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Year 5 Path > Chemical Pathology > Flashcards

Chemical Pathology Flashcards

1
Q

What are the roles of calcium?

A
  • Part of the skeleton (99% of body calcium in skeleton)

- Metabolic: Action potentials and IC signalling

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2
Q

Serum calcium is found in which 3 forms?

A

(1% of body calcium in serum)
- Free (“ionised”) ~50%- biologically active

  • Protein-bound ~40%- albumin
  • Complexed ~10%- citrate/phosphate
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3
Q

What is the total serum Ca2+?

A
  • 2.2- 2.6 mmol/L
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4
Q

What is “Corrected” Ca2+?

A
  • serum Ca2+ + 0.02*(40 - serum albumin in g/L)

- calcium levels important in muscle depolarisation and thus in the control of nerve and muscle

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5
Q

What is the significance of corrected Ca2+?

A
  • If you have a low albumin, the bound calcium will be low but the free calcium will be normal thus the corrected calcium refers to that
  • The corrected calcium tells you that the problem is with the albumin and that the ionised calcium will be also be normal
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6
Q

What does chronic calcium deficiency lead to?

A
  • Loss of calcium from bone in order to maintain circulating calcium
  • Plasma concentration must thus be maintained despite calcium and vitamin D deficiency
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7
Q

How does the parathyroid gland respond to low calcium?

A
  • Hypocalcaemia detected by parathyroid gland
  • Parathyroid gland releases PTH
  • PTH obtains Ca2+ from 3 sources
    • Bone
    • Gut (absorption)
    • Kidney (reabsorption and renal 1 alpha hydroxylase activation)
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8
Q

What two key hormones are involved in calcium homeostasis?

A
  • PTH

- Vitamin D

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9
Q

What is PTH and what is its roles?

A
  • 84 aa protein
  • Only released from parathyroids

Roles

  • Bones & renal Ca2+ resorption
  • Stimulate 1,25(OH)2 vit D synthesis (1 alpha hydroxylation)
  • Also stimulates renal Pi wasting
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10
Q

What are the stages of vitamin D synthesis?

A
  • Sun converts 7-dehydrocholesterol to Cholecalciferol (D3)
  • D3 is converted to 25-hydroxycholecalciferol in the liver (25 alpha hydroxylase)
  • 25-OH D3 is converted to 1,25-dihydroxycholcalciferol in the kidneys (1 alpha hydroxylase)
  • 1,25(OH)2 D3 is the physiologically active form
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11
Q

What is ergocalciferol?

A
  • Vitamin D2- a plant vitamin
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12
Q

Where else is 1 alpha hydroxylase expressed?

A
  • Rarely, this enzyme can be expressed in lung cells of sarcoid tissue
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13
Q

What are the roles of 1,25(OH)2 vitamin D?

A
  • Intestinal Ca2+ absorption
  • Intestinal Pi absorption
  • Critical for bone formation
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14
Q

What are the roles of the skeleton? (Orthopaedic view)

A
  • Structural framework
  • Strong
  • Relatively lightweight
  • Mobile
  • Protects vital organs
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15
Q

What are the roles of the skeleton? (Metabolic view)

A
  • Metabolic role in calcium homeostasis

- Main reservoir of calcium, phosphate and magnesium

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16
Q

What are some metabolic bone diseases?

A
  • Osteoporosis
  • Osteomalacia
  • Paget’s disease
  • Parathyroid bone disease
  • Renal osteodystrophy
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17
Q

What is vitamin D deficiency?

A
  • Defective bone mineralisation
  • Childhood -> Rickets
  • Adulthood -> Osteomalacia
  • Vitamin D deficiency in the UK
    • More than 50% adults have insufficient vitamin D
    • 16% have severe deficiency during winter and spring
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18
Q

What are the risk factors of vitamin D deficiency?

A
  • Lack of sunlight exposure
  • Dark skin
  • Dietary
  • Malabsorption
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19
Q

What are the clinical features of vit D deficiency?

A
  • Osteomalacia
    • Bone & muscle pain
    • Increased risk
    • Biochem: low Ca2+ and Pi, raised ALP
    • Looser zones
  • Rickets
    • Bowed legs
    • Costrochondral swelling
    • Widened epiphyses at the wrists
    • Myopathy
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20
Q

Outline osteomalacia

A
  • Bone is demineralised
  • Caused by vitamin D deficiency
  • Renal failure
  • Anticonvulsants induce breakdown of vitamin D
  • Lack of sunlight
  • Chappatis
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21
Q

Outline osteoporosis

A
  • Cause of pathological fracture
  • Occurring more often as people live longer
  • Loss of bone mass
  • Bone slowly lost after age 20
  • Residual bone normal in structure
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22
Q

How does osteoporosis compare to osteomalacia?

A
  • Reduction in bone density (bone mineralisation is normal)
  • BIOCHEMISTRY NORMAL
  • Asymptomatic until fracture. Then its too late
  • Typical fracture: neck of femur, vertebral, wrist (Colle’s)
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23
Q

How is osteoporosis diagnosed?

A
  • DEXA scan
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24
Q

What is the T-score?

A
  • SD from mean of young healthy population (useful to determine risk)
  • Osteoporosis - T-score < - 2.5
  • Osteopenia - T-score between -1 and -2.5
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25
Q

What is the Z-score?

A
  • SD from mean of aged-matched control (useful to identify accelerate bone loss in younger patients)
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26
Q

What are causes of osteoporosis?

A
  • Childhood illness: failure to obtain peak bone mass
  • Menopause
  • Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional
  • Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings
  • Drugs: steroids
  • Others eg genetic, prolonged intercurrent illness
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27
Q

What are some treatments for osteoporosis?

A
  • Lifestyle: weight-bearing exercise, stop smoking, reduce EtOH
  • Drugs:
    • Vitamin D/Ca
    • Bisphosphonates (eg alendronate) –↓ bone resorption
    • Teriparatide (PTH derivative) – anabolic
    • Strontium – anabolic + anti-resorptive
      (Oestrogens – HRT)
    • SERMs eg raloxifene
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28
Q

What are symptoms of hypercalcaemia?

A
  • Polyuria/polydipsia
  • Constipation
  • Neuro - confusion/seizures/coma
  • Unlikely unless Ca2+ > 3.0 mmol/L
  • Overlap with Sx of hyperPTH
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29
Q

What is the hormonal response to hypercalcaemia?

A
  • PTH release should be suppressed
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30
Q

What are causes of hypercalcaemia?

A
  • If PTH is suppressed
    • Malignancy
    • Others (rare): sarcoid, vitamin D excess, thyrotoxicosis, milk akali syndrome
  • If PTH is not suppressed
    • Primary hyperparathyroidism (common)
    • Familial hypocalciuric hypercalcaemia (rare)
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31
Q

Outline primary hyperparathyroidism

A
  • Commonest cause of hypercalcaemia
  • Parathyroid adenoma/hyperplasia/carcinoma
  • Hyperplasia associated with MEN1
  • Women > men
  • Increased serum Ca, increased or inappropriate PTH, decreased serum Pi, increased urine Ca (due to hypercalcaemia)
  • BONES (PTH bone disease) and STONES (renal calculi)
  • Hypercalcaemia -> abdominal MOANS (constipation, pancreatitis), psychiatric GROANS (confusion)
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32
Q

What causes familial hypocalciuric (/benign) hypercalcaemia (FHH/FBH)?

A
  • CaSR mutation
  • Higher “set point” for PTH release -> mild hypercalcaemia
  • Reduced urine Ca2+
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33
Q

What are the 3 types of hypercalcaemia in malignancy?

A
  • Humoral hypercalcaemia of malignancy (e.g. small cell lung cancer)
    • PTHrP
  • Bone metastases (e.g. breast cancer)
    • Local bone osteolysis
  • Haematological malignancy (e.g. myeloma)
    • cytokines
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34
Q

What are other causes of non-PTH driven hypercalcaemia?

