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Year 5 Pathology > Chemical Pathology > Flashcards

Chemical Pathology Flashcards

1
Q

Why is the level of calcium in the blood important?

A

Nerves and muscles rely on calcium for depolarisation

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2
Q

What is the normal range of calcium in the blood?

A

2.2 - 2.6mmol/l

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3
Q

What are the symptoms of hypercalcaemia?

A

Stones, bones, groans, moans + nephrogenic DI

o Polyuria or polydipsia

o Bones

o Stones

o Abdo - constipation

o Neuro – confusion, seizures, coma

o Unlikely unless Ca >3mmol/L (2.2-2.6)

o Overlap with symptoms of hyperPTH

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4
Q

What are the symptoms of hypocalcaemia?

A

Epilepsy (aberrant firing of nerves and muscles) – CATS go numb:

  • Convulsions
  • Arrhythmias
  • Tetany
  • Numbness in the hands and feet and around the mouth
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5
Q

Which form is calcium found in the body?

A

o Free, ionised calcium, biologically active - 50% maintain at a fixed level

o Protein-bound as albumin - 40%

An abnormal albumin affects the free calcium (e.g. in sepsis)
“Corrected ca” reported by labs
This compensates for albumin
Serum Ca + 0.02 x (40 – serum albumin (g/l))
In blood gas machines, ionised Ca can also be measured (around 1.1mmol/L)

o Complexed with citrate/phosphate - 10%

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6
Q

How can you detect if the problem is calcium or albumin?

A

o Bound calcium will be low, but free calcium is normal

o Corrected Ca refers to that (the corrected calcium can tell you what is wrong with albumin)

o So, if albumin = 30 and total Ca = 2.2

o Corrected Ca = 2.2 +(0.02 x 10) = 2.4mM

o So, corrected ca shows if the problem is albumin, and that ionised ca will be normal

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7
Q

What are the roles of PTH?

A

o 1 alpha hydroxylase activation –> calcidol to calcitriol –> gut effects

o Osteoclast activation - Ca2+ liberation

o Direct renal calcium resorption

o Direct renal phosphate excretion

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8
Q

Which two steroid hormones are involved in calcium metabolism?

A

PTH and Vitamin D (steroid hormone) are two key hormones involved in Ca homeostasis

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9
Q

Which enzyme activates vitamin D?

A

Vitamin D has 2 forms (types of alfacalcidol) – both activated by 1-alpha hydroxylase

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10
Q

What are the two types of vitamin D?

A

§ D3 → animal product, from sunlight hitting skin → cholecalciferol

§ D2 → plants → ergocalciferol

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11
Q

What is PTH?

A

84 aa protein; only released from parathyroid gland

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12
Q

Summarise the three roles of PTH

A

· Bone and renal Ca2+ resorption
· Stimulates 1,25 (OH )2 vitamin D synthesis (1α hydroxylation)
· Also stimulates renal phosphate wasting (in urine)

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13
Q

How would you measure vitamin D levels in the blood?

A

Measurement = 25-OH Vitamin D3

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14
Q

How is vitamin D processed in the liver?

A

o All of any absorbed vitamin D is hydroxylated at the 25 position

o Enzyme – 25 hydroxylase (100% of Vitamin D)

o 25 hydroxy vitamin D is inactive

o This is the stored and measured form of Vitamin D

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15
Q

How is vitamin D activated?

A

o Normally happens in the kidney; Enzyme – 1α hydroxylase

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16
Q

Why is vitamin D raised in sarcoidosis?

A

o Rarely, this enzyme is expressed in lung cells of sarcoid tissue
o Sarcoid = causes hypercalcemia (seasonal) – summer hypercalcemia
o In sunlight, calcium goes up (more vitamin D activation)

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17
Q

Describe the processing of vitamin D

A

Vitamin D3 / Cholecalciferol –> 25-hydroxy vitamin D3 –> under PTH –> 1, 25 dihydroxy vitamin D3 / Calcitriol

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18
Q

What is the role of 1,25 (OH)2 Vitamin D/Calcitriol?

A

o Intestinal Ca2+ absorption and intestinal phosphate absorption
o Critical for bone formation (with osteoblasts)
o Other physiological effects
§ Vitamin D receptor controls many genes – cell proliferation, immune system
§ Vitamin D deficiency associated with cancer, autoimmune disease, metabolic syndrome

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19
Q

What is vitamin D deficiency in children and adults?

A

Childhood → rickets

Adults → osteomalacia

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20
Q

What are the clinical features of osteomalacia?

A

· Bone and muscle pain
· Increase fracture risk
· Bio-chem → low Ca2+ + low phosphate and raised ALP
· Looser’s zones (pseudo fractures)

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21
Q

What are the clinical features of rickets?

A
  • Bowed legs
  • Costochondral swelling
  • Widened epiphyses at the wrists
  • Myopathy (weak muscles)
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22
Q

What are some risk factors of osteomalacia?

A

Renal failure
Anticonvulsants induce breakdown of Vitamin D (phenytoin)
Lack of sunlight
Chappatis – phytic acid (cause osteomalacia)

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23
Q

What is osteoporosis normally due to?

A

Reduced oestrogen levels

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24
Q

What is the biochemical presentation of osteoporosis?

A

Reduction in bone density but with a normal calcium and normal biochemistry

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25
Q

How is osteoporosis diagnosed?

A

Diagnosis using DEXA scan (dual energy X-ray absorptiometry):

  • Hip (femoral neck) and lumbar spine
  • T score – SD from mean of young healthy population – determine fracture (%) risk
  • Z score – SD from mean of age-matched control – identify accelerated bone loss in younger people
  • Osteoporosis – T score
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26
Q

How does osteoporosis normally present?

A

Asymptomatic until first fracture

Typically: Vertebral, Wrist (Colle’s)

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27
Q

What are some treatments of osteoporosis?

A
  • Vitamin D/Ca
  • Bisphosphonates (alendronate) – decrease bone resorption – osteonecrosis of jaw
  • Teriparatide – PTH derivative – anabolic
  • Strontium – anabolic + anti-resorptive
  • Oestrogens – HRT
  • SERMs (oestrogen-like drug) – raloxifene (like Tamoxifen)
  • Denosumab – biologic anti-RANK-L antibody
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28
Q

How can high albumin affect calcium levels?

A

High albumin = artificially elevated calcium levels

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29
Q

What is the most common cause of primary hyperparathyroidism?

A 
Parathyroid adenoma (80%)
MEN1, 2a
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30
Q

What are the calcium, PTH and phosphate levels in primary hyperparathyroidism?

A
  • Increased serum Ca
  • Increased or inappropriately normal PTH
  • Decreased serum phosphate
  • Increased urine calcium due to hypercalcemia
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31
Q

What would happen to calcium, PTH and phosphate levels in malignancy?

A
  • High calcium
  • Low phosphate
  • Low PTH – appropriate
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32
Q

How would you distinguish between malignancy and primary hyperparathyroidism?

A

Malignancy - low PTH

Primary hyperparathyroidism - raised or inappropriately normal PTH

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33
Q

What are the 3 types of malignancy where hypercalcaemia may be a sign?

