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Y5 Pathology > Chemical > Flashcards

Chemical Flashcards

1
Q

Where is calcium taken in through???

A

The gut

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2
Q

Where is calcium excreted through?

A

The kidneys

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3
Q

Where is calcium stored?

A
  • 99% in bones
  • 1% in the blood
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4
Q

What are the roles of calcium?

A
  • Skeleton
  • Action Potentials/Nerves/Muscles
  • Intracellular Signalling
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5
Q

What forms of calcium are present in the serum?

A
  • Free/Ionised = 50% = Biologically Active
  • Protein Bound = 40% = Albumin
  • Complexed = 10% = In Citrate or Phosphate
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6
Q

Normal Serum Calcium?

A

2.2-2.6 mmol/L

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7
Q

What is corrected calcium?

A
  • takes into account albumin level (low albumin will cause the appearance of more ‘apparent calcium’ as more is free - usually reported and more accurate measure - Serum Ca + 0.02 x (40-serum albumin)
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8
Q

Describe the homeostatic response to low calcium.

A
  1. Hypocalcaemia detected by parathyroid gland
  2. Releases PTH
  3. PTH obtains calcium
  • Bone (osteoclasts activated)
  • Gut (absorption through Vit D activation)
  • Kidney (resorption and renal 1-alpha hydroxylase activation)
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9
Q

What 2 hormones are most important in calcium homeostasis?

A
  • PTH
  • Vitamin D
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10
Q

Describe the mechanism of PTH?

A
  • Released from parathyroid glands
  • Activates osteoclasts and Vit D synthesis
  • Stimulates renal phosphate excretion
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11
Q

What are the sources of Vitamin D?

A

Sunlight and Diet - Sun converts cholesterol in skin to cholecalciferol (Vit D3) - Cholecalciferol (Vit D3) is also sourced from food

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12
Q

How is Vitamin D activated?

A
  1. Cholecalciferol (Vit D3) is hydroxylated in the liver to form 25-hydroxycholecalciferol (inactive) - stored in the blood/what is measured
  2. PTH activates this in the kidney into 1,25-dihydroxycholecalciferol (active)
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13
Q

What pathology exists where active Vitamin D is made in locations other than the kidney?

A

Sarcoid tissue - ectopic alpha hydroxylase is expressed in lung cells

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14
Q

What happens to Vitamin D in pancreatic failure?

A
  • Reduced absorption of dietary Vit D
  • Low 25-hydroxycholecalciferol causes secondary hyperparathyroidism (high PTH)
  • High 1,25-hydroxycholecalciferol (any remaining 25-hydroxy is converted)
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15
Q

What happens to Vitamin D in chronic renal failure?

A
  • Low 1-alpha hydroxylase
    • High 25-hydroxycholecalciferol
    • Low 1,25-dihydroxycholecalciferol
    • Secondary and tertiary hyperparathyroidism (high PTH)
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16
Q

What happens to Vitamin D in Vitamin D resistance?

A
  • High 25-hydroxy
  • High 1,25-dihydroxy
  • High PTH
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17
Q

What happens to Vitamin D in hypoparathyroidism (post-surgery)?

A

Low PTH - High 25-hydroxycholecalciferol - Low 1,25-hydroxycholecalciferol

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18
Q

What happens to Vitamin D in sarcoidosis?

A
  • Ectopic 1-alpha hydroxylase
  • High 1,25-dihydroxycholecalciferol
  • High calcium
  • Low PTH
  • (High ALP if liver involved)
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19
Q

What are the primary roles of Vitamin D?

A
  • Intestinal calcium absorption
  • Intestinal phosphate absorption
  • Bone formation
  • (osteoclasts release calcium into blood which activates osteoblasts)
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20
Q

What does high ALP indicate?

A

Bone disease - Produced by osteoblasts

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21
Q

What happens to ALP in multiple myeloma?

A

Normal ALP - osteoblasts are not affected/only osteoclasts affected

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22
Q

What is the biochemical role of the skeleton?

A
  • Metabolic role in calcium homeostasis
  • Main reservoir of calcium, phosphate and magnesium
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23
Q

Define osteoporosis.

A

Reduced bone mass due to reduced calcium

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24
Q

What happens to bone structure in osteoporosis?

A

Normal structure and quality just at a lower quantity/density

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25
Q

What are the 2 types of osteoporosis?

A

High turnover = high bone resorption

Low turnover = low bone formation

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26
Q

What are the primary causes of osteoporosis?

A
  • Age
  • Post-menopausal
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27
Q

What are the secondary causes of osteoporosis?

A
  • Drugs
  • Systemic disease
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28
Q

What are the risk factors for osteoporosis?

A

Lack of oestrogen in a female

Caucasian, Asian Old

Age

Family history/Genetics

Immobilisation

Smoking, drugs, alcohol

Low weight

Chronic medical conditions

Endo diseases

Medication - steroids, thyroxine replacement

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29
Q

What is the consequence of long-term steroids on the bones?

A

Decreased bone quantity leading to osteonecrosis or fractures

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30
Q

What is the presentation of osteoporosis?

A
  • Pathological Fracture - colic, hip, pelvis, vertebrae
  • May have back pain due to a fracture
  • Usually asymptomatic until a fracture occurs
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31
Q

What investigations are appropriate for suspected osteoporosis?

A

Bloods - calcium, phosphate, PTH and ALP are normal (ALP may be high if recent fracture) Urine - high urinary calcium Imaging/X-ray DEXA

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32
Q

What DEXA score is considered osteoporosis and osteopenia?

A

Osteoporosis = T score < -2.5 Osteopenia = T score -1 to -2.5

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33
Q

Define T score and Z score in DEXA scans.

A
  • T score = relative to mean of young healthy pop (age 30)
  • Z score = relative to mean of aged-matched control
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34
Q

What is the treatment of osteoporosis?

A
  1. Lifestyle - weight-bearing exercise, stop smoking, reducing alcohol
  2. Drugs - Vit D, bisphosphonates, strontium, oestrogen, SERMs
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35
Q

What is the mechanism of bisphosphonates?

A

Inhibits bone resorption (and also formation)

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36
Q

What are the side effects and contraindications of bisphosphonates?

A

Side effects

  • Upper GI irritation/oesophageal damage

Contraindications

  • Pregnancy/breastfeeding (affect foetal skeleton development)
  • Hypocalcaemia
  • Very low GFR
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37
Q

How are bisphosphonates used in osteoporosis?

A

Prevention and treatment

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38
Q

How is strontium ranelate used in osteoporosis?

A

Prevention against vertebral and hip fractures

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39
Q

How are SERMs used in osteoporosis?

A

Prevention against vertebral fractures in established osteoporosis

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40
Q

How are parathyroid hormone peptides used in osteoporosis?

A

Reduce the risk of vertebral fractures

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41
Q

How is denosumab used in osteoporosis?

A

Prevention against fracture in post-menopausal women

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42
Q

What is the mechanism of denosumab?

A
  • Monoclonal antibody against RANKL on osteoblasts
    • Reduces osteoclast activity thereby increasing bone density
    • SC injection every 6 months
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43
Q

What 4 organs are affected by PTH?

A
  • Parathyroid glands
  • Kidneys
  • Bone
  • Proximal small intestine
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44
Q

Define Osteomalacia.

A

Defective bone mineralisation due to deficiency of vitamin D or calcium.

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45
Q

What are the 2 types of osteomalacia?

A

Vitamin D deficiency

Phosphate deficiency

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46
Q

Describe bones in osteomalacia.

A
  • Abnormal bones
  • De-mineralised bone structure - weakers bones
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47
Q

What does Vitamin D deficiency cause?

A

Adults - osteomalacia Children - rickets

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48
Q

What are the risk factors for Vitamin D deficiency?

A
  • Lack of sunlight exposure
  • Dark skin
  • Diet
  • Malabsorption (pancreatic, cystic fibrosis)
  • Anticonvulsants (phenytoin)
  • Chronic liver disease
  • Pregnancy and breastfeeding
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49
Q

What are the clinical features of osteomalacia?

A

Bone and muscle pain/tenderness

Fractures

Proximal weakness

Bone deformities

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50
Q

What investigations are appropriate for suspected osteomalacia?

A

Bloods - low calcium, low phosphate, high PTH, high ALP Radiological - horizontal pseudofractures in Looser’s zone

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51
Q

What are the clinical features of osteomalacia?

A

Costochondral swelling

Widened epiphyses at wrists

Bowed legs

Myopathy

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52
Q

Define Paget’s disease.

A

Disorder of bone turnover resulting in excessive and abnormal bone remodelling

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53
Q

What are the 3 phases of Paget’s disease?

A
  1. Osteolytic - giant osteoclasts with multiple nuclei rapidly resorb bone
  2. Osteolyitc-osteosclerotic - combination of osteoclast/osteoblast activity resulting in the formation of mosaic patterned bone
  3. Quiescent osteosclerotic - bone formation continues but is woven and weak
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54
Q

What is the presentation of Paget’s disease?

A
  • May be asymptomatic
  • Intense localised pain of bones
  • Microfractures
  • Bony deformities/increased bone size
  • Warm bones (hypervascularity)
    • If affects tibia: can cause bowing
    • If affects spine: kyphosis
  • Nerve compression
  • Skull changes: can put medulla at risk
  • Haemodynamic changes, HF SOB - high output HF due to bone marrow infiltration of weak woven bone
  • Hearing lose
  • Sarcomas - rare
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55
Q

What are the signs of Paget’s disease on a head X-ray?