A
  • Sarcoidosis (non-renal 1 alpha hydroxylation)
  • Thyrotoxicosis (thyroxine -> bone resorption)
  • Hypoadrenalism (renal Ca2+ transport)
  • Thiazide diuretics (renal Ca2+ transport)
  • Excess vitamin D (eg sunbeds…)
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35
Q

What is the treatment of hypercalcaemia?

A
  • Fluids
  • Bisphosphonates (if cause known to be cancer) otherwise avoid.
  • Treat underlying cause
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36
Q

What are clinical signs of hypocalcaemia?

A
  • Neuro-muscular excitability
  • Trosseau’s sign
  • Convulsions
  • Hyperreflexia
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37
Q

What are causes of (low) PTH-derived hypocalcaemia?

A
  • Surgical (inc. post-thyroidectomy)
  • Auto-immune hypoparathyroidism
  • Congenital absence of parathyroids (e.g. diGeorge syndrome)
  • Mg deficiency (PTH regulation)
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38
Q

What are causes of non-PTH driven hypocalcaemia? (secondary hyperthyroidism if PTH is raised)

A
  • vitamin D deficiency - dietary, malabsorption, lack of sunlight
  • chronic kidney disease (1 alpha hydroxylation)- can progress to tertiary hyperparathyroidism
  • PTH resistance (“pseudohypoparathyroidism”)
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39
Q

What is Paget’s disease?

A
  • Focal disorder of bone remodeling
  • Focal PAIN, warmth, deformity, fracture, SC compression, malignancy, cardiac failure
    Pelvis, femur, skull and tibia
  • Elevated alkaline phosphatase
  • Nuclear med scan / XR
  • Treatment = Bisphosphonates for pain
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40
Q

What are some other metabolic bone disorders?

A
  • In primary hyperparathyroidism
    • Loss of cortical bone -> # risk
    • Osteitis fibrosa
  • Renal osteodystrophy
    • Due to secondary hyperparathyroidism + retention of aluminium from dialysis fluid
  • Both rare due to modern Rx of underlying disorders
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41
Q

What is hyponatraemia?

A
  • Serum sodium < 135 mmol/L

- Commonest electrolyte abnormality in hospitalized patients

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42
Q

What is the underlying pathogenesis of hyponatraemia?

A
  • Increased extracellular water
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43
Q

What is ADH?

A
  • A hormone which resaborbs water
  • Acts on V2 receptors (collecting duct)
  • Insertion of aquaporin-2
  • V1 receptors
    • vascular smooth muscle
    • vasoconstriction (higher concentrations)
    • alternative name ‘vasopressin’
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44
Q

What are the two main stimuli for ADH secretion?

A
  • Serum osmolality (mediated by hypothalamic osmoreceptors).

- Blood volume/pressure (mediated by baroreceptors in carotids, atria, aorta)

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45
Q

What is the effect of increased ADH secretion on serum sodium?

A
  • Hyponatraemia
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46
Q

What is the first step in the clinical assessment of a patient with hyponatraemia?

A
  • Clinical assessment of volume status

- Hypovolaemic? Euvolaemic? Hypervolaemic?

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47
Q

What are the clinical signs of hypovolaemia?

A
  • Tachycardia
  • Postural hypotension
  • Dry mucous membranes
  • Reduced skin turgor
  • Confusion/drowsiness
  • Reduced urine output
  • Low urine Na+ (<20)
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48
Q

What are the clinical signs hypervolaemia?

A
  • Raised JVP
  • Bibasal crackles (on chest examination)
  • Peripheral oedema
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49
Q

What are the causes of hypovolaemic hyponatraemia?

A
  • Diarrhoea
  • Vomiting
  • Diuretics
  • Salt losing nephropathy
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50
Q

What are the causes of euvolaemic hyponatraemia?

A
  • Hypothyroidism
  • Adrenal insufficiency
  • SIADH
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51
Q

What are the causes of hypervolaemic hyponatraemia?

A
  • Cardiac failure
  • Cirrhosis
  • Nephrotic syndrome
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52
Q

What are causes of SIADH?

A
  • CNS pathology
  • Lung pathology
  • Drugs (SSRI, TCA, opiates, PPIs, carbamazepine)
  • Tumours
  • Surgery
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53
Q

What investigations would you order in a patient with euvolaemic hyponatraemia?

A
  • ? Hypothyroidism: Thyroid function tests
  • ? Adrenal insufficiency: Short Synacthen test
  • ? SIADH: Plasma & urine osmolality (low plasma & high urine osmolality)
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54
Q

How would you manage a hypovolaemic patient with hyponatraemia?

A
  • Volume replacement with 0.9% saline
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55
Q

How would you manage a hypervolaemic patient with hyponatraemia?

A
  • Fluid restriction

- Treat the underlying cause

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56
Q

How would you manage a euvolaemic patient with hyponatraemia?

A
  • Fluid restriction

- Treat the underlying cause

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57
Q

Describe severe hyponatraemia

A
  • Reduced GCS
  • Seizures
  • Seek expert help (Treat with Hypertonic 3% saline)
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58
Q

What is the most important point to remember while correcting hyponatraemia?

A
  • Serum Na must NOT be corrected > 8-10 mmol/L in the first 24 hours
  • Risk of osmotic demyelination (central pontine myelionlysis)
    • quadriplegia, dysarthria, dysphgia, seizures, coma, death
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59
Q

What drugs can be used to treat SIADH?

If water restriction is insufficient

A
  • Demeclocycline
    • Reduces responsiveness of collecting tubule cells to ADH
    • Monitor U&Es (risk of nephrotoxicity)
  • Tolvaptan
    • V2 receptor antagonist
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60
Q

What is hypernatraemia?

A
  • Serum [Na+] > 145 mmol/L
  • Unreplaced water loss
    • Gastrointestinal losses, sweat losses
    • Renal losses: osmotic diuresis, reduced ADH release/action (Diabetes insipidus)
  • Patient cannot control water intake e.g. children, elderly
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61
Q

What investigations would you order in a patient with suspected diabetes insipidus?

A
  • Serum glucose (exclude diabetes mellitus)
  • Serum potassium (exclude hypokalaemia)
  • Serum calcium (exclude hypercalcaemia)
  • Plasma & urine osmolality
  • Water deprivation test
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62
Q

How do you treat hypernatraemia?

A
  • Fluid replacement
  • Treat the underlying cause
  • Correct water deficit
    • 5% dextrose
  • Correct extracellular fluid volume depletion
    • 0.9% saline
  • Serial Na+ measurements
    • Every 4-6 hours
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63
Q

What are the effects of of diabetes mellitus on serum sodium?

A
  • Variable
  • Hyperglycaemia draws water out of the cells leading to hyponatraemia
  • Osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia
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64
Q

What is the most abundant intracellular cation?

A
  • Potassium
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65
Q

What is the serum concentration of potassium?

A
  • 3.5-5.0 mmol/L
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66
Q

Which hormones are involved in renal regulation of potassium?

A
  • Angiotensin II

- Aldosterone

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67
Q

How does aldosterone control potassium secretion?

A
  • Aldosterone number of open Na+ channels in the luminal membrane
  • Increased sodium reabsorption makes the lumen electronegative & creates an electrical gradient
  • Potassium is secreted into the lumen
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68
Q

What are the stimuli for aldosterone secretion?

A
  • Angiotensin II

- Potassium

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69
Q

What are the main causes of hyperkalaemia?

A
  • Renal impairment: reduced renal excretion
  • Drugs: ACE inhibitors, ARBs, spironolactone
  • Low Aldosterone
    • Addison’s disease
    • Type 4 renal tubular acidosis (low renin, low aldosterone)
  • Release from cells: rhabdomyloysis, acidosis
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70
Q

What is the main the ECG change associated with hyperkalaemia?