A
  1. Humoral hypercalcaemia of malignancy – squamous cell lung cancer
    a. PTHrP
  2. Bone mets – breast cancer
    a. Local bone osteolysis
  3. Haematological malignancy – myeloma
    a. Cytokines
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34
Q

How is hypercalcaemia treated?

A
  • FLUIDS (0.9% saline, 1L/hour and reassess)
  • Treat underlying cause
  • Cinacalcet acid – activates CaSR
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35
Q

What are the signs and symptoms of hypocalcaemia?

A

Neuromuscular excitability -> Chvostek’s sign
Hyperreflexia - > Trousseau’s sign
CATs go numb
Convulsions, arrhythmia, tetany, numbness in fingers/feet

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36
Q

What are the diagnostic tests for hypocalcaemia?

A

1st -> repeat bloods and adjust for albumin (as the albumin can bind ionised calcium)
2nd -> what is the PTH?

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37
Q

What are some causes of secondary hyperparathyroidism?

A
  • Vitamin D deficiency – dietary, malabsorption, lack of sunlight
  • Chronic kidney disease (1α hydroxylation) –> can progress to tertiary hyperparathyroidism
  • PTH resistance (pseudohypoparathyroidism) – short 4th MCP
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38
Q

What are the causes of low PTH?

A

Surgical (inc. post-thyroidectomy)

Auto-immune hypoparathyroidism

Congenital absence of parathyroids (E.G. DiGeorge syndrome)

Mg deficiency (PTH regulation)

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39
Q

What is Paget’s disease?

A

Focal disorder of bone remodelling

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40
Q

What are the signs and symptoms of Paget’s disease?

A 
Bone pain
Warmth
Cardiac failure
Deformity
Fracture
Malignancy
Compression
Pelvis, femur, skull and tibia
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41
Q

Which investigations would you do for someone with Paget’s disease?

A

o Elevated alkaline phosphatase

  • Ca and PO4 are NORMAL as…
  • Osteoclasts and blasts are both active together

o Nuclear med scan / XR

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42
Q

How would you treat Paget’s disease?

A

Bisphosphonates

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43
Q

Describe the structure of atheroscleortic plaque

A

Fibrous cap
Foam cells
Necrotic core with cholesterol crystals

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44
Q

List lipoprotein from largest to smallest

A

Chylomicrons
VLDL
LDL
HDL

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45
Q

What are the percentages of each lipoprotein in fasting plasma?

A

Chylomicrons <5%
VLDL 13%
LDL 70%
HDL 17%

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46
Q

Describe cholesterol movement from the small intestine to the liver

A

Diet + bile –> Transported from jejunum NPC1L1 (with ABC G5/G8 cause reverse movement into small intestine) + bile acids through BAT into liver –> cholesterol down regulates HMG CoA reductase

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47
Q

Describe what happens to cholesterol when it gets into the liver

A

1) Converted to bile acids by 7alphaOHxy-lase
2) Esterified by enzyme ACAT to form cholesterol ester - packaged by MTP and apoB into VLDL
3) VLDL –>LDL
4) VLDL –> HDL using CETP
5) LDL taken up by LDL receptor on liver
6) HDL goes to peripheral cells uses ABC A1 to pick up excess cholesterol

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48
Q

Which protein does cholesterol ester use to move back into the liver?

A

SR-B1

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49
Q

How much triglycerides in % are picked up by each lipoprotein?

A

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

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50
Q

What is the cause of familial hypercholesterolaemia?

A

Dominant mutations of LDL receptor, apoB or PCSK9 (rare - less LDLR broken down = low LDL) genes. (Rarely autosomal recessive inheritance - LDLRAP1)

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51
Q

What is the cause of familial hyper-alpha-lipoproteinaemia?

A

Sometimes CETP deficiency

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52
Q

What is the cause of polygenic hypercholesterolaemia?

A

Multiple loci including NPC1L1, HMGCR, CYP7A1 polymorphisms

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53
Q

What is the cause of phytosterolaemia?

A

Mutations of ABC G5 and G8

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54
Q

How does LDL get into the liver?

A

LDL receptor

Binds to receptor in coated pits and undergoes endocytosis - lysosomes

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55
Q

What is the problem with hypercholesterolaemia?

A

Atherosclerosis

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56
Q

What are some clinical signs of hypercholesterolaemia?

A

Tendon xanthoma
Corneal arcus
Xanthelasma

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57
Q

What are the differences between primary hypertriglyceridaemia types I, IV and V?

A 
I = lipoprotein lipase or apoC II deficiency
IV = increased triglyceride synthesis
V = due to apoA V deficiency (more severe of IV)
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58
Q

Describe consequences of ApoE polymorphisms

A 
E4 = higher risk of Alzheimer's
E3 = normal
E2 = familial mixed hyperlipidaemia (type 3)
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59
Q

What are some signs of familial mixed hyperlipidaemia (type 3)?

A

Palmar straie

Elbow xanthomas

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60
Q

What are some causes of secondary hyperlipidaemia?

A

Hormonal - pregnancy, hormones, hypothyroid

Metabolic - obesity, diabetes, gout, storage disorders

Renal dysfunction - nephrotic syndrome, renal failure

Obstructive liver diseases

Toxins - alcohol, hydrocarbons

Iatrogenic - antihypertensives, immunosuppressants

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61
Q

What are the different types of hypolipidaemia?

A
  • A-beta-lipoproteinaemia: MTP deficiency (recessive)
  • Hypo-beta-lipoproteinaemia: truncated apoB (dominant)
  • Tangier disease: HDL deficiency caused by ABC AI mutations
  • Hypo-alpha-lipoproteinaemia: sometimes due to apoA-I-mutations
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62
Q

What are the different lipid-regulating drugs?

A

Atorvastatin - best at lowering LDL, don’t increase HDL by that much
Nicotinic acid - very good at increasing HDL
Gemfibrozil - very good at reducing triglyceride levels
Eztimibe
Colestyramine

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63
Q

What are the treatments for obesity?

A

Medical - orlistat
Gastric bypass
Biliopancreatic diversion

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64
Q

What are the benefits of bariatric surgery?

A
  • Success >50% in excess weight
  • Diabetes
  • Serum triglyceride lowering
  • Increase in HDL cholesterol
  • Fatty liver reduced
  • Reduced hypertension
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65
Q

A patient’s BP is 140/80 on atenolol. Would you add a thiazide diuretic?

A

Yes - this will decrease CV risk significantly if bP is kept low - even if the bP is borderline

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66
Q

What are some management options for someone at high risk of MI/stroke?

A
  • Intensive lifestyle modification
  • Aspirin
  • High dose statin (Atorvastatin 40-80mg od)
  • Optimal BP control
  • Thiazides
  • Assessment for probable T2D (check HbA1c)
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67
Q

Fill in the gaps: AGGRESSIVE
management of
* * and * * improves SURVIVAL

A

AGGRESSIVE management of BLOOD PRESSURE and LIPIDS improves SURVIVAL

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68
Q

What are some options for statin intolerant patients?

A
  • Niacin NO LONGER AVAILABLE
  • Ezetemibe
  • Plasma Exchange where available
  • Evolocumab (PCSK9 monoclonal antibody)
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69
Q

How does a proprotein convertase subtilisin kexin 9 (PCSK9) monoclonal antibody treatment (evolocumab) work?

