind loops at superior border; branches include the arteria pancreatica magna
  • Superior and inferior pancreaticoduodenal arteries: supply head & uncinate process
123
Q

Describe the gross anatomy + histology of the thyroid gland

A
  • 2 highly vascular lobes on either side of trachea connected by isthmus + pyramidal lobe
  • Surrounded by thin fibrocollagenous capsule: septa extend inwards separating the gland into lobes
  • Contains follicles made up of a single layer of cells surrounding a lumen which contains colloid (largely thyroglobulin)
124
Q

Describe the release of thyroid hormones into the circulation

A
  • When stimulated, follicular cells become columnar and lumen is depleted of colloid via endocytosis
  • Colloid cleaved by proteases within follicular cells, releasing thyroglobulin from T3 & T4
  • T3 & T4 enter circulation, thyroglobulin recycled back to lumen
  • When suppressed, follicular cells become squamous and colloid accumulates in the lumen
125
Q

Describe the function of thyroglobulin

A

Main storage mechanism for thyroid hormones

Synthesised in rER of thyroid epithelial cells and secreted into lumen of follicle (colloid)

Polypeptide backbone for synthesis and storage of thyroid hormones

Iodine attachment to tyrosine residues on thyroglobulin is the preliminary step in thyroid hormone formation

126
Q

Describe the process of thyroid hormone biosynthesis

A
  • Iodide actively transported into follicular cells by sodium iodide transporter on basolateral membrane

> diffuses to apex of cell & transported by prendrin into vesicles > fusion with apical cell membrane

  • Iodide oxidised to iodine > attaches to tyrosine residues on thyroglobulin
  • Process of organification happens, catalysed by thyroid peroxidase, in the presence of hydrogen peroxide in apical colloid facing cells
  • Forms monoiodotyrosine & diiodotyrosine (MIT/DIT)
    > 2x DIT form T4, 1x MIT + 1x DIT form T3
  • Endocytosis of thyroglobulin, release of T3 & T4 after droplets fuse with lysosome and thyroglobulin is hydrolysed
127
Q

Describe the process of thyroid hormone deiodination

A

Triiodothyronine (T3) acts at the cellular level (active hormone)

L-thyroxine (T4) is a pro-hormone (released in greatest quantity)
> deiodinated to T3 by deiodinase in the periphery (5’ deiodination, outer ring)

Reverse T3 is produced by 5’ deiodination of the inner ring

Different deiodinases found in different organs, allowing local control

128
Q

Describe the distribution of circulating thyroid hormones

A
  • Free (0.5%)
  • Bound (99.5%)
    Bound to thyroglobulin, transthyretin and albumin
129
Q

Explain the actions of thyroid hormones

A

Cytosolic T3 is transported to the nucleus and binds to thyroid hormone nuclear receptor (TR) which influences gene expression

Nuclear receptor binds T3 more avidly than T4

Alpha and beta T3 receptors vary between tissues
> beta T3 found in brain, heart, liver, kidneys, pituitary

Influence almost every system

  • Determinants of brain and somatic development
  • Skeletal: bone turnover
  • Cardiovascular: heart rate
  • Metabolic: lipids & glucose
130
Q

Describe the actions of calcitonin

A
  • Calcitonin is produced by parafollicular cells (aka C cells or clear cells)
  • Peptide hormone which regulates calcium levels:
    > inhibits osteoclast activity
    > physiological antagonist to PTH
    > Inhibits renal calcium reabsorption
131
Q

State the causes of hyperthyroidism

A
  • Excess thyroid hormone production
Causes:
> Autoimmune - Graves' disease
> Thyroiditis
> Toxic adenoma
> Multinodular goitre
> Excess administration of thyroxine
132
Q

Describe the clinical manifestation of primary hyperthyroidism

A
  • Low TSH high T4, primary cause is Graves’ disease
  • Weight loss
  • Tremor, sweating
  • Heat intolerance
  • Diarrhoea
  • Tachycardia, atrial fibrillation, warm peripheries
  • Hypertension
  • Palpitations
133
Q