A
  • Peaked T waves
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71
Q

How would you manage a patient with hyperkalaemia?

A
  • 10 ml 10% calcium gluconate
  • 50 ml 50% dextrose + 10 units of insulin
  • Nebulized salbutamol
  • Treat the underlying cause
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72
Q

What are the causes of hypokalaemia?

A
  • GI loss
  • Renal loss
    • Hyperaldosteronism, (Excess cortisol)
    • Increased sodium delivery to distal nephron
    • Osmotic diuresis
  • Redistribution into the cells
    • Insulin, beta-agonists, alkalosis
  • Rare causes: Renal tubular acidosis type 1& 2, hypomagnesaemia
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73
Q

What are the clinical features hypokalaemia?

A
  • Muscle Weakness
  • Cardiac arrhythmia
  • Polyuria & polydipsia (nephrogenic DI)
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74
Q

What screening test would you order in a patient with hypokalaemia and hypertension?

A
  • Aldosterone: Renin ratio
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75
Q

How would you manage a patient with hypokalaemia?

A
  • Serum potassium 3.0-3.5 mmol/L
    • Oral potassium chloride (two SandoK tablets tds for 48 hrs)
    • Recheck serum potassium
  • Serum potassium < 3.0 mmol/L
    • IV potassium chloride
    • Maximum rate 10 mmol per hour
    • Rates > 20 mmol per hour are highly irritating to peripheral veins
  • Treat the underlying cause e.g. spironolactone
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76
Q

How do you work out osmolality?

A
  • 2(Na + K) + U + G
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77
Q

How do you work out anion gap?

A
  • Anion gap = Na + K – Cl – bicarb
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78
Q

What is Schmidt’s syndrome?

A
  • Addison’s disease and primary hypothyroidism occur together more commonly than by chance alone
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79
Q

What is the test for Addison’s?

A
  • Short SYNACTHEN test.
  • Measure cortisol + ACTH at start of test
  • Administer 250 micrograms synthetic ACTH by IM injection.
  • Check cortisol at 30 and 60 minutes
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80
Q

What are potential abnormal adrenal masses?

A
  • Phaeochromocytoma
    (Adrenal medullary tumour secreting adrenaline).
  • Conn’s syndrome (adrenal tumour secreting aldosterone)
  • Cushing’s syndrome (secretes cortisol)
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81
Q

What is a phaeochromocytoma?

A
  • Adrenal medullary tumour that secretes adrenaline, and can cause severe hypertension, arrhythmias and death.
  • THUS A MEDICAL EMERGENCY
  • Urgent alpha blockade with phenoxybenzamine.
  • Add beta blockade.
  • Finally arrange surgery.
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82
Q

What is Conn’s syndrome?

A
  • Conn’s syndrome.
  • The adrenal gland secretes high levels of aldosterone autonomously. This will cause hypertension and this will in turn suppress the renin at the JGA
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83
Q

What is the test for Cushing’s?

A
  • Dexamethasone suppression. This will usually suppress cortisol levels to undetectable levels.
  • Not so in Cushing’s.
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84
Q

What are causes of Cushing’s syndrome?

A
  • Being on oral steroids for something else
  • Pituitary dependent Cushings disease (85%)
  • Ectopic ACTH (5%)
  • Adrenal adenoma (10%)
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85
Q

Describe pituitary sinus sampling

A
  • Distinguishing from ectopic ACTH
  • Needs excellent angiography
  • Not always available
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86
Q

What are the normal ranges in acid/base equations?

A
  • pH: 7.35 - 7.45
  • CO2: 4.7 - 6kPa
  • Bicarbonate: 22 – 30 mmol/l
  • O2: 10 – 13kPa
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87
Q

What are the causes of metabolic acidosis?

A
  • Lactate build up DKA
  • Renal tubular acidosis
  • Intestinal fistula
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88
Q

What are the causes of metabolic alkalosis?

A
  • Pyloric stenosis
  • Hypokalaemia
  • Ingestion of bicarbonate
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89
Q

What are the causes of respiratory acidosis?

A
  • Lung injury – pneumonia,
  • COPD
  • Decreased ventilation – Morphine OD
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90
Q

What are the causes of respiratory alkalosis?

A
  • Mechanical Ventilation

- Anxiety/ panic attack

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91
Q

What is a mnenomic for elevated anion gap metabolic acidosis?

A
  • Ketoacidosis (DKA, alcoholic, starvation)
  • Uraemia (renal failure)
  • Lactic Acidosis
  • Toxins (ethylene glycol, methanol, paraldehyde, salicylate)
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92
Q

What is the normal glomerular filtration rate?

A
  • 120ml/min

- Age related decline approximately 1ml/min per year

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93
Q

What is clearance?

A
  • The volume of plasma that can be completed cleared of a marker substance in a
    unit of time
  • If marker is not bound to serum proteins, freely filtered at the glomerulus, and not secreted/reabsorbed by tubular cells, Clearnce = GFR
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94
Q

What is the gold standard measure of GFR?

A
  • Inulin.
  • But requires steady state infusion and difficult to
    assay so it is reserved for research purposes only
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95
Q

What are clinically viable measures of GFR?

A
  • 51Cr-EDTA
  • 99Tc- DTPA
  • Iohexol
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96
Q

What are endogenous markers of GFR?

A
  • Creatinine

- Urea

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97
Q

How do you work out clearance?

A
  • (U x V)/P
  • U = Urinary conc
  • P = Plasma conc
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98
Q

What are characteristics ideal for measuring clearance?

A
  • Not plasma protein bound
  • Freely filtered at glomerulus
  • Not modified by tubules
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99
Q

Describe creatinine as an endogenous marker for GFR

A
  • Derived from muscle cells (small amount from intestinal absorption)
  • Freely filtered
  • Creatinine is actively secreted into urine by tubular cells
  • Generation is not equivalent in different individuals
    • Muscularity
    • Age
    • Sex
    • Ethnicity
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100
Q

What is Cockcroft Gault?

A
  • eCCr = (1.23 x (140-age) x weight) / serum creatinine
  • Adjust by 0.85 if female
  • Estimates creatinine clearance (not GFR)
  • May overestimate GFR, especially when <30ml/min
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101
Q

What is the MDRD equation? (modification of diet in renal disease study)

A
  • eGFR = 186 x ( Creat x 0.0113) -1.154 x Age -0.203
  • Adjust by 0.742 if female
  • Requires age, sex, serum creatinine and ethnicity
  • May underestimate GFR if above-average weight and young
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102
Q

What are alternative endogenous markers of GFR?

A
  • Cystatin C
    • 13.6kD protein
    • Cysteine protease inhibitor
    • Constitutively produced by all nucleated cells
    • Constant rate generation
    • Freely filtered
    • Almost completely reabsorbed and catabolised by tubular cells
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103
Q

Describe measurement of renal function in practice

A
  • Serum creatinine is an insensitive marker of GFR
  • Other endogenous blood markers (ie Cystatin C) are better
  • Constant rate infusion GFR measurement is a research tool
  • Single injection GFR measurement is reserved for specific situations
  • In practice, estimated GFR / CCr is the best compromise
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104
Q

What is Urine protein:creatinine ratio?

A
  • Quantitative assessment of amount of proteinuria

- Measurement of creatinine corrects for urinary concentration

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105
Q

Describe 24 hour urine collection

A
  • Cumbersome and messy
  • Highly inaccurate without specific patient education
  • Estimation of proteinuria superceded by urinary PCR
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106
Q

What are examples of urine examination and their uses?