A
  • PCSK9 regulates the levels of the LDL receptor
  • Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease
  • Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease
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70
Q

What are the benefits of adding evolocumab?

A

Very little difference on overall death reduction - reserve for statin intolerant patients with uncontrolled lipids

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71
Q

What are the benefits of extended periods of glycemic control?

A

Tight control takes a long time to prevent heart attacks. Heart attacks occur after many years or poor control in new onset diabetes - ‘legacy effect’

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72
Q

How do SGLT2 inhibitors work?

A

They work by stopping the kidneys from reabsorbing glucose back into the blood.

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73
Q

What are 3 examples of GLP-1 analogues?

A
  • Exanatide
  • Liraglutide (Victoza or Saxenda)
  • Semaglutide
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74
Q

What is the commonest electrolyte abnormality in hospitalised patients?

A

Hyponatraemia

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75
Q

What is hyponatraemia?

A

Serum sodium < 135 mmol/L

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76
Q

What are the underlying pathogenesis of hyponatraemia?

A

Increased extracellular water:
Excess water
Vomiting

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77
Q

How does ADH (vasopressin) work?

A

Water retention - acts on V2 receptors and increases water channels (aquaporin-2) in collecting duct

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78
Q

Where would you find V1 receptors?

A
  • Vascular smooth muscle

- Vasoconstriction

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79
Q

What are the two main stimuli for ADH secretion?

A
  • Increase in serum osmolarity (mediated by hypothalamic osmoreceptors) –> thirst
  • Decerase in blood volume/pressure (mediated by baroreceptors in carotids, atria, aorta)
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80
Q

How do you manage a patient with hyponatraemia?

A

1 - Clinic assessment: hypo/eu/hypervolaemia?

2-

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81
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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82
Q

What are the clinical signs of hypervolaemia?

A
  • Raised JVP
  • Bibasal crackles (on chest examination)
  • Peripheral oedema
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83
Q

What are the causes of hyponatraemia in a hypovolaemic patient?

A
  • Renal: diuretics

- Extra-renal: diarrhoea, vomiting

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84
Q

What are the causes of hyponatraemia in a euvolaemic patient?

A
  • Hypothyroidism
  • Adrenal insufficiency
  • SIADH
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85
Q

What are the causes of hyponatraemia in a hypervolaemic patient?

A
  • Cardiac failure
  • Cirrhosis
  • Nephrotic syndrome
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86
Q

Why does hypovalaemia lead to hyponatraemia?

A

After loss of water + sodium –> ADH released –> leads to more water retention therefore diluting sodium concentration

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87
Q

What are the causes of SIADH?

A
  • CNS pathology
  • Lung pathology
  • Drugs (SSRI, TCA, opiates, PPIs, carbamazepine)
  • Tumours
  • Surgery
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88
Q

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

A
  • Hypothyroidism: TFTs
  • Adrenal insufficiency: short synacthen test
  • SIADH: plasma & urine osmolality (low plasma and high urine osmolality)
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89
Q

How is the diagnosis of SIADH made?

A
  • No hypovolaemia
  • No hypothyroidism
  • No adrenal insufficiency
  • Reduced plasma osmolality AND increased urine osmolality (>100)
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90
Q

How would you manage a hypovolaemic patient with hyponatraemia?

A

Volume replacement with 0.9% saline

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91
Q

How would you manage a hypovolaemic patient with hyponatraemia?

A
  • Fluid restriction

- Treat underlying cause

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92
Q

What would you see in a patient with severe hyponatraemia?

A
  • Reduced GCS
  • Seizures
  • Seek expert help (treat with hypertonic 3% saline)
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93
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 24hrs
  • Risk of osmotic demyelination (central pontine myelinolysis): quadriplegia, dysarthria, dysphagia, seizures, coma, death
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94
Q

If water restriction is insufficient, which drugs can be used to treat SIADH?

A

1) Demeclocycline: reduces responsiveness of collecting tubule cells to ADH. Monitor U&Es (risk of nephropathy).
2) Tolvaptan: V2 receptor antagonist

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95
Q

Which is the most abundant intracellular cation? What is its serum concentration?

A

Potassium

3.5-5 mmol/L

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96
Q

Which hormones are involved in renal regulation of potassium?

A
  • Angiotensin II

- Aldosterone

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97
Q

Describe the renin-angiotensin-aldosterone system

A

1) Renin released from JGA in kidneys
2) Stimulates conversion of angiotensinogen to angiotensin I in the liver
3) Angiotensin one stimulates release of converting enzyme in the lungs –> angiotensin II
4) Angiotensin II triggers adrenal glands to release aldosterone
5) Aldosterone triggers Na+ and H2O retention, and loss of K+

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98
Q

What are the two stimulants of aldosterone release from the adrenal glands?

A
  • K+ (hyperkalaema)

- Angiotensin II

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99
Q

How does aldosterone work?

A
  • Acts on cortical collecting tubule principle cells
  • Causes the release of K+ and H20 and Na+ retention
  • Binds to mineralocorticoid receptor
  • Increase in Sgk-1 and sodium channels (ENaC)
  • Causes lumen to become electronegative –> creates electrical gradient
  • Cause potassium to move due to change in electrochemical gradient
  • Potassium secreted in the lumen
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100
Q

What are the main causes of hyperkalaemia?

A

Renal impairment: reduced renal excretion, reduced GFR

Drugs: ACE inhibitor, Ag II blocker (e.g. losartan), Aldosterone antagonist (e.g. spironolactone)

Low aldosterone: Addison’s, type 4 renal tubular acidosis (low renin, low aldosterone)

Release from cells: rhabdomyolysis, acidosis

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101
Q

Why does acidosis lead to hyperkalaemia?

A

H+ goes in = high positive charge inside of cell

–> K+ released from cells to balance out

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102
Q

What are the ECG changes associated with hyperkalaemia?

A

Peaked T waves

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103
Q

How would manage a patient with hyperkalaemia?

A
  • 10ml 10% calcium gluconate
  • 50ml 50% dextrose + 10 units of insulin
  • Nebulised salbutamol
  • Treat underlying cause
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104
Q

What are the causes of hypokalaemia?

A
  • GI loss
  • Renal loss: hypoaldosteronism, increased 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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105
Q

What are the causes of Na+/K+/Cl- channel dysfunction in the loop of Henle and DCT?

A

LoH

  • Loop diuretics
  • Bartter syndrome

DCT

  • Thiazide diuretics
  • Gitelman syndrome
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106
Q

How do medications like loop diuretics increase renal potassium loss?

A

More sodium reabsorbed distally at the principle cells in collecting duct. This leads to more potassium loss via Na+/K+ pump.

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107
Q

What are the clinical features of hypokalaemia?

A
  • Muscle weakness
  • Cardiac arrhythmia
  • Polyuria and polydipsia (nephrogenic DI)
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108
Q

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

A

Aldosterone:Renin ratio

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109
Q

How you you manage hypokalaemia if serum potassium was 3-3.5mml/L?