Name the clinical signs which are specific to Graves’ disease

A 
- Graves' ophthalmopathy
Lid retraction and periorbital oedema
Proptosis (exophthalmos)
Diplopia 
Nerve compression (rare)
  • Pretibial myxoedema
  • Thyroid acropachy
134
Q

Discuss treatments for primary hyperthyroidism

A
  • Anti-thyroid drugs
    > Thionamides: carbimazole, propylthiouracil
  • Surgery
    > Thyroidectomy
  • Radioactive iodine: destroys thyroid tissue in beta emission
  • Beta-blockers: sympathetic nervous system symptoms
  • Steroids: if thyroiditis or thyroid storm
  • Iodine: blocks hormone release (short-term)
135
Q

Outline the mechanism of action of thionamides, including side-effects

A
  • Inhibit iodide oxidation
  • Inhibition of thyroid peroxidase
    > Inhibit iodination of tyrosine
    > Inhibit coupling of iodotyrosines

Carbimazole:
Metabolised to methimazole via first-pass metabolism
Side-effect: aplasia cutis, avoid during pregnancy

Propylthiouracil:
Side-effects: possible hepatotoxicity

Side-effects for both: agranulocytosis (rare) & rash

136
Q

Describe the causes of hypothyroidism

A
  • Autoimmune: Hashimoto’s thyroiditis
  • Thyroidectomy
  • Thyroiditis (viral)
  • Follow radio-iodine therapy
  • Drug-induced e.g. amiodarone, lithium, sunitinib
  • Secondary hypothyroidism (pituitary disease)
  • Severe iodine deficiency
137
Q

List symptoms of hypothyroidism

A
  • Hypotension & bradycardia
  • Cold intolerance
  • Depression, lethargy, poor concentration
  • Weight gain
  • Constipation
  • Hoarseness
  • Menorrhagia
  • Goitre
  • Dry skin and coarse thin hair
  • Anaemia
  • Slow relaxing reflexes
138
Q

Discuss treatment & long-term goals for hypothyroidism

A
  • Levothyroxine, metabolised to T3

Goals: euthyroid - resolve symptoms & normalised TSH

Full suppression of TSH associated with atrial fibrillation and osteoporosis

139
Q

Describe the risk to surrounding structures in case of pituitary enlargement

A

Pituitary enlargement can result in compression of:

  • Optic canal (anterior)
  • Foramen spinosum - middle meningeal artery
  • Carotid canal - internal carotid (posterolateral)
  • Foramen ovale: mandibular branch of trigeminal nerve
140
Q

Outline the gross anatomy, blood supply & venous drainage of the parathyroid glands

A

Usually 4 endocrine glands on the posterior surface of the thyroid gland (range 2-6)

Embedded in a fibrous capsule (their own or the thyroid’s); separated into nodules by thin fibrous septa

Blood supply: inferior thyroid arteries

Venous drainage: parathyroid veins

141
Q

Describe the cell types of the parathyroid gland

A
  • Chief cells (aka principal cells)
    Detect ionised calcium levels and produce parathyroid hormone
  • Water clear cells
    Resting clear chief cells; contain pools of glycogen
  • Oxyphil cells: unknown function
142
Q

What is meant by the term “goitre”?

A

Diffuse, irregular enlargement of the thyroid gland; moves when swallowing

Characterised by hypertrophy & colloid cyst formation

Can be caused by low iodine levels but patient can present with normal thyroxine

143
Q

Discuss the process of screening for microvascular complications in diabetes

A
  • Diabetic retinopathy
    Every year since age 12, if sight is threatened refer to ophthalmology
  • Diabetic nephropathy
    Every year since diagnosis, test for microalbuminuria
    > If present give ACE inhibitor or ARB
  • Diabetic neuropathy
    Check vibration sense, reflexes & pain every year
    > Review schedule is determined by risk
    Low: normal sensation and pulses, annual review
    Medium-moderate: absent pulses or neuropathy, every 3-6 months
    High: deformities or ulceration, every 1-3 months
144
Q

Summarise the key clinical trials emphasising the importance of glycaemic control in reducing the incidence of microvascular complications

A

DCCT: patients with type 1DM, conventional v intensive (basal bolus)