A
  • Single sample
    • Dipstick testing
    • Microscopic examination
    • Proteinuria quantification
    • Electrolyte estimation
  • 24hour collection
    • Creatinine clearance estimation
    • Stone forming elements
    • (Proteinuria quantification)
    • (Electrolyte estimation)
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107
Q

Describe urine dipstick testing

A
  • pH
    • 4.5 to 8.0
  • Specific gravity
    • 1.003 to 1.035
    • (Bowmans space 1.007 to 1.010)
  • Protein
    • Sensitive to albumin, not BJPs
    • Zero, Trace, 1+ to 4+
  • Blood
  • Leucocyte esterase
    • Negative result is significant
  • Nitrite
    • Detects bacteria, esp. Gm negatives
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108
Q

Describe urine microscopy

A
  • Centrifuge at 3000rpm
    • 5-10 minutes
  • Examine sediment for:
    • Crystals
    • Red blood cells
    • White blood cells
    • Casts
    • Bacteria
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109
Q

What are the different types of renal imaging?

A
  • Plain KUB films
  • Intravenous urogram (IVU)
  • KUB ultrasound
  • Cross-sectional imaging (CT and MRI)
  • Functional imaging (static and dynamic renograms)
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110
Q

What is normal liver function?

A
  • Intermediary Metabolism
  • Protein Synthesis
  • Xenobiotic Metabolism
  • Hormone Metabolism
  • Bile Synthesis
  • Reticulo-endothelial
111
Q

What is intermediary metabolism?

A
  • Enzyme-catalysed processes within cells that extract energy from nutrient molecules and use that energy to construct cellular components
  • Glycolysis
  • Glycogen storage
  • Glucose synthesis
  • Amino-acid synthesis
  • Fatty acid synthesis
  • Lipoprotein metabolism
112
Q

Describe Xenobiotic metabolism in the liver

A
  • Chemical modification
    • P450 Enzyme System
    • Acetylation / de-acetylation
    • Oxidation / Reduction

–>

  • Conjugation
    • glucuronate
    • sulphate
  • Excretion
113
Q

Describe Vitamin D metabolism in the liver

A
  • Vitamin D
    • hydroxylation
  • Steroid Hormone
    • conjugation
    • excretion
  • Peptide Hormone
    • catabolism
114
Q

What are the constituents and functions of bile?

A

Constituents

  • Water
  • Bile salts/acids
  • Bilirubin
  • Phospholipids
  • Cholesterol
  • Proteins
  • Drugs and Metabolites

Function

  • Excretion
  • Micelle formation
  • Digestion`
115
Q

Describe the reticulo-endothelial function in the liver

A
  • Kupffer Cells
    • Clearance of infection and LPS
    • Antigen presentation
    • Immune modulation
    • cytokines etc.
  • Erythropoesis
116
Q

What are the LFTs?

A
  • Alanine Transaminase
  • Aspartate Transaminase
  • Alkaline Phosphatase
  • Gamma glutamyl transferase
117
Q

What are the markers of liver cell damage?

A

LFTs

  • ALT
  • AST
  • ALP
  • GGT
118
Q

What are the markers of synthetic function?

A
  • Albumin
  • Clotting (INR)
  • Glucose
  • Bilirubin
119
Q

Describe ALT

A
  • Found primarily in the liver, more sensitive than AST for hepatocyte damage
  • Raised when hepatocytes die. AST:ALT =1 supportive of
    viral hepatitis
120
Q

Describe AST

A
  • Found in the Liver, cardiac and skeletal muscle, and the kidney and brain
  • AST:ALT = 2 is supportive of alcoholic hepatitis
121
Q

Describe ALP

A
  • Found in the liver, bones, placenta
  • Raised with cholestasis (either intrahepatic or extrahepatic) and
    bone disease, ↑++ in pregnancy
122
Q

Describe GGT

A
  • Found in hepatocytes and biliary cells, also found in the kidney and pancreas.
  • Elevated in chronic alcohol use
  • Also bile duct disease and metastases. Used to confirm hepatic source of ↑ALP
123
Q

Describe albumin (Synthetic hepatocellular dysfunction)

A
  • Average adult synthesises 200mg/kg of albumin per day
  • Important serum protein which binds many hormones, calcium and other metabolites.
  • Hypoalbuminaemia is common in hospital patients as acute illness/systemic inflammation and malnutrition can contribute to a reduced albumin
  • Hypoalbuminaemia in critically ill patients is a poor prognostic factor
124
Q

Describe clotting factors (Synthetic hepatocellular dysfunction)

A
  • The liver synthesises Factor V, VII, IX, X, XII, XIII and fibrinogen and prothrombin
  • In practical terms INR (International normalised ratio) is measured, this is the prothrombin time standardised for age and population expressed as a ratio of ‘normal’.
  • Deranged clotting is not diagnostic of hepatocellular dysfunction on its own as it could be due to multiple other aetiologies – for example iatrogenic (therapeutic warfarinisation), hereditary thrombophillia, acquired consumption
    (DIC)
125
Q

What is Alpha-feto protein? (AFP)

A
  • glycoprotein MW 69 000 /albumin superfamily
  • Fetal transport-immune regulation/tolerance in fetal life made by yolk sac, GI epithelium and liver
  • In adult concentration low / no known function
    used in diagnosis of hepatocellular carcinoma (but may rise too late or not at all)
  • Also raised in hepatic damage/regeneration raised in pregnancy and testicular cancer
126
Q

What is jaundice?

A
  • Elevated serum bilirubin manifesting as yellowing of the skin or sclera (icterus)
127
Q

What is bilirubin?

A
  • Bilirubin is a breakdown product of heme, and the majority is produced by breakdown
    of haemoglobin.
  • Normal metabolism of bilirubin involves conjugation in hepatocytes, and subsequent secretion into the bile ducts and then the GI tract
  • Conjugated bilirubin is metabolised further in the GI tract into urobilinogen
  • Urobilinogen is then partially reabsorbed and excreted in the kidneys as Urobilin
  • The rest of the urobilinogen is converted to stercobilin which is the brown pigment in faeces.
  • Disorder of bilirubin metabolism can therefore be pre-hepatic [raised bilirubin production], hepatic [decreased ability to conjugate bilirubin] or post hepatic [decreased ability to excrete conjugated bilirubin].
128
Q

What are pre-hepatic causes of jaundice?

A
  • Haemolysis

- Congestive heart failure

129
Q

What are lab findings of pre-hepatice jaundice?

A
  • Elevated unconjugated bilirubin
  • Rediced haemoglobin
  • Reduced haptoglobin
  • Raised LDH
130
Q

What are hepatic causes of jaundice?

A
  • Acute or chronic liver failure
  • Gilbert syndrome
  • Crigler-Najjar syndrome
  • Viral Hepatitis
  • Alcoholic Hepatitis
  • PBC
131
Q

What are lab findings of hepatic jaundice?

A
  • Elevated Unconjugated bilirubin
  • Raised Aminotransferases
  • Synthetic dysfunction may be
    present
132
Q

What are post-hepatic causes of jaundice?

A
  • Obstruction of the biliary tree from any cause (Think intraluminal – Stones, strictures, Luminal – Mass/Neoplasm,
  • Inflammation e.g. PSC/PBC,
  • Extra-luminal – Pancreatic Ca, cholangio Ca
133
Q

What are lab findings of post-hepatic jaundice?

A
  • Elevated conjugated bilirubin

- Elevated bilirubin in the urine [Dark urine pale stools]

134
Q

Where is ALP found in high concentrations?

A
  • Present in high concentrations in liver, bone, intestine and placenta
135
Q

How to differentiate raised ALP due to liver disease or due to bone disease?

A
  • We can differentiate liver from bone ALP either by seeing if there is a rise in gamma-GT (liver ALP rises with this)
  • Electrophoresis
  • Bone-specific assay of ALP
136
Q

What are causes of raised ALP?