A
  • Osteoporosis circumscripta - large, well-defined lytic lesions
    • Cotton wool appearance - mixed lytic and sclerotic lesions of the skull
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56
Q

What are the appropriate investigations for suspected Paget’s disease?

A
  • X-ray
  • Bloods
    • Normal calcium and phosphate
    • High ALP and urinary hydroxyproline (both due to high osteoclast activity)
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57
Q

What types of hearing loss occurs in Paget’s disease?

A
  • Sensorineural (8th CN) - compression of nerve due to lesion
  • Conductive - disease affecting the ossicles
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58
Q

What examination allows you to determine whether hearing loss is sensorineural or conductive?

A
  • Weber’s test using tuning fork on the forehead
    • Usually air conduction > bone conduction so patient still hears sound when moved from bone to in front of ear
    • If conductive loss, BC > AC so patient won’t be able to still hear sound when moved
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59
Q

Define parathyroid bone disease.

A

Cancer of parathyroid which over-produces PTH and high levels of calcium resorption resulting in bone disease (combo of osteoporosis and osteomalacia)

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60
Q

Define renal osteodystrophy.

A
  • Increased bone resorption (osteitis fibrosa cystica)
    • Osteomalacia
    • Osteosclerosis
    • Osteoporosis
  • Growth retardation - In renal failure Vit D cannot be activated nor phosphate excreted
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61
Q

Define osteitis fibrosa.

A

Primary hyperparathyroidism causes osteoclast resorption of calcified bone - bone is replaced by fibrous tissue

Can lead to fractures

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62
Q

What are the most common differentials of hypercalcaemia?

A
  • Cancer - most common
  • Primary hyperparathyroidism
  • Sarcoidosis
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63
Q

What are causes of hypercalcaemia with raised or inappropriately high PTH?

A
  • Hyperparathyroidism - tumour most common
  • Familial hypocalciuric hypercalcaemia
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64
Q

What are causes of hypercalcaemia with appropriate PTH?

A
  • High ALP
    • Malignancy
    • Ectopic PTH or metastases
    • Thyrotoxicosis
    • Sarcoid = lung expression of renal 1-alpha hydroxylase
  • Normal ALP
    • Myeloma
    • Vit D excess - sunbeds
    • Milk alkali syndrome
    • Thiazide diuretics
    • Sarcoidosis
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65
Q

Describe the biochemistry of primary hyperparathyroidism.

A
  • High or inappropriately normal PTH
  • High calcium
  • Low phosphate
  • Normal vitamin D (can be low as it is activated and consumed)
  • High or normal ALP
  • High urinary calcium
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66
Q

What are the symptoms of primary hyperparathyroidism?

A
  • Asymptomatic or present with depression
  • Polyuria and polydipsia (nephrogenic DI)
  • Bones - osteitis fibrosa cystica, bone resorption, fractures
  • Stones - calcium oxalate renal stones
  • Groans - constipation, acute pancreatitis, peptic ulcer
  • Moans - depression, psychosis
  • Neuro dysfunction
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67
Q

What are the signs of primary hyperparathyroidism on examination?

A
  • Band keratopathy - calcium deposition across front of eye (not present in malignancy)
  • Brown cell tumours - multi-nucleate giant cells (activated osteoclasts)
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68
Q

What is the inheritance pattern of Familial hypocalciuric hypercalcaemia?

A

Autosomal dominant - mutation in calcium sensor so cannot sense calcium

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69
Q

Describe the biochemistry of familial hypocalciuric hypercalcaemia.

A
  • Mild hypercalcaemia
  • Low urinary calcium
  • Normal or slightly high PTH
  • Slightly elevated magnesium
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70
Q

How must familial hypocalciuric hypercalcaemia not be managed?

A

Do not surgically remove

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71
Q

What are the risk factors for renal stones?

A
  • Family history
  • Dehydration
  • Hypercalciuria (without primary hyperparathyroidism)
  • Hypercalcaemia
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72
Q

What is the presentation of renal stones?

A
  • Colic pain - can moves down ureter
  • Haematuria
  • Recurrent infections/UTIs
  • Renal failure
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73
Q

What are the appropriate investigations for suspected renal stones?

A
  • KUB x-ray
  • Stone analysis
  • Urine and serum biochemistry
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74
Q

What is the treatment for renal stones?

A
  • Lithotomy (remove stones)
  • Lithotripsy (shock waves to break up stones)
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75
Q

How do you prevent the formation of renal stones?

A
  • Drink water
  • Treat hypercalcaemia
    • Thiazide diuretics to treat hypercalciuria
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76
Q

What are the acute treatments of hypercalcaemia?

A
  • Fluids
  • Furosemide
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77
Q

What are the non-acute treatments of hypercalcaemia?

A
  • Bisphosphonates
  • Surgery
  • Avoidance of thiazides
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78
Q

What are the clinical features of hypocalcaemia?

A
  • Neuro-muscular excitability
    • CATs go numb
      • Convulsions
      • Arrythmias
      • Tetany
      • Numbness
    • Perioral paraesthesia
      • Carpal spasm (provoked using BP cuff)
      • Trousseau’s sign
      • Chvostek’s sign = tap cheek (facial nerve just anterior to external auditory meatus) = ipsilateral facial contraction
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79
Q

What is the treatment of hypocalcaemia?

A

Mild = calcium (Alfacalcidol in chronic renal disease)

Severe = IV 10% Calcium gluconate

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80
Q

What are causes of hypocalcaemia with high PTH?

A
  • Secondary hyperparathyroidism
  • Vit D deficiency
  • CKD
    • Can progress to tertiary hyperparathyroidism
  • Calcium malabsorption
  • Pseudohypoparathyroidism
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81
Q

What are causes of hypocalcaemia with low PTH?

A
  • Surgical
    • Post parathyroid removal or thyroid removal
  • Autoimmune hypoparathyroidism
    • Congenital absence of parathyroid e.g. Di George syndrome
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82
Q

What are the features of the atherosclerotic lesions?

A
  • Fibrous cap Foam cells
  • Macrophages full of cholesteryl ester (can leak out)
  • Necrotic core
    • Full of cholesterol crystals deposited by dead macrophages
  • Released enzymes that hydrolyse cholesteryl ester into free cholesterol which then crystallises
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83
Q

How is cholesterol transported?

A

Plasma lipoproteins

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84
Q

What are the different types of lipoproteins?

A

Chylomicrons (largest) - <5% (high in TGs) VLDL - 13% (high in TGs) LDL - 70% (main carrier of cholesterol) HDL - 17% (smallest)

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85
Q

What are the sources of cholesterol?

A

Diet and Bile

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86
Q

How is cholesterol level regulated?

A

Amount being absorbed by the liver

  • The amount regulates the activity of HMG-CoA reductase
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87
Q

What happens to cholesterol once it has been absorbed or synthesised?

A
  1. Hydrolysis by 7a-OHxylase to form bile acids which enter the bile duct
  2. Esterified by ACAT - cholesterol ester which together with TG and apoB - incorporated into VLDL via MTP which is important in the packaging process
    1. VLDL is the main precursor of LDL
    2. LDL after circulating in the plasma for 3-4 days is taken up into the liver by LDL receptor
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88
Q

What is the role of HDL lipoproteins?

A

Collects cholesterol from peripheral cells (not liver) - Good cholesterol

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89
Q

What is the role of LDL lipoproteins?

A

Transports cholesterol to the peripheries (not the liver)

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90
Q

How are triglycerides transported in the plasma?

A

Chylomicrons = <5% VLDL = 55% LDL = 29% HDL = 11%

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91
Q

What are the sources of triglycerides?

A
  • Diet - major source
  • Chylomicrons (into free fatty acids) - hydrolysed by enzymes
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92
Q

Where are free fatty acids stored?

A

Liver and adipose tissue

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93
Q

Name 4 types of hypercholesterolaemia.

A
  • Primary hypercholesterolaemia - FH ect
  • Polygenic hypercholesterolaemia
  • Familial hyper-a-lipoproteinaemia
  • Phytosterolaemia
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94
Q

What is FH?

A

A dominant mutation of LDL receptor, apoB or PCSK9 genes - Rarely autosomal recessive inheritance of LDLRAP1

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95
Q

What are the signs of FH?

A
  • Homozygous FH = corneal arcus in young children
    • Very uncommon 1 in 1,000,000
  • Heterozygous FH = corneal arcus with xanthalasma around eyes, tendon xanthoma are all tell-tale signs
    • More common 1 in 500
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96
Q

What is the role of the proteins produced from the PCSK9 genes?

A
  • Bind to LDL receptor and promote its degradation - if mutated there is an increase in the rate of degradation of LDL
    • Therefore increasing high LDL circulating
  • Is a novel drug target if this mutation is found
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97
Q

What is polygenic hypercholesterolaemia?

A

Multiple loci including NPC1L1, HMGCR, CYP7A1 polymorphisms Each have a small effect which gives a large combined effect

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98
Q

What is hyper-a-lipoproteinaemia?