A
  • Oral potassium chloride (two SandoK tablets tds for 48hrs)

- Recheck serum potassium

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110
Q

How you you manage hypokalaemia if serum potassium was <3.0mml/L?

A
  • IV potassium chloride
  • Maximum rate 10 mmol per hour
  • Rates >20 mmol per hour are highly irritating to peripheral veins
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111
Q

What is the treatment for Addison’s disease?

A
  • Hydrocortisone

- Fludrocortisone

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112
Q

Which hormones does thyroid releasing hormone stimulate?

A

Prolactin

TSH

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113
Q

Which hormone is the only one controlled by negative regulation in the pituitary gland?

A

Prolactin –> controlled by dopamine

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114
Q

Which hormone does corticotrophin releasing hormone control?

A

ACTH - adrenocorticotropic hormone

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115
Q

What is the size of a macroadenoma?

A

> 1cm

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116
Q

What scan confirms the presence of a pituitary adenoma?

A

CT scan

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117
Q

What is the normal level of prolactin?

A

<600

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118
Q

What does a prolactin level of over 6,000 denote?

A

Prolactinoma

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119
Q

How do you test for pituitary gland function?

A

You test to see if pituitary responds adequately to metabolic stress –> ensure gonadotrophs and thyrotrophs are working

Administer LHRH + TRH + stress (hypoglycaemia)

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120
Q

What would be the result of a normal pituitary function test?

A

Increases CRF and thus ACTH

Increases GHRH and thus GH

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121
Q

What is the CPFT or ‘triple test’?

A

Test to see pituitary gland function:

  • induce hypoglycaemia by giving insulin
  • increase CRF and thus ACTH
  • increase GHRH and thus GH
  • TRH stimulates TSH and prolactin
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122
Q

What are the contraindications for pituitary function test?

A
  • cardiac problems (do ECG prior)

- epilepsy

122
Q

What are the contraindications for pituitary function test?

A
  • cardiac problems (do ECG prior)

- epilepsy

123
Q

What is the target glucose for pituitary testing?

A

2.2mM –> reverse hypoglycaemia if it gets below 1.5mM (may get neuroglycopenia - aggressive)

124
Q

What do you do if glucose drops below 1.5mM in pituitary function tests?

A

Give 50ml of 20% dextrose

124
Q

What do you do if glucose drops below 1.5mM in pituitary function tests?

A

Give 50ml of 20% dextrose

125
Q

What would you do to prepare a patient for pituitary function testing?

A
  • Fast overnight
  • Ensure good IV access
  • Weigh patient (insulin is 0.15 units per kg)
  • TRH 200mcg
  • LHRH 100mcg

May sweat and vomit

Take blood for glucose, cortisol, HG, LH, FSH, TSH and prolactin every 30 mins up to 60 mins plus basal thyroxine

126
Q

List all the replacement treat for pituitary failure

A
  • Hydrocortisone
  • Thyroxine
  • Oestrogen
  • GH
  • Bromocriptine/cabergoline
127
Q

Which hormone is essential to replace initially in pituitary failure?

A

Hydrocortisone - so can respond to stress

128
Q

Prolactin is 2944. What is your diagnosis?

A

Non-functioning pituitary adenoma

>6000 to be a prolactinoma, but over 600 so not normal

129
Q

Why does a non-functioning adenoma cause problems?

A
  • Press on stalk and cause pituitary failure
  • Prevent dopamine reaching pituitary
  • Thus cause hyperprolactinoma
130
Q

Why is prednisolone better to give than cortisol?

A

Longer half life and more potent than cortisol
2.3x binding affinity than cortisol
Mimics circadian rhythm more closely

131
Q

What is the best treatment for acromegaly?

A

In order:

  • Surgery
  • Radiotherapy
  • Cabergoline
  • Octreotide
132
Q

What is the normal range of CO2 in an ABG?

A

4.5 kPa

133
Q

How do you calculate osmolality?

A

Osmolality = charged molecules + uncharged

= cations + anions + urea + glucose

since cations = anions

= 2(Na+K) + U + G

134
Q

What is the anion gap?

A

Anion gap is the difference between anion and cation concentration –> there may be an underlying acidosis e.g. suggests extra ketones

135
Q

How do you calculate the anion gap?

A

Anion gap = Na + K - Cl - bicarb

136
Q

What is the normal anion gap inside of the body?

A

18 mM

137
Q

What is the underlying cause of respiratory alkalosis in most patients?

A

Primary hyperventilation - anxiety

138
Q

What other electrolyte imbalances (apart from Na and K) occur in respiratory alkalosis?

A

Increase in calcium –> albumin gets more sticky in alkali conditions for calcium

139
Q

What is the complication of too much metformin?

A

Lactic acidosis

Inhibits lactate conversion to glucose in the liver (the Cori cycle)

140
Q

What are the values which define type 2 diabetes?

A

Fasting glucose > 7.0mM

Glucose tolerance test (75g glucose given)
Plasma glucose > 11.1mM at 2 hrs

2hr value 7.8-11.1 = impaired glucose tolerance

HbA1c
42 + = impaired glucose tolerance
48 + = diabetes

141
Q

Which part of the adrenal cortex makes the following:

  • cortisol?
  • adrenaline?
A

Glomerulosa: aldosterone

Fasciculata: cortisol

Reticularis: androgens

Medulla: adrenaline

142
Q

What are hypertrophic and wasted adrenal glands caused by?

A

Wasted adrenal glands are likely to be caused by Addison’s disease or long-term steroid treatment
Hyperplastic adrenal glands may result from Cushing’s disease or ectopic ACTH

143
Q

What is the blood supply in the adrenal glands?

A 
Many arteries (~57) but only 1 vein 
Test adrenal output through IVC to adrenal vein

Left –> drains to left renal vein
Right –> drains to IVC

144
Q

What is Schmidt’s syndrome?

A

 
Addison’s disease + primary hypothyroidism

AKA: Polyglandular autoimmune syndrome type II
Antibodies against the thyroid and adrenal glands

145
Q

Which results would be indicative of Addison’s disease?

A

Unusual U&Es (hyponatraemia and hyperkalaemia) –> mineralocorticoid deficiency
Hypoglycaemia –> glucocorticoid deficiency

146
Q

How would you diagnose Addison’s disease?

A

1) Measure cortisol and ACTH at start
2) 250ug ACTH, IM
3) Check cortisol at 30 and 60 minutes

147
Q

How would you manage Addison’s disease?

A

IV 0.9% saline (1L/hour)

IV hydrocortisone

148
Q

What is the difference between Conn’s, Cushing’s and pheochromocytoma?

A

Conn’s syndrome –> glomerulosa secreting aldosterone
Cushing’s syndrome –> fasciculata tumour secreting cortisol
Pheochromocytoma –> medulla tumour secreting adrenaline

149
Q

How is pheochromocytoma managed?

A

EMERGENCY

1) Immediate alpha blockade (phenoxybenzamine) –> reflex tachycardia –> move to step 2
2) Add beta blockade
3) Surgery

150
Q

How would you confirm the diagnosis of pheochromocytoma?

A 
Urinary catecholamines (high)
MIBG (Meta-Iodobenzylguanidine) Scan
151
Q

What is the triad in pheochromocytoma?