A
  • Physiological: Pregnancy (3rd trimester), Childhood (during growth spurt)
  • Pathological:
    • > 5x the upper limit of normal = Bone (Pagets, osteomalacia) Liver (Cholestatis, Cirrhosis)
    • <5x the upper limit of normal = Bone (tumours, fractures, osteomyelitis), Liver (infiltrative disease, hepatitis)
  • ALP not raised in osteoporosis unless complicated by fractures
137
Q

Describe amylase as an enzymatic marker of pancreatitis

A
  • Secreted by exocrine pancreas
  • High serum amylase activity in acute pancreatitis
  • Usually > 10 times upper limit of normal
  • Remember salivary isoenzyme exists
  • Small increases may be seen in other acute abdomen states
138
Q

What is the most widely used marker for muscle damage?

A
  • Creatine Kinase
139
Q

What are the three forms of creatine kinase?

A
  • CK-MM- skeletal muscles
  • CK-MB (1 & 2) – cardiac muscles
  • CK- BB – brain – activity minimal even in severe brain damage
140
Q

What are raised levels of CK due to?

A
  • Physiological: Afro-Caribbean (<5x upper limit of normal)

- Pathological: Duchenne Muscular Dystrophy (>10xULN), MI (>10xULN), Statin related myopathy, Rhabdomyolysis

141
Q

What is the spectrum for statin related myopathy?

A
  • Myalgia to rhabdomyolysis
142
Q

What are the risk factors for statin related myopathy?

A
  • Polypharmacy ( fibrates – gemfibrosil, cyclosporin, other drugs metabolised by the CYP 3A4 system)
  • High dose
  • Genetic predisposition
  • Previous history of myopathy with another statin
143
Q

What is troponin?

A
  • A myocardial injury biomarker
  • Measure at 6 hours and then at 12 hours post onset of chest pain/post MI (100% Se and 98% Sp at
    12-24 hours).
  • Remains elevated for 3 - 10 days
144
Q

What is an IU?

A
  • International unit
  • 1 international unit is the quantity of enzyme that catalyses 1uMol of substrate in a minute (at a given temp and pH)
  • It is a measure of enzyme MASS or CONCENTRATION, not activity
145
Q

What is the diagnostic criteria for acute MI?

A

Either one of the following

  • Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) with at least one of the following:
    • (a) ischemic symptoms
    • (b) pathologic Q waves on the ECG
    • (c) ECG changes indicative of ischemia
    • (d) coronary artery intervention
  • Pathological findings of an acute MI
146
Q

What are biomarkers of heart failure?

A
  • Atrial natriuretic peptide – secreted by the atria

- Brain natriuretic peptide – secreted by the ventricles

147
Q

When is BNP released?

A
  • Released in response to ventricular stretch
148
Q

What are some of the roles of BNP?

A

Reducing
- systemic vasoconstriction

  • sodium retention
  • renal sympathetic activity
149
Q

Describe BNP levels with regards to heart failure

A
  • Levels of <100 are highly specific for excluding heart failure, >400 is highly sensitive for heart failure
    • Confounding factors to interpretation include CKD
  • NT-proBNP is more sensitive than BNP and has greater prognostic value
150
Q

What is the acute management of hypoglycaemia in adults?

A
  • Alert and orientated: oral carbohydrates, rapid acting; juice/sweets, longer acting; sandwich
  • Drowsy/confused but swallow intact: buccal glucose, e.g. hypostop/glucogel, start thinking about IV access
  • Unconscious or concerned about swallow: IV access, 50ml, 50% glucose mini-jet OR 100mls 20% glucose
  • Deteriorating/refractory/insulin induced/difficult IV access: consider IM/SC 1mg Glucagon
151
Q

What are symptoms of hypoglycaemia?

A
  • Adrenergic
    • Tremors
    • Palpitations
    • Sweating
    • Hunger
  • Neuroglycopaenic
    • Somnolence
    • Confusion
    • Incoordination
    • Seizures, coma
152
Q

How is low glucose counter-regulated?

A
  • Decreased insulin and increased glucagon
    • Reduced peripheral intake of glucose
    • Increase glycogenolysis
    • Increase gluconeogenesis
    • Increase lipolysis
  • Low neuronal glucose sensed in hypothalamus leads to sympathetic activation (catecholamines) and ACTH, cortisol and GH production
  • This leads to increased glucose and FFA production (which leads to increased ketone bodies)
153
Q

How can glucose be measured?

A
  • Lab glucose
    • Grey top (flouride oxalate)
    • Venous sample
    • 2 mls blood
    • Gold std to make the diagnosis
    • Delay in results
  • Blood glucose meter
    • Point-of-care device
    • Instant result
    • Capillary blood
    • Poor precision at low glucose levels
    • Often poorly maintained
154
Q

What are causes of hypoglycaemia without diabetes?

A
  • Fasting or reactive?
  • Critically unwell
  • Organ failure
  • Hyperinsulinism
  • Post gastric-bypass
  • Drugs
  • Extreme weight loss
  • Factitious
155
Q

What are causes of hypoglycaemia with diabetes?

A

May be related to

  • Medications
  • Inadequate CHO intake / missed meal
  • Impaired awareness
  • Excessive alcohol
  • Strenuous exercise
  • Co-existing autoimmune conditions
156
Q

What are some diabetic medications?

A
  • Oral hypoglycaemic
    • Sulphonylureas
    • Meglitinides
    • GLP-1 agents
  • Insulin
    • Rapid acting with meals: inadequate meal
    • Long-acting : hypo’s at night or in between meals
  • Other drugs
    • B-blockers, salicylates, alcohol ( inhibits lipolysis)
157
Q

Describe diabetes and co-morbidities

A
  • Co-existing renal / liver failure alters drug clearance, and reduced doses needed.
  • Rarely concurrent Addison’s can result in hypos (polygladular autoimmune syndrome)
  • Caveats
    • Poor awareness can occur due to autonomic neuropathy
    • Very serious problem at night, and an indication for continuous glucose monitoring
    • A very good HbA1c level in a diabetic, may be due to recurrent hypos.
    • End of the honeymoon period
158
Q

What is C-peptide?

A
  • C-peptide levels are a good marker of beta-cell function
  • Also good to help differentiate the cause of hypoglycaemia
  • Half-life, ~ 30 minutes Renal Clearance
159
Q

What type of hypoglycaemia is linked with low insulin and low C-peptide?

A
  • Hypoinsulinaemic hypoglycaemia
160
Q

What type of hypoglycaemia is linked with high insulin and high C-peptide?

A
  • Hyperinsulinaemic hypoglycaemia
161
Q

What type of hypoglycaemia is linked with high insulin and low C-peptide?

A
  • Exogenous insulin
162
Q

What is neonatal hypoglycaemia?

A
  • Explainable
    • Premature, co-morbidities, IUGR, SGA
    • Inadequate glycogen and fat stores
    • Should improve with feeding
  • Pathological
    • Inborn metabolic defects
163
Q

What is neonatal hypoglycaemia with suppressed insulin + C-peptide?

A
  • FFA raised, but low ketones
  • Inherited metabolic disorders
    • FAOD : no ketones produced
    • GSD type 1 ( gluconeogentic disorder)
    • Medium chain acyl coA dehydrogenase def.
    • Carnitine disorders
  • Expect high FFA
  • Expect detectable ketone bodies ( beta hydroxybutyrate, acetoacetate /acetone)
  • Good differentiators in neonatal hypoglycaemia
    • Insulin / C-peptide
    • FFA
    • KB
    • Lactate
    • Hepatomegaly
164
Q

What causes inappropriate levels of insulin?