A

An increase in HDL - relatively benign presentation in terms of CV disease Sometimes associated with a CETP deficiency

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99
Q

What is phytosterolaemia?

A

Mutations of ABC G5 and G8 (gate keepers)

  • Plant sterols can enter the plasma and there is premature risk of atherosclerosis
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100
Q

What is type I primary hypertriglyceridaemia?

A

Deficiency in lipoprotein lipase that degrades chylomicrons of apoC II

  • In standing blood chylomicrons float on the top
  • Patients may have eruptive xanthomas on skin (pustules/ papules)
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101
Q

What is type IV primary hypertriglyceridaemia?

A
  • Increased synthesis of TG
    • No chylomicrons floating to the top but there is VLDL seperates
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102
Q

What is type V primary hypertriglyceridaemia?

A

apoA V deficiency - VLDL and chylomicrons above on standing blood

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103
Q

What are the causes of mixed hyperlipidaemia?

A
  • Primary mixed hyperlipidaemia
    • Familial combined hyperlipidaemia
    • Familial hepatic lipase deficiency
    • Familial dys-b-lipoproetinaemia
  • Secondary hyperlipidaemia
    • Hormonal factors - pregnancy, hypothyrodism ect
    • Metabolic - diabetes, gout, storage disorders
    • Renal dysfunction - nephrotic syndrome, CKF
    • Obstructive liver disease
    • Toxins
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104
Q

What are the causes of hypolipidaemia?

A
  • AB lipoproteinaemia
  • HypoB-lipoproteinaemia
  • Tangier disease
  • Hypo-a-lipoproteinaemia
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105
Q

Describe AB lipoproteinaemia.

A
  • Recessive MTP deficiency
  • Gives rise to extremely low levels of cholesterol
  • Extremely rare
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106
Q

Describe HypoB-lipoproteinaemia.

A
  • Truncated ApoB
  • Autosomal dominant
  • Causes low LDL
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107
Q

Describe Tangier disease.

A

HDL deficiency caused by ABC A1 mutations (mediates the movement of cholesterol from peripheral cells into HDL)

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108
Q

Describe the process of atherosclerosis formation.

A
  1. LDL becomes oxidised once penetrated the vascular wall 2. Oxidised LDL is taken up by macrophages and the cholesterol in LDL becomes esterified = foam cells - Lipid rich coronary plaques can rupture - Thrombus can heal - Mural intraluminal thombus and intraintimal thrombus - Occlusive intraluminal thrombus
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109
Q

What is the mechanism of statins?

A

HMG-CoA reductase inhibitors - Reduce LDL cholesterol - Slight increase in HDL - Small reduction in TG

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110
Q

What is the mechanism of fibrates?

A

PPAR activation

  • Not great at redcuing LDL cholesterol
  • Good at raising HDL
  • Very good at lowering TG
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111
Q

What is the mechanism of ezetimibe?

A

Cholesterol absorption blocker at NPC1L1 transporter in the intestine - Reduce LDL

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112
Q

What is the mechanism of colestyramine?

A

Ion exchange resin that binds bile acids (made from cholesterol hence reducing circulating levels) - Reduces LDL

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113
Q

Name 2 licensed novel LDL-lowering therapies.

A

MTP inhibitor - lomitapide - Replicates symptoms of AB-lipoproteinaemia such as impaired fat absorption and fatty liver Anti-PCSK9 monoclonal antibody - REGN727

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114
Q

Name 2 licensed novel HDL-based therapies.

A
  • Apoliprotein A1 or A1 mimetic infusion therapy
  • CETP inhibitors
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115
Q

What are the treatment of obesity?

A
  • Hypocaloric diet and exercise
  • Drug/Iatrogenic malabsorption = Orlistat - Pancreatic lipase inhibitor
    • Causes steatorrhea
  • Bariatric surgery
    • BMI >40kg/m2
    • Success is >50% reduction in weight
    • Reduces diabetes by 72%
    • Reduces serum TG by 60%
    • Increases HDL by 47%
    • Reduces fatty liver and hypertension
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116
Q

Describe the 3 approaches of bariatric surgery.

A
  • Gastric banding - size of stomach reduced to increase satiety after a meal
  • Roux-en-Y gastric bypass - distal part of the jejunum is anastomosed to the stomach
  • Biliopancreatic diversion - stomach is reduced in size and a connection is made straight from the stomach to the terminal ileum
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117
Q

Define hyponatraemia.

A

Serum calcium <135 mmol/L

  • Most common electrolyte abnormality in hospitalised patients (25%)
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118
Q

What is the underlying pathogenesis of hyponatraemia?

A

Increased extracellular water

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119
Q

Describe ADH.

A

Synthesised in hypothalamus

Secreted from posterior pituitary, acts on CD in the kidney via the insertion of aquaporin 2 (AQA2)

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120
Q

What is the mechanism of ADH?

A
  1. Acts on V2 receptors in collecting duct via the insertion of AQA2
  2. V1 receptors - found on vascular smooth muscle causing vasoconstriction - only occurs at very high concentrations (gives the alternative name “Vasopressin”)
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121
Q

What are the 2 main stimuli for ADH secretion?

A

High serum osmolality – mediated by hypothalamic osmoreceptors

Low blood volume/pressure – mediated by baroreceptors in carotids, atria, aorta

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122
Q

What are the effects of ADH on serum sodium?

A

Hyponatraemia/Low sodium - ADH only absorbs water (not any sodium)

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123
Q

What is the first step in the management of a hyponatreamic patient?

A

Cclinical assessment of volume status

  • Hypovolaemia, euvolemia, hypervolaemia
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124
Q

What are the clinical signs of hypovolaemia?

A
  • Tachycardia
  • Postural hypotension
  • Dry mucous membranes
  • Reduced skin turgor
  • Confusion or drowsiness
  • Reduced urine output
  • Low urine Na+ (<20 mEq/L)
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125
Q

What is the normal range of urine sodium?

A

40-220 mEq/L

  • <20 non-renal loss
  • >20 in renal loss
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126
Q

What medication can cause unreliable urine sodium?

A

Diuretics

  • Hypovolaemic but no hyponatraemia
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127
Q

What are the clinical signs of hypervolaemia?

A

Raised JVP

Bi-basal crackles

Peripheral oedema

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128
Q

What are the causes of hyponatraemia in a hypovolaemic patient?

A

Diuretics

Diarrhoea

Vomiting

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129
Q

How does hypovolaemic hyponatraemia occur?

A
  1. Start euvolaemia
  2. Hypovolemia quickly develops causing a release of ADH
  3. ADH causes water retention and dilutes Na+ conc
130
Q

What are the causes of hyponatraemia in a hypervolaemic patient?

A

Cardiac failure

Cirrhosis

Renal failure

  • All cause excess water and excess ADH

NOTE - don’t forget psychiatric induced hyponatreamia due to excess water consumption

131
Q

How does cardiac failure cause hyponatraemia?

A
  1. Low pressure due to reduced cardiac output
  2. Detected by baroreceptors which causes ADH release
132
Q

How does cirrhosis cause hyponatraemia?

A
  1. Vasodilation due to excess NO
  2. Reduced BP
  3. Detected by baroreceptors which causes ADH release
133
Q

How does renal failure cause hyponatraemia?

A

Reduced water excretion leads to reduced Na+ conc

134
Q

What are the causes of hyponatraemia in a euvolaemic patient?

A

Hypothyroidism

Adrenal insufficiency

SIADH

135
Q

How does hypothyroidism cause hyponatraemia?

A
  1. Reduced cardiac contractility
  2. Reduced BP
  3. Sensed by baroreceptors which trigger ADH release
136
Q

How does adrenal insufficiency cause hyponatraemia?

A

Less aldosterone so less Na+ reabsorption

137
Q

How does SIADH cause hyponatraemia?

A
  1. Excess ADH is released
  2. Water is retained due to action on AQA2
  3. The increased volume suppresses RAAS therefore reducing aldosterone release
  4. Less Na+ is reabsorbed
138
Q

What are the causes of SIADH?

A
  • CNS pathology – stroke, haemorrhage, tumour
  • Lung pathology – pneumonia, pneumothorax
  • Drugs – SSRI, TCA, PPI, carbamazepine, opiates
  • Tumours
  • Surgery
139
Q

What investigations must be ordered for a euvolaemic hyponatraemia?

A
  • Hypothyroidism → thyroid function tests
  • Adrenal insufficiency → short SynACTHen test
  • SIADH → plasma and urine osmolality → low plasma and high urine osmolality
140
Q

How is a diagnosis of SIADH made?

A
  • Hypovolaemia, hypothyroidism and adrenal insufficiency all ruled out
  • Reduced plasma osmolality (resorbing lots of water)
  • Increased urine osmolality - >100mEq/L (concentrating the urine)
141
Q

What is the management of hypovolaemic hyponatraemia?

A

Volume replacement with 0.9% saline

142
Q

What is the management of euvolaemic hyponatraemia?

A

Fluid restriction (<500-1000ml/day + ABx infusions)

Treat underlying cause

143
Q

What is the management of hypervolaemic hyponatraemia?

A

Fluid restrict (<500-1000ml/day + ABx infusions)

Treat underlying cause

144
Q

What are the additional signs of severe hyponatraemia?

A
  • Reduced GCS
  • Seizures
145
Q

What is the management of severe hyponatraemia?