A

Headaches
Tachycardia
Hyperhidrosis

152
Q

What are the clinical features of Conn’s syndrome?

A

Adrenal gland autonomously secretes aldosterone –> HTN –> suppress renin production at JGA

Hypertension

Hypokalaemia

Alkalosis

153
Q

How is the diagnosis of Conn’s syndrome made?

A

Plasma  aldosterone/renin ratio is the first-line investigation  in suspected primary hyperaldosteronism

Should show high aldosterone levels alongside low renin levels (negative feedback due to sodium retention from aldosterone)

Following this a high-resolution CT abdomen and adrenal vein sampling is used

154
Q

How is Conn’s syndrome managed?

A

Adrenal adenoma: surgery

Bilateral adrenocortical hyperplasia: aldosterone antagonist e.g. spironolactone

155
Q

What is the typical presentation in Cushing’s disease?

A

A hypokalaemic metabolic alkalosis may be seen, along with impaired glucose tolerance (high glucose)

Ectopic ACTH secretion (e.g. secondary to small cell lung cancer) is characteristically associated with very low potassium levels.

156
Q

How is a Cushing’s diagnosis made?

A
  1. Screening Cushing’s:

a) 11pm salivary cortisol if low, the cause is not Cushing’s; AND/OR
b) LDDST at 11pm –> 1mg dexamethasone and measure cortisol before 9am next day
 
LDDST will have to be abnormal (not supressed cortisol) to ANY cause:

Oral steroids (over treatment of another condition with oral steroids)
85% Pituitary-dependant Cushing’s disease
5% Ectopic ACTH (SCLC)
10% Adrenal adenoma

Clinical picture 1 11pm 1mg dexamethasone = 9am cortisol = <50nM
Normal Suppression (i.e. pseudo-Cushing’s Syndrome)
Clinical picture 2 11pm 1mg dexamethasone = 9am cortisol = 500nM
Cushing’s Syndrome of indeterminate cause  do IPSS
 
2. Confirm cause of Cushing’s – Inferior Petrosal Sinus Sampling (IPSS):
A catheter is fed into the jugular vein
Distinguishes pituitary dependant from ectopic ACTH

157
Q

How is Cushing’s syndrome treated?

A

Adrenal mass –> adrenalectomy ± steroid replace (beware Nelson’s syndrome)

Nelson’s syndrome = removal of adrenal leads to pituitary enlargement (hypopituitarism by compressing stalk) and +++ ACTH (pigmentation)

Ectopic –> ketoconazole, metyrapone, mifepristone

Pituitary adenoma –> surgery

158
Q

What is the most common cause of congenital adrenal hyperplasia?

A

21-hydroxylase deficiency = 95% of CAH

60-70% of patients salt-losing crisis (low aldosterone) at 1-3 wks of age
Virilisation of female genitalia (high testosterone/androgens)
Precocious puberty in males

CRH stimulates ACTH which stimulates:

Cortisol production
Androgen production

159
Q

What are two less common causes of congenital adrenal hyperplasia?

A

11-beta hydroxylase deficiency

virilisation of female genitalia
precocious puberty in males
hypertension
hypokalaemia

17-hydroxylase deficiency

non-virilising in females
inter-sex in boys
hypertension

160
Q

What are some clinical signs found in Addison’s disease?

A

Hyponatraemia

Hyperkalaemia

161
Q

How is the diagnosis of Addison’s disease made?

A

9am cortisol

Short SynACTHen test

162
Q

How is Addison’s disease treated?

A

Hydrocortisone + sick-day rules

Fludrocortisone

163
Q

What is the normal glomerular filtration rate?

A

120ml/min normal (7.2L/hour)

164
Q

What is the age related decline of GFR?

A

Age related decline approximately 1ml/min per year

165
Q

How do you calculate GFR and clearance?

A

If marker is not bound to serum proteins, freely filtered at the glomerulus, and not secreted/reabsorbed by tubular cells

C = GFR
At any one time: C = (U x V)/P
U – urinary conc P – plasma conc

166
Q

What are some ways in which GFR can be calculated?

A

Single injection plasma clearance measurements:
• 51 Cr-EDTA
• 99 Tc-DTPA
• Iohexol

Direct: Clearance calculated from urine collection

Indirect: Clearance calculated from plasma regression curve

167
Q

What would make an ideal injectable marker of renal function?

A
  • Not plasma protein bound
  • Freely filtered at glomerulus
  • Not modified by tubules
168
Q

Why is blood urea no longer used in GFR?

A

By-product of protein metabolism
Freely filtered at glomerulus
Variable (30-60%) reabsorption by tubular cells
Dependent on nutritional state, hepatic function, GI bleeding
Very limited clinical value

169
Q

Describe some features of serum creatinine as an endogenous marker of 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
170
Q

How is creatinine clearance be calculated?

A

Derived equation to estimate creatinine clearance:

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

171
Q

How is estimated GFR calculated?

A

Complex equation derived from cohort studies (MDRD)
Requires age, sex, serum creatinine and ethnicity
eGFR = 186 x ( Creat x 0.0113) -1.154 x Age -0.203
Adjust by 0.742 if female
May underestimate GFR if above-average weight and young

172
Q

What are the clinical alternatives to serum creatinine?

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

173
Q

How is renal function actually measured in practice?

A
  • Serum creatinine is an insensitive marker of GFR
  • Other endogenous blood markers (i.e. 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
174
Q

What is a quantitative assessment of amount of proteinuria?

A

Urine protein:creatinine ratio (PCR)

175
Q

Why is 24 hours urine collection not used?

A

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

176
Q

What do nitrites detect in urine dipsticks?

A

Detects bacteria esp Gm negatives

177
Q

Is a negative leucocyte esterase test on urine dip important?

A

Yes - negative result is significant

178
Q

Is a negative leucocyte esterase test on urine dip important?

A

Yes - negative result is significant

179
Q

What is the best measure of kidney function?

A

GFR

180
Q

When is urinalysis helpful?

A

Urinalysis - dip, microscopy, protein measurements can be used in diagnosis and monitoring

181
Q

What is the difference in AKI and CKD?

A

AKI
Abrupt decline in GFR
Potentially reversible
Treatment targeted to precise diagnosis and reversal of disease

CKD
Longstanding decline in GFR
Irreversible
Treatment targeted to prevention of complications of CKD and limitation of progression

182
Q

Define what AKI is and the 3 stages of AKI

A

Defined as a rapid reduction in kidney function, leading to an inability to maintain electrolyte, acid-base and fluid homeostasis.

AKI Stage 1: Increase in sCr by ≥26 µmol/L, or by 1.5 to 1.9x the reference sCr
AKI Stage 2: Increase in sCr by 2.0 to 2.9x the reference sCr
AKI Stage 3: Increase in sCr by ≥3x the reference sCr, or increase by ≥354 µmol/L

183
Q

What are the 3 types of AKI?

A

1]) pre-renal

2) intrinsic renal
3) post-renal

184
Q

What is pre-renal AKI caused by?

A

Hallmark is reduced renal perfusion
as part of generalised reduction in tissue perfusion or selective renal ischaemia

No structural abnormality

True volume depletion
Hypotension
Oedematous states
Selective renal ischaemia
Drugs affecting glomerular blood flow
185
Q

What is the normal response v pre-renal AKI response to reduced circulating volume?