A
  • Islet cell tumours – insulinoma
  • Drugs; insulin, sulphonylurea
  • Islet cell hyperplasia
    • Infant of a diabetic mother
    • Beckwith Weidemann syndrome
    • Nesidioblastosis
165
Q

What is an insulinoma?

A
  • 1-2/million/year
  • Usually small solitary adenoma
  • 10% malignant
  • 8% associated with MEN1
  • Diagnosis, based on biochemistry + localisation
  • Treatment: resection
166
Q

What is a non-islet cell tumour hypoglycaemia?

A
  • Tumours that cause a paraneoplastic syndrome
  • Secretion of ‘big IGF-2’
  • Big IGF2 binds to IGF-1 receptor and insulin receptor
  • Mesenchymal tumours ( mesothelioma /fibroblastoma)
  • Epithelial tumours ( carcinoma)
167
Q

What are autoimmune causes of hypoglycaemia?

A
  • Autoimmune conditions: rare
    • Antibodies to insulin receptors usually present with insulin resistance but rarely hypoglycaemia.
  • Autoimmune insulin syndrome
    • Ab’s directed to insulin, sudden dissociation may precipitate hypoglycaemia
    • Japan
    • Certain drugs : hydralazine, procainamide etc
168
Q

Describe genetics and hypoglycaemia

A
  • Glucokinase activating mutation
  • Congenital hyperinsulinism
    • KCNJ11 /ABCC8
    • GLUD-1
    • HNF4A
    • HADH
169
Q

What is reactive/post-prandial hypoglycaemia?

A
  • Hypoglycaemia following food intake
  • Can occur post-gastric bypass
  • Hereditary fructose intolerance
  • Early diabetes
  • In insulin sensitive individuals after exercise or large meal
  • True post-prandial hypo’s
    • Difficult to define
170
Q

Describe purine catabolism

A
  • Purine —> Hypo-Xanthine —> Xanthine (by Xanthine Oxidase) —> Urate (by Xanthine Oxidase) —> Allantoin (by Uriease)
171
Q

What are the plasma concentrations of monosodium urate?

A
  • Men 0.12 – 0.42 mmol/l

- Women 0.12 – 0.36 mmol/l

172
Q

What is Lesch Nyhan Syndrome?

A
  • Complete HGPRT deficiency
  • Normal at birth
  • Developmental delay apparent at 6/12
  • Hyperuricaemia
  • Choreiform movements (1 year)
  • Spasticity, mental retardation
  • Self mutilation (85%) aged 1-16
173
Q

What are causes of hyperuricaemia due to increased urate production?

A

Primary

  • Lesch Nylan Syndrome
  • Partial HGPRT deficiency
  • Glyocogen storage disorders
  • Fructose intolerance
  • PRPP synthetase overactivity

Secondary

  • Myeloproliferative disorders
  • Lymphoproliferative disorders
  • Carcinomatosis
  • Chronic haemolytic anaemia
  • Gaucher’s disease
  • Severe psoriasis
174
Q

What are causes of hyperuricaemia due to decreased urate excretion?

A

Primary
- FJHN

Secondary

  • CRF
  • Down Syndrome
  • Diuretics
  • Aspirin
175
Q

What are causes of hypouricaemia due to decreased urate production?

A
  • Xanthine oxidase deficiency
  • Severe hepatic disease
  • Allopurinol
176
Q

What are causes of hypouricaemia due to increased urate excretion?

A
  • Idiopathic hypouricaemia
  • Fanconi syndrome e.g. idiopathic, cystinosis, myeloma
  • Uricosuric drugs
  • URATI inactivation
177
Q

What is gout?

A
  • Monosodium urate crystals
  • Can be acute (Podagra) or chronic (Tophaceous)
  • Males 0.5 – 3% prevalence
  • Females 0.1 – 0.6% prevalence
  • Post pubertal males and post menopausal females
178
Q

What are clinical features of acute gout?

A
  • Rapid build up of pain
  • “Exquisite”
  • Affected joint red, hot and swollen
  • 1st MTP joint first site in 50%
  • This joint is involved in 90% overall
179
Q

How do you reduce inflammation when treating acute gout?

A
  • NSAIDs
  • Colchicine
  • Glucocorticoids
  • Do NOT attempt to modify plasma urate concentration
180
Q

How do you manage hyperuricaemia?

A
  • Drink plenty (water!)
  • Reverse factors putting up urate
  • Reduce synthesis with allopurinol
  • Increase renal excretion with probenecid: “uricosuric”
181
Q

What are the side effects of allopurinol?

A
  • Interacts with azathioprine, making it more toxic on bone marrow etc.
  • Azathioprine is metabolised to mercaptopurine and then to thioinosinate which interferes with purine metabolism.
  • Allopurinol makes the mercaptopurine last longer.
182
Q

How do you diagnose gout?

A
  • Tap effusion
  • View under polarised light
  • Use red filter
  • Negative birefringent crystals
183
Q

What is pseudogout?

A
  • Occurs in patients with osteoarthritis
  • Pyrophosphate crystals
  • Self limiting 1 – 3 weeks
184
Q

What are different types of primary hypercholesterolaemia?

A
  • Familial hypercholesterolaemia (type II)
    • AD: LDLR, apoB, PCSK9 mutations
    • AR: LDLRAP1 mutation
  • Polygenic hypercholesterolaemia
    • Several polymorphisms
  • Familial hyper alpha-lipoproteinaemia
    • CETP deficiency
  • Phytosterolaemia
    • ABC G5 & G8
185
Q

What are different types of primary hypertriglyceridaemia?

A
  • Familial Type I
    • Lipoprotein lipase or apoC II deficiency
  • Familial Type V
    • apoA deficiency (sometimes)
  • Familial Type IV
    • increased TG synthesis
186
Q

What are different types of primary mixed lipidaemia?

A
  • Familial combined hyperlipidaemia
  • Familial dysβlipoproteinaemia
  • Familial hepatic lipase deficiency
187
Q

What are different types of hypolipidaemia?

A
  • Aβ-lipoproteinaemia
    • MTP deficiency
  • Hypoβ-lipoproteinaemia
    • Truncated apoB protein
  • Tangier disease
    • HDL deficiency
  • Hypoα-lipoproteinaemia
    • apoA-I mutations (sometimes)
188
Q

What is the order of lipoproteins in terms of density?

A
  • Chylomicron < FFA < VLDL < IDL < LDL < HDL
189
Q

What is PCSK9

A
  • Binds LDLR and promotes its degradation
  • Loss of function mutation of PCSK9 –> low LDL
    levels
  • Novel form of LDL-lowering therapy is AntiPCSK9 MAb
190
Q

What is the management of lipoprotein (a)?

A
  • Nicotinic acid
191
Q

What is the management of hyperlipidaemia?

A
  • First line is always conservative – dietary modification and exercise [although dietary intake of cholesterol correlates poorly with actual triglyceride levels]
  • Statin therapy
    • HMG-CoA reductase inhibitor
    • Reduces intrinsic synthesis of
      cholesterol in the liver
    • Side effects – myopathy/rhabdomyolysis, fatigue
  • Other agents more rarely used include Ezetimibe
192
Q

What is the management of obesity?

A
  • Conservative measures
  • Medical
    • No medication has been safely proven to provide sustained weight loss
    • Orlistat (A gut lipase inhibitor) is used however side effects of
      profound flatus and diarrhoea are often too cumbersome for
      patients to tolerate
    • Rimonabant (a cannabinoid antagonist) was trialled and discontinued from use as there was an increased risk of adverse events in the form of suicide
  • Surgical
    • Bariatric surgery is indicated in patients with a BMI >40 or >35 with a comorbidity associated with obesity
    • Includes gastric band, gastric sleeve and gastric bypass (roux en y or mini)
      • Bypass also has the added improvement of improving diabetic control in type 2 diabetics.
  • To be considered requires extensive screening and must commit to long term follow up usually.
193
Q

Describe UK screening via Guthrie blood spot test

A
  • 1969 – Phenylketonuria
  • 1970 – Congenital hypothyroidism
  • 2004 – Cystic Fibrosis
  • 2006 – Sickle cell disease
  • 2009 – Medium Chain AcylCoA dehydrogenase Deficiency
  • The newborn screening programme measures chemicals in the blood spot, it doesn’t involve
    any genetics. An abnormal chemical level doesn’t always mean that there is a genetic
    disorder
194
Q

What are the outcomes and screening tests of phenylketonuria?