A

Hypertnoic 3% saline

  • Must also seek expert help
146
Q

Why must sodium not be corrected to quickly?

A

Can cause Central Pontine Myelinolysis

147
Q

What is the maximum rate that sodium should be corrected in the first 24 hours?

A

8-10mmol/L

148
Q

What is Central Pontine Myelinolysis?

A

Rapid rise in sodium concentration is accompanied by the movement of small molecules and pulls water from brain cells.

This shift in water and brain molecules leads to the destruction of myelin

  • Rapid sodium correction is the biggest cause
149
Q

What are the signs and symptoms of Central Pontine Myelinolysis?

A

Quadriplegia

Dysarthria

Dysphagia

Seizures

Coma

  • Can cause death
150
Q

What is the management of SIADH?

A
  • Demeclocycline - induce nephrogenic diabetes insipidus
    • Reduces responsiveness of collecting tubule cells to ADH
    • Requires monitoring of U&Es as risk of nephrotoxicity
  • Tolvaptan – V2 receptor antagonist
151
Q

Define hypernatraemia?

A

Serum Na+ >145mmol/L

152
Q

What are the causes of hypernatraemia?

A

Increase in sodium

  • Medical/dietary high intake (hypertonic saline, sodium bicarbonate)
  • Conn’s syndrome/Bilateral Adrenal Hyperplasia
  • Renal artery stenosis
  • Cushing’s syndrome (overactivation of MR by cortisol à aldosterone-like effect)

Loss of water

  • Renal losses - osmotic diuresis, diabetes insipidus
  • Non-renal losses - GI/sweat loss

Dehydration

153
Q

What are Conn’s syndrome and bilateral adrenal hyperplasia?

A
  • Conn’s = excess aldosterone secretion
  • BAH = hyperplasia of the adrenal glands causing increased aldosterone
154
Q

How does renal artery stenosis cause hypernatraemia?

A
  1. Low GFR from RAS causes low BP at juxtaglomerula apparatus
  2. Increased renin causes high aldosterone
155
Q

What is Cushing’s syndrome?

A

Excess cortisol

156
Q

How does Cushing’s syndrome cause hypernatraemia?

A

Overactivation of mineralocorticoid receptor by cortisol

  • Mineralocorticoid had an aldosterone-like effect
157
Q

What is diabetes insipidus?

A

Central = less ADH release Nephrogenic = reduced sensitivity to ADH

  • Solitary water losses causing hypovolaemia
  • Body compensates by resorbing more Na+ to reduce the water loss however water loss persists and so you get a hypovolaemic hypernatraemia
158
Q

What are the investigations for diabetes insipidus?

A

Exclude: diabetes mellitus (serum glucose), nephrogenic DI (hypokalaemia and hypercalcaemia), hyperaldosteronism (high plasma osmolality, low urine osmolality)

Water deprivation test

  • Normal = concentrated urine
  • No ADH = dilute urine
159
Q

What is the management of hypernatraemia?

A

Fluid replacement → dextrose (if the patient is also hypovolemic, then 0.9% saline and 5% dextrose water)

Treat underlying cause

160
Q

What is the managment of this patient?

70-year old man, 3-day history of diarrhoea, altered mental status, dry mucous membranes. Serum Na is 168mmol/L.

A

Correct water deficit → 5% dextrose

Correct ECF volume depletion → 0.9% saline

Serial Na+ measurements → every 4-6 hours

161
Q

What are the effects of diabetes mellitus on serum sodium?

A

Variable

  • Hyperglycaemia draws water out of cells leading to hyponatraemia
  • Osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatremia
162
Q

Does pitiutary failure cause hypotension? Explain your answer.

A

NO

  • loss of aldosterone causes hypotension - still produce aldosterone because the adrenal glands are intact
163
Q

Name the 6 pituitary hormones.

A

GH

Prolactin

TSH

LH

FSH

ACTH

164
Q

What hypothalamic hormones feed into the anterior pituitary hormones?

A
  • GHRH = GH
  • TRH = TSH, Prolactin
  • Dopamine = Prolactin (-ve feedback - only hormone that works this way)
  • LHRH/GnRH = LH, FSH
  • CRH = ACTH
165
Q

What symptoms/signs occur with pituitary failure?

A
  • Galactorrhoea
  • Amenorrhoea
  • Bitemporal hemianopia (if >1cm macroadenoma is the cause pressing on optic chiasm)
166
Q

How big does macroadenomas have to be to cause bilateral hemianopia?

A

>1cm

167
Q

What defines a prolactinoma?

A

A prolactin >6,000

168
Q

What are teh components of the combined pituitary function test (triple test)?

A
  • Insulin hypoglycaemic stress:
    • Increase CRF - increase ACTH - increase cortisol - increase glucose
    • Increase GHRH - increase GH - increase glucose
  • TRH:
    • Increase TRH - increase TSH, increase prolactin
  • GnRH/LHRH:
    • Increase LHRH/GnRH - increase LH, FSH
169
Q

What is important to monitor during the triple test (pituitary)?

A
  • Check glucose regularly
  • Ensure an adequate hypoglycaemia (<2.2mM)
  • If severe hypoglycaemia occurs (or unconsciousness), rescue patient with 50mL of 20% dextrose
170
Q

Describe the method of the triple test (pituitary).

A
  1. Fast patient overnight
  2. Ensure good IV access
  3. Weigh patient. and calculate dose of insulin required (0.15U/kg)
  4. Mix and IV. Inject the following (patient may vomit on injection):
    • Insulin 0.15U/kg
    • TRH 200mcg
    • LHRH/GnRH 100mcg
  5. Take bloods at 0, 30 and 60 minutes of glucose, cortisol, GH, LH, FSH, TSH, prolactin and T4
  6. Continue to take bloods at 90 and 120 minutes of glucose, cortisol and GH
171
Q

What is a contraindication of the triple test (pituitary)?

A
  • Patients at risk if they become hypoglycaemic
    • Cardiac risk factors - check ECG ect
    • Epilepsy
172
Q

What processes happen when a patient becomes hypoglycaemic?

A
  • Sympathetic activation occurs causing aggression (if patient needs glucose, this may be difficult so IV access prior to beginning helps)
  • Very low (<1.5mM), neuroglycopaenia may occur (patient loses consciousness/becomes confused)
    • Treat with 50ml of 20% dextrose
173
Q

How is severe hypoglycaemia treated?

A

50ml of 20% dextrose

174
Q

What is the normal response to triple test (pituitary)?

A
  • Glucose has dropped to <2.2mM (if not, give more insulin) and then recovers
  • Normal = Cortisol has reached 550nM and GH has reached 10IU/L
  • The glucose drop has raised the TRH stressor which has in turn stimulated prolactin
175
Q

What is response of a patient in pituitary failure to a triple test (pituitary)?

A
  • Reduced production of all hormones
176
Q

Which hormone needs urgent replacement due to pituitary failure?

A

Hydrocortisone

177
Q

What is the treatment of pituitary failure?

A
  • Hydrocortisone replacement
  • Thyroxine replacement
  • Oestrogen replacement
  • GH replacement
  • Dopamine agonists
    • Cabergoline or Bromocriptine – if prolactinoma is the cause it shrinks the tumour
178
Q

A 27 year old female presents with bitemporal hemianopia. On testing she has a 2cm pituitary adenoma and the following results. What does she have?

A

Non-functioning pituitary adenoma

  • Prolactin is high but lower than in prolactinoma (>6,000)
    • Adenoma presses on pituitary stalk
    • Dopamine prevented from reaching anterior pituitary
    • No -ve inhibition on prolactin release
    • Hyperprolactinaemia
179
Q

What is the treatment of non-functioning pituitary adenomas?

A
  • Hydrocortisone replacement
  • Thyroxine replacement
  • Oestrogen replacement
  • GH replacement
  • Cabergoline or Bromocriptine
    • Brings down prolactin and allows women to ovulate and men to be fertile
180
Q

A 28 year old man presents with bitemporal hemianopia. On testing he had persistantly high GH and a 2cm pituitary adenoma?

A

Acromegaly

181
Q

What tests should be ran for suspected acromegaly?

A
  • Oral glucose tolerance test (OGTT) - 75g of glucose then measure glucose in 2 hours
    • GH should drop with glucose
    • In acromegaly, you get a paradoxical rise in GH with glucose administration
  • IGF-1 (produced by the liver in response to GH which promotes tissue and bone growth)
182
Q

What is the treatment of acromegaly?

A
  • Pituitary surgery (the best treatment option)
  • Pituitary radiotherapy
  • Cabergoline
  • Octreotide (somatostatin analogue; good at reducing the size of the tumour)
183
Q

What is the normal range of serum sodium?

A

135-145 mmol/L

184
Q

What is the normal range of serum potassium?

A

3.5-5.3 mmol/L

185
Q

What is the normal range of serum urea?

A

2.5-6.7 mmol/L

186
Q

What is the normal range of serum creatinine?

A

70-100 umol/L

187
Q

What is the normal range of haemoglobin?

A

Men: 130-180 g/L

Women: 115-160 g/L

188
Q

What is the normal range of WBCs?

A

4-11 x109 cells/L

189
Q

What is the normal range of platelets?

A

150-400 x109 cells/L

190
Q

What hormones regulate serum potassium?