UKPDS: patients with type 2DM, conventional v intensive

Both trials show that intensive glycaemic control lowers HbA1c and reduces risk of microvascular complications (short-term) and cardiovascular disease (long-term)

145
Q

Describe the different pharmacological preparations of vasopressin available in clinical practice

A
  • Maintenace therapy
    Oral - low bioavailability
    Sublingual
    Intranasal
  • Acute therapy
    Subcutaneous
    Intramuscular
    Intravenous (variceal bleeding/shock)
146
Q

Describe the different preparations of insulin available in clinical practice

A
  • Short-acting: usually for meal times to cover quick-acting carbohydrates
    Human e.g. Humulin S
    Animal e.g. Hypurin bovine neutral
    Analogues e.g. Novorapid
  • Intermediate/long-acting
  • Pre-mixed (short + long-acting insulin), given 2x/day
147
Q

Name the different delivery methods for insulin

A
  • Subcutaneous injection (common with pre-filled pens/cartridges)
  • Continuous subcutaneous insulin infusion (CSII)
  • Intravenous (acute illness)
  • Intramuscular
148
Q

Describe the key differences between different preparations of glucocorticoids used in clinical practice & name routes of administration

A

Hydrocortisone

  • Closest to physiological cortisol
  • Equal glucocorticoid & mineralocorticoid action

Prednisolone
- 4x glucocorticoid effect

Dexamethasone & betamethasone
- 30x potency of hydrocortisone, no mineralocorticoid effect

Routes of administration
- Topical, nasal, inhaled, oral, subcutaneous, intramuscular, intravenous

149
Q

Describe the biosynthesis of steroid hormones

A
  • Derived from enzymatic modification of cholesterol

> Cholesterol is taken up from circulation or synthesised de novo from acetyl CoA

> Rate-limiting step in cholesterol synthesis is HMG CoA reductase

> Cholesterol is also taken up by cell as LDL, later broken down into esterified cholesterol and free cholesterol

  • Synthesis occurs mainly in mitochondria and smooth ER
  • Not stored prior to secretion as steroid hormones are lipid soluble
  • Immediately released upon synthesis & circulate in blood
150
Q

Describe the biosynthesis of oestrogens

A

Circulating oestrogens are a mixture of oestradiol and oestrone

  • Oestrone is secreted directly from ovary or converted from androstenedione
  • Oestradiol produced by the ovary is derived by direct synthesis in developing follicles or conversion of oestrone via aromatase
151
Q

Describe the synthesis of androgens

A

E.g. testosterone, dihydrotestosterone, androstenedione, dehydroepinandrosterone (DHEA)

Synthesised from cholesterol in the testes, ovaries and adrenal gland

152
Q

Describe the synthesis of progestins

A

Synthesised from cholesterol & produced primarily in corpus luteum, placenta and adrenal glands

153
Q

Describe the mechanism of action of steroid hormones

A
  • Steroid hormone enters target cells and binds to a steroid hormone receptor (nuclear receptor superfamily)
  • Hormone-receptor complex enters the nucleus & acts as a transcription factor
  • Binds to a glucocorticoid response element (DNA sequence) in the 5’ flanking region of target genes
  • Binding initiates gene transcription to produce mRNA, which travels to cytoplasm and is translated into proteins > cell response
154
Q

Describe the domains found within steroid hormone receptors

A

A/B: N-terminal domain

C: DNA binding domain; contains 2 zinc fingers to bind DNA sequences

D: Hinge region; controls movement of receptor to nucleus

E: Ligand-binding domain; binds steroid

F: C-terminal domain

155
Q

Describe how pre-receptor regulation influences the action of aldosterone and cortisol

A

Cortisol can bind to the mineralocorticoid receptor and its concentration is much higher than that of aldosterone

Mechanism is needed to protect the mineralocorticoid receptor from illicit occupation by glucocorticoids

11 beta hydroxysteroid dehydrogenase (11-beta HSDII) catalyses the conversion of cortisol to cortisone (inactive) in selective tissues e.g. kidney

> Allows aldosterone to function normally (enzyme inhibited by liquorice)

Year 2 Medicine (6 decks)

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