A
  • Phenylalanine hydroxylase deficiency

- Screening test: Phenylalanine levels

195
Q

What are the outcomes and screening tests of congenital hypothyroidism?

A
  • Dysgenesis/Agenesis of the thyroid gland

- TSH levels

196
Q

What are the outcomes and screening tests of cystic fibrosis?

A
  • Mutation in CFTR - viscous secretions → ductal blockages

- Immune reactive trypsin. If positive → DNA mutation detection

197
Q

What is specificity?

A
  • the probability (in %) that someone without the disease will correctly test negative
  • TN/(TN+FP)
198
Q

What is sensitivity

A
  • the probability that someone with the disease will correctly test positive
  • TP/(TP+FN)
199
Q

What is PPV?

A
  • the probability that someone who tests positive actually has the disease
  • TP/(TP+FP)
200
Q

What is NPV?

A
  • the probability that someone who tests negative actually doesn’t have the disease
  • TN/(TN+FN)
201
Q

What are examples of metabolic disorders due to accumulation of toxins?

A
  • Organic acidaemias
    • Includes propionic acidaemia etc…
  • Urea cycle disorders
    • 9 in total, includes ornithine transcarbamylase deficiency
  • Aminoacidopathies
    • Includes PKU and maplesyrup urine disease
202
Q

What are features of metabolic disorders due to accumulation of toxins?

A
  • Organic acidaemias
    • High urea, ketones
    • Metabolic acidosis
    • Treat with low protein diet, acylcarnitine and
      haemofiltration
    • Often have funny smells due to the organic
      acids
  • Urea cycle disorders
    • High ammonia (>200uM) leading to
      encephalopathy and developmental delay
    • Respiratory alkalosis
    • Vomiting?diarrhoea
    • Treat with low protein diet (stops urea
      formation)
  • Aminoacidopathies
    • High phenylalanine, blue eyes and fair hair/skin
    • Retardation
    • MSUD apparently causes sweaty feet…
203
Q

What are examples of metabolic disorders to due reduced energy stores?

A
  • Glycogen storage disorders
    • Includes Von Gierke’s
  • Galactossaemia
  • Fatty acid oxidation disorders
    • Includes MCADD
204
Q

What are key features of metabolic disorders to due reduced energy stores?

A
  • Glycogen storage disorders
    • Hypoglycaemia and lactic acidosis
    • Hepatomegaly, developmental delay
    • Hepatoblastoma risk high
    • Treat with regular CHO
  • Galactossaemia
    • Increased Gal-1-phosphate levels cause
      cataracts
    • Hypoglycaemia, neonatal conjugated jaundice
    • Test urine reducing agents
    • Treat with low lactose/galactose diet
  • Fatty acid oxidation disorders
    • Hypoglycaemia, cardiomyopathy, rhabdomyolysis
    • Low ketones
    • Screened with blood acylcarnitine
    • Test urine organic acids
    • Treat with regular carbohydrate
205
Q

What are metabolic disorders of large molecule synthesis?

A
  • Peroxisomal disorders
    • Cannot catabolise very long fatty acids or make
      bile acids
  • Glycosylation disorders
206
Q

What are key features of metabolic disorders of large molecule synthesis?

A
  • Peroxisomal disorders
    • Poor feeds, seixures
    • Retinopathy
    • Hepatomegaly and mixed hyperbiliribinaemia
  • Glycosolation disorders
    • Measure serum transferrins
    • Lead to retardation and nipple inversion
207
Q

What are metabolic disorders with defects in large molecule metabolism?

A
  • Lysosomal disorders

- Include Tay Sachs disease

208
Q

What are key features of metabolic disorders with defects in large molecule metabolism?

A
  • Very slow progressing
  • Neuroregression, hepatosplenomegaly
  • Cardiomyopathy
  • Test urine mucooligopolysaccharides and WBC
    enzyme levels
209
Q

What are examples of mitochondrial metabolic disorders?

A
  • Various: MELAS, Kearn’s, Sayre, POEMS
210
Q

What are key features of mitochondrial metabolic disorders?

A
  • Involve the CNS, muscle and heart
  • High lactate and CK
  • Muscle biopsy diagnostic
211
Q

What are common problems in low birth weight?

A
  • Respiratory distress syndrome
  • Retinopathy of prematurity
  • Intraventricular haemorrhage
  • Patent ductus arteriosus
  • Necrotizing enterocolitis – inflammation of bowel wall – necrosis and perforation
212
Q

When does functional maturity of GFR happen?

A
  • By 2 years old
213
Q

What are consequences of low GFR for surface area in children?

A
  • slow excretion of a solute load

- limited amount of Na+ available for H+ exchange

214
Q

Why is there less rebasorption in a child than in an adult?

A
  • Due to shorter proximal tubule

- Although usually adequate for small filtered load

215
Q

Why is there a reduced concentrating ability of urine in children?

A
  • shorter loops of Henle and distal collecting ducts
216
Q

What is the maximum urine osmolality in children?

A
  • 700 mmol/kg
217
Q

Why is there persistent sodium loss in children?

A
  • Distal tubule resistant to aldosterone
218
Q

Why is there high water loss in children?

A
  • High surface area to bodyweight ratio
  • Skin blood flow is increased
  • Higher metabolic/respiratory rate than adults
  • Skin is less of a good barrier due to being immature
219
Q

When in infancy is hypernatraemia more common?

A
  • First 2 weeks of life

- Although can be a marker of dehydration or over-concentrated milk formula

220
Q

Why would hyponatraemia occur in first 4/5 weeks of life?

A
  • Excess total body water usually due to excessive intake.

- Rarely may be SIADH secondary to infection (pneumonia/meningitis) or intraventricular haemorrhage

221
Q

Why would hyponatraemia occur in after first 4/5 weeks of life

A
  • Sodium loss due to immature tubular function in patients on diuresis
222
Q

What are other causes of hyponatraemia in children?

A
  • Factitious (i.e. Na+ normal but appears low) e.g. hyperglycaemia
  • Congenital Adrenal Hyperplasia
    • Addisonian presentation
    • Usually identified on Guthrie spot
223
Q

What are causes of neonatal jaundice?

A
  • Jaundice within the 1st 24 hours of life (acute haemolysis or sepsis)
  • Jaundice after 2 weeks of life (hepatobiliary failure)
  • Conjugated hyperbilrubinaemia at any stage of infancy
224
Q

What is a porphyria?

A
  • 7 disorders caused by deficiency in enzymes involved in haem biosynthesis, leading to a build up of toxic haem precursors
225
Q

What is acute intermittent porphyria? (AIP)

A
  • Autosomal dominant inheritance

- HMB (Hydroxymethylbilane) synthase deficiency

226
Q

What are the symptoms of acute intermittent porphyria?

A
  • (neuro-visceral only) - abdo pain, seizures, psych disturbances, nausea & vomiting, tachycardia, hypertension, sensory loss, muscle weakness, constipation, urinary incontinence. NO cutaneous manifestations due to absence of porphyrinogens
227
Q

How is acute intermittent porphyria diagnosed?

A
  • ALA + PBG in urine (“Port wine urine”)
228
Q

What are precipitating factors of AIP?