A

Angiotensin

Aldosterone

191
Q

Describe the renin-angiotensin-aldosterone system (RAAS).

A
  1. Angiotensinogen is converted to Ang-1 via renin from JGA
    • Renin released via
      • Low BP (in renal artery)
      • Low Na+ in macula dense by JGA
      • SNS beta-1 receptor activation
  2. Ang-1 converted to Ang-2 in the lungs via ACE
  3. Ang-2 acts on the adrenals to release aldosterone
  4. Aldosterone excretes K+ and increases Na+ retention
192
Q

What are the triggers of aldosterone release?

A
  • Angiotensin II
  • Potassium (high)
193
Q

What is the mechanism of aldosterone?

A
  1. Aldosterone ­increases the number of open Na+ channels in luminal membrane which
  2. Increased­ Na+ resorption
  3. This makes the lumen electronegative and creates an electrical gradient
  4. K+ is secreted into the lumen
194
Q

What are the main causes of hyperkalaemia?

A
  • Renal impairment – reduced renal excretion
  • Drugs – ACEi, ARBs, spironolactone
  • Low aldosterone
    • Addison’s disease
    • T4 renal tubular acidosis (low renin, low aldosterone)
  • Release from cells – rhabdomyolysis, acidosis
195
Q

What ECG changes are associated with hyperkalaemia?

A
  • Peaked T wave (early)
  • Broad QRS
  • Flat P-wave
  • Prolonged PR with bradycardia
  • Sine wave (latest)
196
Q

What is the management of hyperkalaemia?

A
  • 10mL 10% Calcium Gluconate - stabilise the myocardium
  • 100mL 250% Dextrose (drive K+ into cells)
  • 10U Insulin
  • Nebulised salbutamol
  • Tx underlying cause
197
Q

What are the causes of hypokalaemia?

A
  • GI losses - diarrhoea, vomiting, fistulas
  • Renal losse
    • MR excess - Hyperaldosteronism/Conn’s or Cushing’s
    • Increased Na+ delivery to DCT - diuretics, Bartter syndrome, Gitelman syndrome
    • Osmotic diuresis
  • Redistribution into cells
    • Insulin/insulinomas
    • Beta-agonists
    • Alkalosis
  • Rare causes - RTA T1, T2, Hypomagnesaemia
198
Q

How do diuretics cause hypokalaemia?

A
  1. Triple- or co-transporter is blocked
    • Triple = Loop diuretics (furosemide)
    • Co-transporter = Thiazides (bendroflumethiazide)
  2. Less Na+ is resorbed in the ascending LoH so more goes to the DCT
  3. More Na+ reaches and is absorbed in the DCT making a more electronegative nephron
  4. This results in loss of K+ down the electrochemical gradient through ROMK channels
199
Q

How does alkalosis cause hypokalaemia?

A
  1. Low H+
  2. Shifts K+ into cells in exchange for H+ via the H+/K+ anti-transporter causing hypokalaemia
200
Q

What are the clinical features of hypokalaemia?

A
  • Muscle weakness
  • Cardiac arrhythmias
  • Polyuria and polydipsia (nephrogenic DI from low K+ or a high Ca2+)
201
Q

What ECG changes are associated with hypokalaemia?

A
  • ST depression
  • Flat T waves
  • U waves
202
Q

What should patients with hypokalaemia and hypertension screened for and how is this done?

A
  • Conn’s syndrome
    • Aldosterone: Renin ratio - Conn’s = high aldosterone: renin ratio because aldosterone supresses renin
203
Q

What is the management of hypokalaemia?

A
  • Tx underlying cause (i.e. with spironolactone – a K+-sparing diuretic)
  • K+ = 3.0-3.5mmol/L
    • Oral KCl
    • 2 SandoK tablets, TDS, 48 hours then recheck K+
  • K+ = <3.0mmol/L
    • IV KCl
      • Maximum rate 10mmol/hour (rate >20mmol/hour irritates peripheral veins)
204
Q

Hyperkalaemia is a side-effects of which of the following:

Furosemide

Bendroflumethiazide

Salbutamol

Ramipril

A
  • Ramipril - ACEi blocks eventual aldosterone production, so less potassium excreted
    • Furosemide - blocks co-transporter so more Na+ to DCT /more Na+ resorbed, more K+ excreted
    • Bendroflumethiazide - blocks triple transporter so more Na+ to DCT/more Na+ resorbed, more K+ excreted
    • Salbutamol - causes hypokalaemia (shift K+ intracellularly)
205
Q

Hypokalaemia is a side-effects of which of the following:

Spironolactone

Furosemide

Indomethacin

Perindopril

A
  • Furosemide - blocks co-transporter so more Na+ to DCT/more Na+ resorbed, more K+ excreted
    • ​Spironolactone - aldosterone antagonist so less K+ excretion
    • Indomethacin - NSAID so renin blocker so less eventual aldosterone productio
    • Perindopril - ACEi so blocks eventual aldosterone production
206
Q

A 67-year-old man was started on bendroflumethiazide for hypertension 2 weeks ago. He has had D& V for 2 days. He has dry mucous membranes and decreased skin turgor.

Urea & electrolytes:

  • Na+: 129 mmol/L
  • K+: 3.5 mmol/L
  • Ur: 8.0 mmol/L
  • Cr: 100 μmol/L

What is the diagnosis and management of this man?

A

Hypovolaemia due to diarrhoea and nausea plus diuretics

  • 0.9% saline volume replacement
207
Q

A 57yo woman has breathlessness worse on lying flat. Her past medical history includes a Non-STEMI. She is on ramipril, bisoprolol, aspirin and simvastatin. She has elevated JVP, bi-basal crackles and bilateral leg oedema.

Urea & electrolytes:

  • Na+: 128 mmol/L
  • K+: 4.5 mmol/L
  • Ur: 8.0 mmol/L
  • Cr: 100 μmol/L

What is the diagnosis and management of this woman?

A

CCF causes low BP then ADH release - hyponatraemia and hypervolaemia

  • Fluid restrict to 1L or 1.5L
  • Treat the underlying cause
208
Q

A 55-year-old man has jaundice. He has a past history of excessive alcohol intake. He has multiple spider naevi, shifting dullness and splenomegaly.

Urea & electrolytes:

  • Na+: 122 mmol/L
  • K+: 3.5 mmol/L
  • Ur: 2.0 mmol/L
  • Cr: 80 μmol/L

What is the diagnosis and management of this man?

A

Liver failure (cirrhosis causes NO release, BP down, ADH which in turn causes portal HTN and the clinical features of splenomegaly and spider naevi)

  • Fluid restriction
  • Tx underlying cause
209
Q

A 40yo woman presents with fatigue, weight gain, dry skin and cold intolerance. O/E she looks pale.

Urea & electrolytes:

  • Na+: 130 mmol/L
  • K+: 4.2 mmol/L
  • Ur: 5.0 mmol/L
  • Cr: 65 μmol/L

What is the diagnosis and management of this woman?

A

Hypothyroidism - euvolaemic

  • Thyroxine replacement
    • Na isn’t too low so no need to correct more than giving T4
210
Q

A 45-year-old woman presents with dizziness and nausea. On examination she looks tanned and has postural hypotension.

Urea & electrolytes:

  • Na+: 128 mmol/L
  • K+: 5.5 mmol/L
  • Ur: 9.0 mmol/L
  • Cr: 110 μmol/L

What is the diagnosis and management of this woman?

A

Adrenal insufficiency

  • Short SynACTHen test - administer synthetic ACTH and measure cortisol 30 minutes later - if minimal response, likely Addison’s
  • Management = hydrocortisone (steroid) and fludrocortisone (mineralocorticoid)
211
Q

A 62-year-old man has chest pain, cough and weight loss. He looks cachectic. He has a 30-pack-year smoking history.

Urea & electrolytes:

  • Na+: 125 mmol/L
  • K+: 3.5 mmol/L
  • Ur: 7.0 mmol/L
  • Cr: 85 μmol/L

What is the diagnosis and management of this man?

A

SIADH (small cell lung cancer) - plasma and urine osmolarity

  • Fluid restriction
212
Q

A 20yo man presents with polyuria and polydipsia. On examination he has bitemporal hemianopia.

Urea & electrolytes:

  • Na+: 150 mmol/L
  • K+: 4.0 mmol/L
  • Ur: 5.0 mmol/L
  • Cr: 70 μmol/L

What is the diagnosis, tests and management of this man?

A

Diabetes insipidus

  • Water deprivation test
  • Plasma and urine osmolarity
  • Exclude
    • DM - serum glucose
    • Hypercalcaemia - serum calcium
    • Hypokalaemia - serum potassium
  • Cranial - Desmopressin
  • Nephrogenic - dietary/reduced salt intake
213
Q

A 50-year-old man is referred with hypertension that has been difficult to control despite maximum doses of amlodipine, ramipril and bisoprolol.

Urea & electrolytes:

  • Na+: 140.0 mmol/L
  • K+: 3.0 mmol/L
  • Ur: 4.0 mmol/L
  • Cr: 70 μmol/L

What is the diagnosis of this man?

A

Conn’s - persistent hypertension

214
Q

A 16yo comes in unconscious after being acutely unwell a few days. He has been vomiting and breathless within this time.