A 
Activation of central baroreceptors	
Activation of RAS
Release of vasopressin
Activation of sympathetic system
Vasoconstriction, increased cardiac output, renal sodium retention

Pre-renal AKI occurs when normal adaptive mechanisms fail to maintain renal perfusion

186
Q

Which drugs predispose to AKI?

A

NSAIDs
Calcineurin inhibitors
ACEi or ARBs
Diuretics

187
Q

What is the difference between pre-renal AKI and ATN?

A

Pre-Renal AKI is not associated with structural renal damage and responds immediately to restoration of circulating volume
Prolonged insult leads to ischaemic injury
Acute Tubular Necrosis does not respond to restoration of circulating volume

188
Q

What is the cause of post-renal AKI?

A

Hallmark is physical obstruction to urine flow

(Intra-renal obstruction)
Ureteric obstruction (bilateral)
Prostatic/Urethral obstruction
Blocked urinary catheter
189
Q

What is the pathophysiology of obstructive uropathy?

A

GFR is dependent on hydraulic pressure gradient
Obstruction results in increased tubular pressure
Immediate decline in GFR

190
Q

What can prolonged post-renal obstruction result in?

A

Glomerular ischaemia
Tubular damage
Long term interstitial scarring

191
Q

What are some renal causes of AKI?

A

Vascular Disease e.g. vasculitis
Glomerular Disease e.g. glomerulonephritis
Tubular Disease e.g. ATN
Interstitial Disease e.g. analgesic nephropathy

192
Q

What are some common mechanisms of renal injury?

A

Most commonly ischaemic

Endogenous toxins
Myoglobin
Immunoglobulins

Exogenous toxins - contrast, drugs
Aminoglycosides
Amphotericin
Acyclovir

193
Q

What types of immune dysfunction can cause renal inflammation?

A

Glomerulonephritis

Vasculitis

194
Q

What type of infiltration/abnormal proteins deposition can cause renal injury?

A

Amyloidosis
Lymphoma
Myeloma-related renal disease

195
Q

What are the found phases of acute wound healing in AKI?

A

Haemostasis
Inflammation
Proliferation
Remodeling

196
Q

Why might AKI not resolve?

A

Pathological responses to renal injury are characterized by imbalance between scarring and remodeling
Replacement of renal tissue by scar tissue results in chronic disease

197
Q

What are the common causes of CKD?

A 
Diabetes
Atherosclerotic renal disease
Hypertension
Chronic Glomerulonephritis
Infective or obstructive uropathy
Polycystic kidney disease
198
Q

What are the consequences of CKD?

A

1) Progressive failure of homeostatic function
- Acidosis
- Hyperkalaemia
2) Progressive failure of hormonal function
- Anaemia
- Renal Bone Disease
3) Cardiovascular disease
- Vascular calcification
- Uraemic cardiomyopathy
4) Uraemia and Death

199
Q

What is renal acidosis and how is it treated?

A

Metabolic acidosis
Failure of renal excretion of protons

Results in:
Muscle and protein degradation
Osteopenia due to mobilization of bone calcium
Cardiac dysfunction

Treated with oral sodium bicarbonate

200
Q

Which medications can be used in diabetics with AKD?

A

ACEi
Spironolactone
’Potassium-sparing’ diuretics

201
Q

What are the ECG changes of hyperkalaemia?

A
  • Tall peaked T waves

- Widening QRS

202
Q

Describe anaemia of chronic renal disease

A

Progressive decline in erythropoietin-producing cells with loss of renal parenchyma
Usually noted when GFR<30mL/min
Normochromic, normocytic anaemia
Distinguish from other causes of anaemia, which are common
iron deficiency
B12 and/or folate deficiency

203
Q

Name 3 erythropoiesis stimulating agents used in CKD treatment

A 
Erythropoietin alfa (Eprex)
Erythropoietin beta (NeoRecormon)
Darbopoietin (Aranesp)
203
Q

Name 3 erythropoiesis stimulating agents used in CKD treatment

A 
Erythropoietin alfa (Eprex)
Erythropoietin beta (NeoRecormon)
Darbopoietin (Aranesp)
204
Q

Which conditions can cause renal bone disease?

A
  • Osteitis fibrosa
  • Osteomalacia
  • Adynamic bone disease
  • Mixed osteodystrophy
205
Q

What is osteitis fibrous?

A

Osteoclastic resorption of calcified bone and replacement by fibrous tissue

Hyperparathyroidism

206
Q

What is dynamic bone disease?

A

Excessive suppression of PTH results in low turnover and reduced osteoid

207
Q

How can renal bone disease be treated?

A

Phosphate control
Dietary
Phosphate binders

Vit D receptor activators
1-alpha calcidol
Paricalcitol

Direct PTH suppression
Cinacalcet

208
Q

What is vascular calcification?

A

Renal vascular lesions are frequently characterised by heavily calcified plaques, rather than traditional lipid-rich atheroma

209
Q

What are the phases of uraemia cardiomyopathy?

A

Three phases:
Left ventricle (LV) hypertrophy
LV dilatation
LV dysfunction

210
Q

What is meant by St John’s wort?

A

Hypericum perforatum (St John’s wort) is used in the treatment of depression similar to paroxetine

211
Q

What is a Smith’s, Coll’s and Pott’s fracture?

A

Smith’s fracture = posterior displacement of the radius (i.e. radius towards the BACK of the hand), falling on a flexed wrist
Treated with manipulation under anaesthesia (MUA) and plaster
Colles fracture = anterior displacement of the radius (i.e. radius towards the PALM of the hand), falling on an extended wrist
Pott’s fracture = ankle fracture involving both tibia and fibula

212
Q

What is the normal range of PTH?

A

1.1-6.8 pM

213
Q

What is the normal calcium range in the body?

A

2.20-2.60

214
Q

What would the PTH, calcium and phosphate levels be like in primary hyperparathyroidism?

A

High calcium
High/normal PTH
Low phosphate

215
Q

What would the PTH, calcium and phosphate levels be like in secondary hyperparathyroidism?

A

Low calcium
High PTH
Low phosphate

216
Q

What would the PTH, calcium and phosphate levels be like in tertiary hyperparathyroidism?

A

High calcium
High PTH
High phosphate

217
Q

What is the difference in PTH levels for sarcoidosis, cancer or primary hyperparathyroidism?

A

Sarcoid –> PTH suppression/low (as produces lots of calcium which suppresses PTH)

Cancer –> PTH high (endogenous production) –> from PTHrP or invading bone cancer

Primary HPT –> PTH normal/high (despite hypercalcaemia)

218
Q

What are the roles of PTH?

A

Kidneys:
Activate 1-alpha hydroxylase - vitamin D activation

Absorb calcium from gut

Absorb phosphate from gut

Directly resorb calcium

Directly excrete phosphate

Bone:
Activate osteoclasts

219
Q

What are the features of hypercalcaemia?