A
  • ALA synthase inducers (steroids, ethanol, barbiturates)
  • Stress (infection, surgery)
  • Reduced caloric intake and endocrine factors (e.g. premenstrual)
229
Q

What is the treatment of AIP?

A
  • avoid precipitating factors, analgesia, IV carbohydrate/ haem arginate
230
Q

What are acute porphyrias with skin lesions?

A
  • Hereditary coproporphyria (HCP) and Variegate porphyria (VP)
  • Autosomal dominant
  • Raised porphyrins in faeces or urine
231
Q

What are symptoms of acute porphyrias with skin lesions?

A
  • neurovisceral + skin lesions
232
Q

What are non-acute porphyrias with skin lesions?

A
  • Congenital Erythopoietic porphyria (CEP)
  • Erythropoietic protoporphyria (EPP)
  • Porphyria Cutanea Tarda (PCT)
233
Q

What are clinical features of EPP?

A
  • Photosensitivity, burning, itching oedema following sun exposure
234
Q

What is PCT?

A
  • Inherited/ acquired

- Uroporphyrinogen decarboxylase deficiency

235
Q

What are symptoms of PCT?

A
  • (cutaneous) – Vesicles (crusting, pigmented, superficial scarring) on sun exposed sites
236
Q

How is PCT diagnosed?

A
  • ↑ urinary uroporphyrins + coproporphyrins + ↑ ferritin
237
Q

How is PCT treated?

A
  • avoid precipitants (alcohol, hepatic compromise), phlebotomy
238
Q

What condition is characterised by high TSH and low T4?

A
  • Hypothyroidism
239
Q

What condition is characterised by high TSH and normal T4?

A
  • Treated hypothyroidism or subclinical hypothyroidism (look for associated hypercholesterolaemia)
240
Q

What condition is characterised by high TSH and high T4?

A
  • TSH secreting tumour or thyroid hormone resistance
241
Q

What condition is characterised by low TSH and high T3 or T4?

A
  • Hyperthyroidism
242
Q

What condition is charactersied by low TSH and normal T3 or T4?

A
  • Subclinical hyperthyroidism

- This may progress to primary hypothyroidism, especially if the patient is anti-TPO antibody positive

243
Q

What condition is characterised by low TSH and low T4?

A
  • Central hypothyroidism (hypothalamic/pituitary disorder)
244
Q

What condition is characterised by ↑(later ↓)TSH ↓T3 and ↓ T4?

A
  • Sick euthyroidism (with any severe illness).

- The body tries to shut down metabolism as the thyroid gland has reduced output

245
Q

What condition is characteriseed by ↔TSH, abnormal T4 ?

A
  • ? assay interference, changes in TBG, amiodarone
246
Q

What are causes of high uptake hyperthyroidism?

A
  • Graves disease: 40 - 60%, F>M (9:1), autoantibodies ++, high uptake on isotope scan (with Tc99)
  • Toxic multinodular goitre: 30 - 50%, high uptake
  • Toxic adenoma: 5%, ‘hot nodule’ on isotope scan (1 area of uptake)
247
Q

What are causes of low uptake hyperthyroidism?

A
  • Subacute De Quervains thyroiditis: self-limiting post viral painful goiter. Initially hyperthyroid, then hypothyroid
  • Postpartum thyroiditis (like De Quervain’s but postpartum)
248
Q

What are causes of autoimmune hypothyroidism?

A
  • Primary atrophic hypoT: diffuse lymphocytic infiltration & atrophy. No goiter so small thyroid. No known antibodies detected yet
  • Hashimotos thyroiditis: Plasma cell infiltration & goitre. Elderly females. May be initial ‘Hashitoxicosis’. ++ Autoantibody titres (anti TPO/TG)
249
Q

What are causes of other types of hypothyroidism?

A
  • Iodine deficiency (common worldwide)
  • Post thyroidectomy/radioiodine
  • Drug induced – antithyroid drugs, lithium, amiodarone
250
Q

What is the treatment of hyperthyroidism split into?

A
  • Medical
  • Radio-iodine
  • Surgical
251
Q

What is the medical management of hyperthyroidism?

A
  • Symptom relief – Beta blockers, topical steroids for dermopathy, eye drops for patients with symptomatic eye disease in graves.
  • Antithyroid medications
    • Carbimazole most commonly used
    • Two approaches – Titration to normal T3 or block and replace [cause hypothyroidism then give levothyroxine – uncommon as high risk of side effects]
    • Side effects – Agranulocytosis (rare), rashes (common)
252
Q

How is radio-iodine used to manage hyperthyroidism?

A
  • Good efficacy for primary treatment, sometimes used after medical therapy has failed
  • Risk of permanent hypothyroidism
  • Contraindicated in pregnancy and lactating women
253
Q

What are indications for surgical thyroidectomy?

A
  • Women intending to become pregnant in the next 6/12
  • Local compression secondary to thyroid goitre (oesophageal/tracheal)
  • Cosmetic
  • Suspected cancer
  • Co-existing hyperparathyroidism
  • Refractory to medical therapy
  • N.b. Prior to surgery patients MUST be euthyroid prior to surgery
  • Total thyroidectomy patients will require thyroid replacement
254
Q

What is a thyroid storm?

A
  • An acute state that presents as shock, with pyrexia, confusion, vomiting.
  • Must be treated with HDU/ITU support, usually require cooling, high dose anti-thyroid medications, corticosteroids and circulatory and respiratory
    support.
255
Q

How is hypothyroidism treated?

A
  • Thyroid replacement therapy
256
Q

What are different types of thyroid neoplasia?

A
  • Papillary
  • Follicular
  • Medullary
  • Lymphoma
  • Anaplastic
257
Q

What is papillary thyroid neoplasia?

A
  • > 60% of cases, 30-40y, surgery +/- radioiodine, Thyroxine (to ↓TSH). May see psammoma bodies on histology, these patients have a very good prognosis.
258
Q

What is follicular thyroid neoplasia?

A
  • 25%, Middle age, well differentiated but spreads early, Surgery + RI + thyroxine
259
Q

What is medullary thyroid neoplasia?

A
  • 5% originates in parafollicular “C” cells – linked to MEN2. Produce calcitonin
260
Q

What is lymphoma thyroid neoplasia?

A
  • 5% MALT origin. Risk factor: chronic Hashimotos (as lots of lymphocytes that proliferate), good prognosis
261
Q

What is anaplastic thyroid neoplasia?

A
  • Rare. Elderly. Poor response to any treatment.
262
Q

What is Multiple Endocrine Neoplasia?

A
  • These are a group of 3 inherited disorders (autosomal dominant), whereby there is a predisposition to develop cancers of the endocrine system
263
Q

What is MEN1?

A
  • (3Ps): Pituitary, Pancreatic (e.g. insulinoma), Parathyroid (hyperparathyroidism)
264
Q

What is MEN2a?

A
  • (2Ps, 1M): Parathyroid, Phaeochromocytoma, Medullary thyroid
265
Q

What is MEN2b?

A
  • (1P, 2Ms): Phaeochromocytoma, Medullary thyroid, Mucocutaneous neuromas (& Marfanoid)
266
Q

What does deficiency in Vitamin A cause?

A
  • Colour blindness
267
Q

What does excess Vitamin A cause?

A
  • Exfoliation

- Hepatitis

268
Q

What does deficiency in Vitamin D cause?

A
  • Osteomalacia/rickets
269
Q

What does excess Vitamin D cause?

A
  • Hypercalcaemia
270
Q

What does deficiency in Vitamin E?

A
  • Anaemia
  • Neuropathy
  • Malignancy
  • IHD
271
Q

How are Vit ADE tested?

A
  • Serum
272
Q

What does Vit K deficiency cause?

A
  • Defective clotting
273
Q

How is Vit K tested?

A
  • PTT

Year 5 Path (3 decks)

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