Their ABG shows:

  • pH = 6.85
  • pCO2 = 2.3kPa
  • PO2 = 15kPa

What does the ABG show?

A

Metabolic acidosis

215
Q

What are the normal ranges of pH, CO2, bicarbonate and O2?

A
216
Q

Why does a patient with a low pH fall unconcious?

A

Brain enzymes cannot function at a low pH

217
Q

What is the osmolality formula?

A
  • Cations + Anions + Urea + Glucose
  • (Na + K) + (Cl + HCO3 + (PO4 + SO4 + etc) + Urea + Glucose
  • Osmolality = 2(Na + K) + U + G
218
Q

What is the normal plasma osmolality?

A

275-295 mOsmol/kg

219
Q

What is the osmolar gap formula? And what is the normal result?

A

Measured osmolarity – calculated osmolarity

  • <10mM
220
Q

What is the anion gap formula? And what is the normal result?

A

Anion gap = Na + K - Cl - Bicarb

  • 8 - 16mM
221
Q

Name 3 causes of increased anion gap?

A
  • Ketones
  • Methanol
  • Ethanol
  • Lactate
  • Metformin overdose
222
Q

A 19yo presents unconscious.

Their ABG shows:

  • pH = 7.65
  • pCO2 = 2.8kPa
  • Bicarb = 24mM (normal)
  • pO2 = 15kPa

What does the ABG show?

A

Respiratory alkalosis

223
Q

What is a likely diagnosis for a patient presenting with respiratory alkalosis and normal aniona gap?

A

Anxiety caused by hypoglycaemia due to primary hyperventilation

  • When pH increases, plasma proteins start to stick to calcium more than usual
  • Plasma calcium will appear normal, however, there will be less free ionised calcium
  • Fall in free ionised calcium will result in tetany making a patient hyperventilate more worsening the problem
224
Q

A 60yo man presents unconscious with a history of polyuria and poldipsia.

Their ABG shows:

  • Na = 160
  • K = 6.0
  • U = 50
  • pH = 7.30
  • Glucose = 60

What is the osmolality? What is the diagnosis?

A
  • 2(160+6) + 50 + 60 = 442mosm/kg (high osmolality – dehydrated)
  • Hyperosmolar hyperglycaemia state (HHS) from uncontrolled T2DM
    • Un concious due to dehydration
    • Not DKA as pH is reasonable/not really low
225
Q

What is the treatment for hyperosmolar hyperglycaemic state?

A
  • 0.9% saline (500-1,000mL/hour) slowly
    • Lots of fluid quickly causes cerebral oedema and death
  • Do not give insulin immediately (insulin will pull glucose into cells and dehydrate them even more)
226
Q

A 59yo on a good diet and metformin presents unconscious with urine -ve for ketones.

Their ABG shows:

  • Na = 140
  • K = 4.0
  • U = 4.0
  • pH = 7.10
  • Glucose = 4.0
  • PCO2 = 1.3kPa
  • Cl = 90
  • Bicarb = 4.0mM

What does the ABG show? And what would be a suspected diagnosis?

A

Metabolic acidosis

  • Metformin overdose
227
Q

What fracture would a patient most likely suffer from if they fall on a flex wrist?

A
  • Smith’s fracture = posterior displacement of the radius
    • Radius towards the back of the hand
    • Treated with manipulation under anaesthesia and plaster
228
Q

What fracture would a patient most likely suffer from if they fall on an extended wrist?

A
  • Colle’s fracture = anterior displacement of the radius
    • Radius towards the palm of the hand
229
Q

What is a Pott’s fracture?

A

Ankle fracture involving both tibia and fibula

230
Q

What are the complications of hypercalcaemia?

A
  • Renal stones
  • Peptic ulcer disease
  • Pancreatitis
  • Skeletal changes
  • Osteitis fibrosa cystica (i.e. pepper-pot skull)
231
Q

What are the risk factors for renal calcium stones?

A
  • FHx
  • Dehydration
  • Hypercalciuria
  • Hypercalcaemia
  • HPT
  • Recurrent UTI
232
Q

What are the signs and symptoms of renal calcium stones?

A
  • Pain
  • Haematuria
  • Recurrent infections - Proteus mirabilis
  • Renal failure
233
Q

What are the appropriate investigations for suspected renal calcium stones?

A
  • CT-KUB
  • Stone analysis
  • Urine and serum biochemistry
234
Q

What is the management of renal calcium stones?

A
  • Most stones will pass = Painkillers
    • PR diclofenac is very good
  • Lithotripsy
  • Cystoscopy
  • Lithotomy
235
Q

What is the prevention of renal calcium stones?

A
  • Drink more water
  • Treat hypercalciuria (e.g. thiazides)
  • Treat hypercalcaemia
236
Q

What does a hand x-ray show in a patient with hyperparathyroidism?

A
  • Often be normal
  • Later stages → may show cystic changes in the radial aspect
237
Q

What is the histology of hyperparathyroidism?

A
  • Brown tumours = multinucleate giant cells
    • Activated osteoclasts in the bone
      • Seen in long-standing undiagnosed HPT
  • Multinucleate giant cells
238
Q

What is the most helpful investigation for suspected sarcoidosis?

A

CXR → bilateral hilar lymphadenopathy

239
Q

What is the histology of sarcoidosis?

A

Non-caseating granulomas

240
Q

What is the treatment of sarcoidosis?

A

Steroids

241
Q

What is the mechanism of hypercalcaemia in sarcoidosis?

A
  1. Macrophages in the lungs express 1-alpha hydroxylase → activate vitamin D
  2. Vitamin D leads to excessive calcium
  • Patients more likely to become hypercalcaemic in summer months because of increased exposure to sunlight
242
Q

Where is ALP present in high concentrations?

A
  • Liver - esp. in bile ducts
  • Bone
  • Intestines
  • Placenta
243
Q

How are liver and bone ALP differentiated between?

A
  • GGT measurement
    • If GGT raised with ALP = implies ALP from liver
  • Electrophoresis separation
  • Bone-specific ALP immunoassay
244
Q

What are the causes of raised ALP?

A
  • Physiological
    • Pregnancy – 3rd trimester (from placenta)
    • Childhood – growth spurts
  • Pathological:
    • <5x upper limit:
      • Bone → tumours, fractures, osteomyelitis
      • Liver → infiltrative disease, hepatitis (doesn’t go up nearly as much as AST/ALT)
    • >5x upper limit:
      • Bone → Paget’s disease, osteomalacia
      • Liver → cholestasis, cirrhosis
245
Q

What are the causes of raised amylase?

A
  • Acute pancreatitis → very high → >10x upper limit
    • Pancreatic lipase → good marker of acute pancreatitis
  • Parotitis - produces by salivary glands
  • Peritonitis/Inflammatory bowel disease
246
Q

How is raised amylase from chronic pancreatitis and IBD be differentiated?

A
  • Chronic pancreatitis → measure faecal elastase
  • Inflammatory bowel disease → measure faecal calprotectin
247
Q

What are the 3 forms of creatine kinase?

A
  • CK-MM = skeletal muscles → responsible for almost the entire normal plasma activity
  • CK-MB = cardiac muscle
  • CK-BB = brain → activity is minimal even in severe brain damage
248
Q

What are the clinical features of statin-related myopathy?

A

Myalgia → Rhabdomyolysis

  • Mostly commonly with simvastatin when co-prescribed other medications involved in CYP3A4 - i.e. clarithromycin
  • CK-MM can help make the diagnosis (>x10 UL)
249
Q

A 64-year-old man who smokes and has a family history of cardiovascular disease has recently been started on atorvastatin. Three weeks after commencing the tablet, he complains of generalised muscle pain. What is the working clinical diagnosis?

A

Statin-related Myopathy

250
Q

What are the risk factors for statin-related myopathy?

A
  • Polypharmacy
    • Particularly fibrates, cyclosporin and drugs metabolised by CYP3A4
  • High doses
  • Genetic predisposition
  • Previous history of myopathy with another statin
  • Vitamin D deficiency
251
Q

What are the causes of raised creatine kinase?

A
  • Muscle damage due to any cause
  • Myopathy - >x10 Upper Limit
  • Myocardial infarction - >x10 UL
  • Statin-related myopathy - >x10 UL
  • Severe exercise - 5x UL
  • Physiological/Afro-Caribbean - <5x UL
252
Q

Describe troponins.

A
  • Present in contractile apparatus of the cardiac muscle and free cytosolic pool
  • Initially, troponins released from free cytosolic pool → then as contractile bundles break, there will be increased release of troponins
253
Q

What enzyme markers are there for a MI?

A
254
Q

When/How long is cardiac troponin raised following a MI?

A
  • Rise at 4-6 hours post MI
  • Peaks at 12-24 hours
  • Remains elevated for 3-10 days
  • Should be measured at 6 hours and again at 12 hours after the onset of chest pain
  • After 12-24 hours if there is no rise in troponin, then you have almost certainly not had an MI
    • Troponin at 12-24 hours
      • 100% sensitive
      • 98% specific
255
Q

What are the diagnostic criteria for an acute MI?