A

Moans, bones, groans and stones
 
Polydipsia/polyuria (nephrogenic DI) - calcium acts like glucose to carry water with it via osmosis
 
Band keratopathy (calcium deposition across the front of the eye)
This is a feature of CHRONIC hypercalcaemia (so it cannot be hypercalcaemia of malignancy)

Complications: 
Renal stones             
Peptic ulcer disease 
Pancreatitis             
Skeletal changes 
Osteitis fibrosa cystica (i.e. pepper-pot skull)
220
Q

What are the differences between calcium stones and rate stones?

A

Calcium stones are radio-opaque, but urate stones are radio-lucent

221
Q

What is the treatment of renal stones and potential complications if not treated?

A

Most stones will pass –> give painkillers like PR diclofenac
Lithotripsy
Cystoscopy
Lithotomy

Recurrent infections may occur e.g. proteus mirabilis

222
Q

How can hypercalcaemia be managed urgently if over 3mmol/L?

A

Urgent treatment ([Ca2+] >3.0mmol/L ± unwell) – if calcium <2.8mmol/L, this doesn’t need to be as intense

FLUIDS - IV 0.9% saline
4-hourly or 6-hourly bags of 1L 0.9% NaCl
1st bag of 1L given over 1 hour (if severely dehydrated)

IV frusemide (prevent pulmonary oedema and aid calciuresis)
 
MAYBE - IV pamidronate (bisphosphonate), 30-60mg
Hold off to begin with as you can’t measure serum calcium and phosphate if given
Do NOT hold off if hypercalcaemia due to cancer

223
Q

What is the non-urgent treatment of hypercalcaemia?

A

Well hydrated
Avoid thiazides (reduce hypercalciuria but increase plasma calcium)
Surgery (parathyroidectomy)

224
Q

How may the hand X-ray and histological findings look like in someone with HPT?

A

Often be normal
Later stages may show cystic changes in the radial aspect

Histology of the bone shows…
Brown tumours (multinucleate giant cells, activated osteoclasts in the bone)
Multinucleate giant cells

225
Q

45 yr old man with SOB, and CXR reveals bilateral hilar lymphadenopathy. Calcium is raised and PTH suppression. What is your diagnosis?

A

Sarcoidosis

226
Q

What would be the histological findings of someone with sarcoidosis?

A

Non-caseating granulomas

227
Q

What is the mechanism of hypercalcaemia in sarcoidosis?

A

Macrophages in the lungs express 1-alpha hydroxylase –> activate vitamin D
Vitamin D leads to excessive calcium
Patients more likely to become hypercalcaemic in summer months because of increased exposure to sunlight

228
Q

How is sarcoidosis treated?

A

Steroids

229
Q

Which autosomal dominant disorders can lead to a predisposition of cancer and may present with hypercalcaemia?

A

Multiple endocrine neoplasia:

MEN1 (3Ps): pituitary, parathyroids, pancreatic

MEN2a (2Ps, 1M): parathyroid, phaemchromocytoma, medullary thyroid

MEN2b (1P, 2Ms): phaechromocytoma, medullary thyroid, mucocutaneous neuromas

230
Q

What would the bone histology changes of someone with primary hyperparathyroidism?

A

Radial aspect cystic changes

231
Q

What will the bone histology show of someone with primary hyperparathyroidism?

A

Brown tumours (multinucleate giant cells)

232
Q

What would you see on the x ray of someone with sarcoidosis?

A

Bilateral hilar lymphadenopathy

233
Q

What is the PTH in someone with sarcoidosis?

A

Suppressed

234
Q

What’s used to treat sarcoidosis?

A

Steroids

235
Q

What is raised in someone in Paget’s disease of the bone?

A

Alkaline phosphatase (as osteoblasts make more bone tissue = raised alkaline phosphatase)

236
Q

What is raise in a patient with osteomalacia?

A

Alkaline phosphatase, high PTH (due to high bone turnover)

237
Q

What is raised in a patient following acute myocardial infarction?

A

Troponin
CK
AST (aspartate aminotransferase)
LDH

238
Q

What is raised is Addison’s disease?

A

Potassium is raised

Sodium is low

239
Q

What is increased in a patient with gallstones?

A

ALP

240
Q

What is raised in viral hepatitis?

A

ALT

241
Q

What is raised in chronic alcohol cirrhosis?

A

AST

242
Q

What is raised in a patient with prostatic carcinoma?

A

Prostate specific antigen (acid phosphatase)

243
Q

How is Paget’s disease diagnosed?

A

Technetium 99 bisphosphate scan

244
Q

Which can would you do for diagnosis of thyroid disease?

A

Tc pertechnetate

245
Q

Which scans are used for insulinomas?

A

Gallium 68 dotatate PET + CT

246
Q

What is Km (Michaelis-Menten constant)?

A

The Michaelis-Menten constant or Km = [substrate] at which the reaction velocity is 50% of the maximum.

247
Q

What does a high Km or low Km indicate for enzymes and substrates?

A

High Km indicates weak binding

Low Km indicates strong binding

248
Q

Which organs is ALP found in?

A
  • Intrahepatic or extra hepatic bile ducts
  • Bone
  • Placenta
  • Intestine
249
Q

How could you approach unexplained elevated ALP?

A

1) Check LFTs (γ-glutamyl transferase and ALT)
2) Check vitamin D
3) ALP isoenzymes – performed by electrophoresis test

250
Q

What would elevated liver ALP indicate?

A

Intra- or extrahepatic cholestatic liver disease

251
Q

What are the causes of elevated bone ALP?

A 
Fracture
Paget’s disease
Osteomalacia
Rickets
Cancer (primary or metastasis)
1o hyperparathyroidism with bone involvement
Renal osteodystrophy 
Childhood
252
Q

What are the causes of elevated placenta ALP?

A

Pregnancy (last trimester)

Germ-cell tumours

253
Q

Describe the changes in ALP levels change with age

A

At birth, ALP is high because of bone growth, ALP then plateaus until just before puberty in boys and girls and falls to adult levels when bone growth ceases

254
Q

What do elevations in AST and ALT mean?

A

Both AST and ALT are found in many organs, but ALT is predominantly found in the liver while elevations in AST can come from a few organs such as the heart, liver, skeletal muscle or kidneys which is not helpful

255
Q

Which organs is ALT primarily found?

A
  • Hepatic
  • Kidney
  • Pancreatitis
  • Myocardial infarction
256
Q

What would elevated ALT indicate?

A

Hepatitis (viral, alcohol), non-alcoholic fatty liver disease, liver ischaemia, paracetaomol overdose

257
Q

What would elevated γ-glutamyl transferase (γ-GT) indicate?

A

Hepatobiliary disease

Hepatitis, alcoholic liver disease, cholestatic liver disease

Enzyme induction

Alcohol

Rifampicin, phenytoin, phenobarbitone

Pancreatitis and kidney disease - less accurate

258
Q

What is helpful for distinguishing between hepatic and biliary disease?

A

γ-GT not useful for distinguishing between hepatic and biliary disease, the ALT:ALP ratio is more useful

259
Q

How many types of LDH are there?

A

LDH has two monomers – M and H – which combine in various proportions to form 5 isoenzymes

260
Q

Where is LDH made and which diseases is it elevated in?