A
  • Typical rise and gradual fall in troponin or more rapid rise and fall in CK-MB with at least one of the following:
    • Ischaemic symptoms
    • Pathological Q waves on ECG
    • ECG changes of ischaemia
    • Coronary artery intervention
  • Pathological findings of an acute MI
256
Q

A 52-year-old man presented to his GP with a history of exercise-induced central chest pain which radiated to his left arm and neck a week ago. As the pain lasted for half an hour and subsided on rest he decided to not to go to his GP until today. He’s currently pain-free, and his ECG at the GP surgery was normal. Which biomarker measurement might be helpful with the diagnosis?

A

Troponin → stays up for 2 weeks

257
Q

What are the cardiac failure markers?

A
  • Natriuretic peptides
    • Atrial NP - secreted by atria
    • Brain NP - secreted by ventricles
      • Assess ventricular function
      • To exclude heart failure in a clinical setting
258
Q

What enzymes increase following a MI?

A
  • Troponins
  • CK-MB
  • Myoglobin
  • AST
  • LDH
259
Q

Define Rhabdomyolysis.

A

AKI from skeletal muscle damage and the corresponding release of myoglobin (myoglobin is extremely nephrotoxic).

260
Q

How is rhabdomyolysis prevented?

A

IV bicarbonate → allows extra excretion of CK

261
Q

Describe ALT and AST in patients with viral hepatitis.

A

ALT > AST

262
Q

Describe ALT and AST in patients with chronic alcoholic cirrhosis.

A

AST > ALT (2:1)

263
Q

What does a raised acid phosphatase indicate?

A

Prostate cancer

264
Q

What marker rises most in acute and chronic renal failure?

A
  • Acute = Urea - most likely to be caused by dehydration
  • Chronic = Creatinine - caused by a fall in GFR
265
Q

What are the indications for dialysis?

A
  • Refractory hyperkalaemia
  • Refractory fluid overload
  • Metabolic acidosis
  • Uraemic symptoms
    • Encephalopathy
    • Nausea
    • Pruritis
    • Malaise
    • Pericarditis
  • CKD stage 5 (GFR <15mL/min)
266
Q

What are the markers for glucose control in the last 3 weeks and 3 months?

A
  • Last 3 weeks = Fructosamine
  • Last 3 months = HbA1c
267
Q

What are the causes of increased ALP and osteocalcin?

A

Paget’s disease

268
Q

What are the features of Paget’s disease?

A
  • Asymptomatic
  • Bowed tibia
  • Warm bones
  • High risk of fracture
269
Q

What is the management of Paget’s disease?

A

Bisphosphonates → if painful

270
Q

Describe GFR and it naturally changes through life.

A
  • Best measure of kidney function = GFR
    • Normally = 120mL/minute or 7.2L/hour
  • There is an age-related decline of around 1 mL/min per year
271
Q

Define (Renal) Clearance.

A

Volume of plasma that can be completely cleared of a marker substance per unit time

272
Q

Describe (Renal) Clearance.

A
  • Clearance can be used to calculate GFR
  • 3 criteria/markers are needed to measure GFR:
    • Marker is not bound to serum proteins
    • Freely filtered by the glomerulus
    • Not secreted or reabsorbed by tubular cells
  • Clearance = (U x V)/P
    • U = urinary concentration
    • P = plasma concentration
273
Q

What is the gold-standard for measuring/calculating GFP?

A

Inulin clearance

  • Not endogenous
  • Freely filtered and not processed by the tubular cells → perfect marker
  • However, a steady state infusion is required, and measurement of inulin concentration is not simple
  • Thus, it is used as a research tool only
274
Q

What are the exogenous markers of GFR?

A
  • 51Cr-EDTA
  • 99Tc-DTPA
  • Iohexol
275
Q

How can exogenous markers of GFR be used to measure clearance?

A
  • Direct method = Urine collection to a gamma counter
  • Indirect method = Take blood samples and look at the progressive reduction in radioactivity
  • Not how GFR is measured on a day to day basis
  • Only used in special circumstances
276
Q

What are the endogenous markers of GFR?

A
  • Blood urea
  • Serum creatinine
277
Q

Describe blood urea as a marker of GFR.

A
  • A by-product of protein metabolism
  • Variable (30-60%) reabsorption by tubular cells - ideally you don’t want any reabsorption
  • Dependent on nutritional state, hepatic function, GI bleeding
  • Very limited clinical value
  • First endogenous marker of GFR
278
Q

Describe serum creatinine as a marker of GFR.

A
  • Derived from muscle cells
  • Freely filtered and actively secreted into the urine by tubular cells
  • Creatinine: GFR relationship is non-linear:
    • At lower GFRs, level of creatinine is less accurate at predicting precise GFRs
  • The rate of generation of creatinine is affected by:
    • Muscularity (proportional to mass)
    • Age
    • Sex (higher in men)
    • Ethnicity (higher in Afro-Caribbean)
279
Q

What adjustments can be used to the serum creatinine calculations of GFR?

A
  • Cockcroft-Gault adjustment [left]
    • Not the GFR directly - just creatinine
    • May overestimate low GFRs (<30mL/min)
  • Estimated GFR adjusted equation/MDRD [right]:
    • Complex equation derived from cohort studies
    • Requires information about age, sex, serum creatinine and ethnicity
    • May underestimate GFR if above average weight and young
  • CKD-Epidemiology Collaboration (CKD-EPI)
    • The equation is based on the same four variables as MDRD but models the relationship between GFR and serum creatinine, age, sex and race differently
      • Reduces bias at GFRs >60mL/min (but imprecise at higher GFRs)
      • Accurate at low GFRs and less accurate at high GFRs
280
Q

Describe cystatin C as an endogenous GFR marker.

A
  • An alternative endogenous marker
  • This is constitutively produced by all nucleated cells at a constant rate and is freely filtered
  • Almost completely reabsorbed and catabolised by tubular cells
  • NOTE: CKD NICE guidelines have included cystatin C, however, it is not used that frequently
281
Q

How is renal function measured in practice?

A
  • Urine examination:
    • Single sample
      • Dipstick testing
      • Protein:Creatinine ratio (PCR)
      • Microscopic examination
      • Proteinuria quantification
      • Electrolyte estimation
    • 24hour collection
      • Creatinine clearance estimation
      • Stone forming elements
      • (Proteinuria quantification)
282
Q

What is measured in urine dipstick testing?

A
  • pH = 4.5 to 8.0
  • Specific gravity = 1.003 to 1.035
  • Protein = sensitive to albumin, not BJPs = 0 → Trace → 1+ to 4+
  • Blood
  • Leucocyte esterase = negative reliably excludes bacteria
  • Nitrite = detects bacteria, esp. Gm negatives → cannot reliably excludes bacteria if -ve
283
Q

Describe urine microscopy.

A
  • Method = centrifuge at 3,000rpm for 5-10 minutes and examine the sediment
  • Examine for…
    • Crystals = calcium oxalate crystals
    • RBCs = ‘little doughnuts’
    • WBCs = ‘multi-nucleate cells’
    • Casts = ‘fuzzy burritos’
    • Bacteria = ‘wannabe RBCs’
284
Q

Case presentation:

  • 50yo, alcoholic
  • Presents unwell, seemingly intoxicated with AKI
  • Urine microscopy = calcium oxalate crystals

What is the diagnosis?

A
  • Diagnosis = ethylene glycol poisoning = Anti-freeze
  • Ethylene glycol metabolises to form calcium oxalate crystals
285
Q

What imaging is used to assess the kidneys?

A
  • 1st line: CT KUB
  • 2nd line: Ultrasound KUB
    • This can differentiate AKI and hydronephrosis
  • Plain KUB films (can show ‘staghorn calculi’)
  • IV urogram (done more in paediatrics to look for anatomical defects)
  • MRI KUB
  • Functional imaging (static and dynamic renograms)
    • IV radiolabelled nuclei are injected, and kidney uptake is measured
    • Any kidney not showing up on scans signifies a non-functional kidney
    • Renal biopsy is often necessary for various diagnoses (ultrasound or CT guided)
286
Q

What are the stages of AKI?

A
  • AKI Stage 1
    • Serum creatinine = Increase ≥26 µmol/L or 1.5-1.9x the reference
    • Urine output = <0.5mL/kg/hr, 6-12hr
  • AKI Stage 2
    • Serum creatinine = Increase 2.0-2.9x the reference
    • Urine output = <0.5mL/kg/hr, ≥12hr
  • AKI Stage 3
    • Serum creatinine = Increase ≥354 µmol/L or by ≥3x the reference
    • Urine output = <0.3mL/kg/hr, ≥24hr
287
Q

What are the causes of pre-renal AKI?

A
  • Volume depletion → e.g. haemorrhage
  • Hypotension
  • Oedematous state
  • Renal ischaemia → e.g. renal artery stenosis
  • Drugs affecting renal blood flow
    • ACE inhibitors or ARBs – reduce efferent constriction
      • ACEi are very contraindicated in RAS
    • NSAIDs or Calcineurin inhibitors – decrease afferent dilatation
    • Diuretics – affect tubular function, decrease preload
288
Q

What are the differences between pre-renal AKI and acute tubular necrosis?

A
  • Pre-Renal AKI is NOT associated with structural renal damage
    • Responds immediately to circulating volume restoration
    • However, a prolonged AKI insult → ischaemic injury → ATN
  • ATN does NOT respond to restoration of circulating volume
    • Epithelial cell casts would be seen in the urine on microscopy
289
Q

A 68-year-old man with previously normal renal function is found to have a creatinine of 624μmol/l. Renal ultrasound shows hydronephrosis in both kidneys. What is the likely cause AKI?

A

BPH

290
Q

How is renal blood flow able to stay constant over a huge range of pressures?

A
  • Myogenic Stretch
    • Afferent arteriole stretched due to high pressure stimulates constriction to reduce the transmission of that high pressure into the Bowman’s capsule
  • Tubuloglomerular Feedback
    • High chloride concentration in the early distal tubule stimulates constriction of the afferent arteriole which lowers GFR and reduced chloride level in the distal tubule
291
Q

What are the causes of post-renal AKI?

A
  • Intra-renal or Ureteric obstruction
  • Prostatic or Urethral obstruction
  • Blocked urinary catheter
  • Retroperitoneal fibrosis - Ormond’s disease
292
Q

What is the prognosis of post-renal AKI?

A
  • Immediate relief restores GFR with no structural damage
  • Prolonged obstruction results in:
    • Glomerular ischaemia
    • Tubular damage
    • Long-term interstitial scarring
293
Q

What are the causes of intrinsic renal AKI?

A
  • Vascular disease - e.g. vasculitis
  • Glomerular disease - e.g. glomerulonephritis
  • Tubular disease - e.g. ATN = MOST COMMON
  • Interstitial disease - e.g. analgesic nephropathy
    • Long-term excessive use of analgesics
294
Q

What are the stages of CKD?

A
295
Q

What are the causes of CKD?

A
  • Diabetes
  • Atherosclerotic renal disease
  • Hypertension
  • Chronic Glomerulonephritis
  • Infective or obstructive uropathy
  • Polycystic kidney disease
296
Q

What are the roles of the kidneys?

A
  • Excretion of water-soluble waste
  • Water balance
  • Electrolyte balance
  • Acid-base homeostasis
  • Endocrine functions (EPO, RAAS, Vitamin D)
    • 1a hydroxylase in kidneys – sarcoid macrophages express this à sarcoidosis hypercalcaemia
297
Q

What are the consequences of CKD?

A
  • Progressive failure of Homeostatic function
    • Acidosis
    • Hyperkalaemia
  • Progressive failure of Hormonal function
    • Anaemia
    • Renal bone disease
  • Cardiovascular disease
    • Vascular calcification (renal osteodystrophy)
    • Uraemic cardiomyopathy
  • Uraemia
  • Death
298
Q

Regarding hyperkalaemia, which of the following is true?

A. It can lead to ECG changes such as peaked p waves and flattened t waves
B. In those with CKD, dietary intake is a major cause and high potassium levels are found in food such as milk, chocolate, dried fruits and tomatoes
C. NSAIDs can lower potassium levels
D. Hyperaldosteronism is a common cause
E. All of the above

A

B. In those with CKD, dietary intake is a major cause and high potassium levels are found in food such as milk, chocolate, dried fruits and tomatoes

299
Q

What are the complications of renal acidosis?

A
  • Muscle and protein degradation
  • Osteopenia due to mobilisation of bone calcium
    • Protons can be stored in bone
  • Cardiac dysfunction
300
Q

What is the management of renal acidosis?

A

Oral sodium bicarbonate

301
Q

Describe anaemia of CKD.

A
  • Progressive decline in EPO-producing cells
  • Usually occurs when GFR <30 ml/min
  • Causes normochromic, normocytic anaemia
302
Q

What is the management of anaemia of CKD?

A
  • Artificial erythropoiesis-stimulating agents (ESAs)
    • Erythropoietin alfa (Eprex)
    • Erythropoietin beta (NeoRecormon)
    • Darbopoietin (Aranesp)
303
Q

What is the management of renal bone disease?

A
  • Phosphate control → dietary, phosphate binders
  • Vitamin D receptor activators
    • 1-alpha calcidol
    • Paricalcitol
  • Direct PTH suppression
    • Cinacalcet
304
Q

What are the 3 phases of uraemic cardiomyopathy?

A

LV hypertrophy → LV dilatation → LV dysfunction

305
Q

What are the treatments of CKD?

A
  • Transplantation
  • Haemodialysis
  • Peritoneal Dialysis
306
Q

Which of the following are contraindications to transplantation – True/False:

  • HIV
  • BMI >30
  • Active sepsis
  • Age >65yo
  • Malignancy
A
  • HIV = FALSE
  • BMI >30 = FALSE
  • Active sepsis = TRUE
  • Age >65yo = FALSE
  • Malignancy = FALSE
307
Q

Describe haemodialysis.

A
  • Blood is passed through a dialyser which removes most waste products
  • It is done about 3 x per week for around 6 hours
  • Can be done via home dialysis
308
Q

Describe peritoneal dialysis.

A
  • Peritoneal cavity is filled with fluid and the peritoneal membrane is used as the dialysing membrane
  • Increased risk of:
    • Beta-2 macroglobulin amyloidosis
    • Papillary renal cell carcinoma
  • This can be done at home
309
Q

What are the indications for dialysis?

A
  • Refractory hyperkalaemia
  • Refractory fluid overload
  • Metabolic acidosis
  • Uraemic symptoms
    • Encephalopathy, nausea, pruritis, malaise, pericarditis
  • CKD stage 5 - GFR <15mL/min
310
Q

What is the acute management of hypoglycaemia in adults

A
311
Q

Define Hypoglycaemia.

A
  • Hypoglycaemia
    • Hypoglycaemia = <4mmol/L
    • In diabetes = <3.5mmol/L - NR = 4.0-5.4mmol/L (fasting)
    • In paediatrics = <2.5mmol/L - NR = 4.0-7.8mmol/L (2-hour OGTT)
  • Wipple’s triad - new style of definition for hypoglycaemia
    • Symptoms can be:
      • Adrenergic
      • Neuroglycopaenic
      • None – tolerant due to recurrent hypos
    • Summary of triad:
      • Low glucose
      • Symptoms
      • Relief of symptoms upon treatment
312
Q

What physiological changes occur in hypoglycaemia (give in order)?

A
  1. Suppression of insulin
  2. Release of glucagon
  3. Release of adrenaline
  4. Release of cortisol
313
Q

What counter-regulations of blood glucose occurs?

A
314
Q

What are the appropriate investigations for suspected hypoglycaemia?

A
  • Glucose measurement
    • Venous glucose (gold standard)
    • Capillary glucose
    • Continuous glucose monitoring
  • Differentiating the causes of hypoglycaemia → must be done in period of hypoglycaemia
    • History and examination
    • Biochemical tests
      • Insulin levels - exogenous insulin interferes with assays
      • C-peptide - equimolar to insulin → LOOK AT PIC
      • Drug screen
      • Autoantibodies
      • Cortisol/GH
      • FFAs/blood ketones
      • Lactate
315
Q

What are the causes of hypoglycaemia in non-diabetic patients?

A
  • Critically unwell
  • Extreme weight loss
  • Factitious (i.e. an artefact)
  • Organ failure
  • Hyperinsulinism
  • Post-gastric bypass
  • Drugs
316
Q

What are the causes of hypoglycaemia in diabetic patients?

A
  • Medications - particularly insulin
  • Inadequate carbohydrate intake/missed meal
  • Impaired awareness
  • Excessive alcohol
  • Strenuous exercise
  • Co-existing autoimmune conditions
  • Co-morbidities
317
Q

What are the causes of neonatal hypoglycaemia?

A
  • Explainable → improve with feeding
    • Premature
    • Co-morbidities
    • IUGR / SGA
    • Inadequate glycogen and fat stores
  • Pathological
    • Inborn errors of metabolism
318
Q

What is the pathological finding for inborn metabolic disorder?

A

Low ketones

319
Q

What are the causes of inappropriately high insulin?

A
  • Drugs (sulphonylureas)
  • Islet cell tumours (e.g. insulinoma)
  • Islet cell hyperplasia
    • Infant of a diabetic mother
    • Beckwith-Wiedemann syndrome
    • Nesidioblastosis
  • Rare genetic forms of hyperinsulinism
  • Rare autoimmune disease
320
Q

Describe insulinomas.

A

Low glucose, High insulin, High c-peptide

  • Rare - 1-2 per million per year
  • Usually cause fasting hypoglycaemia
  • Usually a small solitary adenoma
    • 10% malignant
    • 8% associated to MEN1
  • Diagnosis on biochemistry and localisation
  • Treatment is simple resection
321
Q

Describe non-islet cell tumour hypoglycaemia.

A

Low insulin, Low insulin, Low c-peptide, Low FFA

  • FFA should be high if insulin is low → something pretending to be insulin (i.e. a paraneoplastic syndrome from secretion of big IGF-2)
    • Produced by
      • Mesenchymal tumours
        • Mesothelioma
        • Fibroblastoma
      • Epithelial tumours
        • Carcinoma
    • Big IGF-2 binds to IGF-1 receptors and insulin receptors → your own endogenous insulin production is switched off and FFA production is suppressed
322
Q

What is reactive/post-prandial hypoglycaemia occur and when does it occur?

A

Hypoglycaemia following food intake

  • After gastric bypass
  • Hereditary fructose intolerance
  • Early diabetes
  • In insulin-sensitive people post-exercise or large meals

Y5 Pathology (5 decks)

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