A

White blood cells - Lymphoma

Red blood cells - Haemolysis

Placenta - Germ-cell testicular cancer (seminoma)

Skeletal muscle - Myositis

Liver injury - Hepatic disease but better biomarkers available

Cardiac - Better biomarkers available

261
Q

When is serum amylase raised?

A

Pancreas - Acute pancreatitis, perforated duodenal ulcer, bowel obstruction (causes secondary injury to pancreas)

Salivary gland - Stones, infection (e.g., mumps)

Macro-amylase (amylase bound to immunoglobulin, often benign but causes confusion. If you suspect this, request amylase electrophoresis for amylase isoenzymes) - Benign

262
Q

Where is creatinine kinase found?

A
  • Skeletal muscle

- Cardiac muscle

263
Q

When is creatinine kinase elevated?

A

Skeletal muscle - rhabdomyolysis, myositis, polymyositis, dermatomyositis, severe exercise,
myopathy (Deuchene muscular dystrophy, statins)

Cardiac muscle - cardiac injury but not used for this purpose (high-sensitivity troponin is better and used instead)

264
Q

What are the primary and secondary cardiac injuries which causes elevated troponin?

A 
Primary Cardiac Injury:
Acute coronary syndrome (STEMI, NSTEMI, unstable angina) or ACS
Myocarditis 
Cardiomyopathy 
Aortic dissection

Secondary Cardiac Injury:
Pulmonary embolism or PE
Systemic infection

265
Q

What are the different types of troponin?

A

There are 3 types of troponin I, T and C found in troponin isoforms are found in skeletal and cardiac muscle

Labs do not measure skeletal muscle troponin, labs measure cardiac troponin I or T, at Imperial we measure high-sensitivity cardiac troponin I.

266
Q

When does troponin begin to rise and then peak?

A

Begins to rise: 2-4 hrs
Peak: 12hr (8-28hrs)
Returns to normal 5-10 days

267
Q

What is the Hs cTnI Reference Range for men and women?

A

Male <35 ng/L

Female <16 ng/L

268
Q

What change in troponin levels would indicate cardiac myocyte injury?

A

50% increase or decrease suggestive of cardiac myocyte injury

269
Q

What is the diagnostic criteria of diabetes?

A

Fasting ≥7.0mmol/L
OGTT ≥11.1mmol>L
HbA1c >6.5% / >48mmol/mol
Random ≥11.1mmol/L

270
Q

What are the causes of metabolic alkalosis?

A

H+ loss (i.e. vomiting, diarrhoea)
Hypokalaemia (and alkalosis)
Ingestion of bicarbonate (i.e. lots of rennie)

271
Q

How can osmolality and anion gap be calculated?

A

Osmolality = 2(Na + K) + U + G

Anion gap = Na + K – Cl – bicarb

272
Q

How are hypokalaemia and alkalosis related?

A

Hypokalaemia –> alkalosis

Alkalosis –> hypokalaemia

273
Q

What are the causes of hypokalaemia?

A

GRRR

GI losses
Renal losses
Redistribution (insulinomas, alkalosis)
Rare causes

274
Q

What information does the dexamethasone suppression test give us on the cause of Cushing’s disease?

A

This indicates an ectopic ACTH cause
Pituitary disease would be suppressed by a high-dose test
Adrenal tumours would suppress ACTH

275
Q

What can you do to check if the renal failure is acute or chronic?

A

Renal biopsy

276
Q

How would you manage an unconscious patient with hypoglycaemia?

A

IM glucagon

277
Q

What is your management plan of someone with hypoglycaemia dependent on?

A

How alert/responsive the patient is

278
Q

How would your management plan change for someone who is alert, drowsy or unconscious with hypoglycaemia?

A

Alert - oral carbs, juice

Drowsy - buccal glucose, glucogel

Unconscious - iV access 20% glucose IV

Any patient deteriorating: consider IM glucagon

279
Q

What is the definition of hypoglycaemia in a healthy adult, a child and a diabetic?

A

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)

280
Q

What is Wipple’s triad for hypoglycaemia?

A
  • Low glucose
  • Symptoms: adrenergic, neuroglucopaenic
  • Relief of symptoms
281
Q

What is the order of physiological change in hypoglycaemia?

A

(1) suppression of insulin
(2) release of glucagon
(3) release of adrenaline
(4) release of cortisol

282
Q

How are FFAs converted to ketones?

A

These methods increase glucose, and so FFA as well
FFAs enter beta-oxidation cycle to make ATP
Excess FFAs can metabolise into ketone bodies

283
Q

What are the different ways of measuring blood glucose?

A

Venous glucose (gold standard):
Fluoride oxalate in grey-top, 2mL blood
Lab analyser with quality control but takes some time

Capillary glucose:
Point of care analyser with instant results
Poor precision at low glucose levels, not quality controlled

Continuous glucose monitoring:
Small device attached to abdomen wall that monitors continually
Not accurate below 2.2mmol/L

284
Q

What are some causes of hypoglycaemia in non-diabetics?

A

Fasting or reactive Paediatric or adult Critically unwell
Organ failure Hyperinsulinism Post-gastric bypass
Drugs Extreme weight loss Factitious (i.e. an artefact)

285
Q

What are some causes of hypoglycaemia in diabetics?

A

Medications (inappropriate insulin)
Inadequate CHO intake/missed meal
Impaired awareness Excessive alcohol
Strenuous exercise Co-existing autoimmune conditions
Liver/kidney failure –> poor clearance of drug

286
Q

Which medications can cause hypoglycaemia?

A

Oral Hypoglycaemics:
Sulphonylureas
Meglitinides
GLP-1 agents

Insulin
Rapid acting with meals
Long acting

Other drugs
Beta-blockers
Salicylates
Alcohol (inhibits lipolysis)

287
Q

What is C peptide?

A

Proinsulin –> cleaved –> insulin + C-peptide

C-peptide is a good marker of beta cell function

Half-life is 30 mins and renally cleared

288
Q

Which condition in Addison’s disease would you get hypoglycaemia?

A

Concurrent Addison’s disease (RARE) –> hypoglycaemia (polyglandular autoimmune syndrome)

289
Q

What investigations would you order for someone with hypoglycaemia?

A
  • Insulin
  • C peptide
  • Drug screen
  • Autoantibodies
  • Lactate
  • FFAs/blood ketones
  • Cortisol/GH
  • Other speciality tests (IGF-2)
290
Q

What do these results suggest about the cause of hypoglycaemia?

A

HIGH insulin + HIGH C-peptide = endogenous insulin (pancreas-produced)

HIGH insulin + LOW C-peptide = exogenous insulin (injected)

291
Q

What do these results suggest about the cause of hypoglycaemia in a neonate?

  • Hypoinsuloinaemic hypoglycaemia + KETONES
  • Hypoinsuloinaemic hypoglycaemia + NO KETONES
A

Hypoinsuloinaemic hypoglycaemia + KETONES = DKA

Hypoinsuloinaemic hypoglycaemia + NO KETONES = inherited metabolic disorder - FAOD/ MCAD, GSD type 2, carnitine disorder

292
Q

Name 3 ketone bodies

A

3-hydroxybutyrate
Acetone
Acetoacetate

293
Q

What are some causes of neonatal hypoglycaemia?

A
  • Premature/IUGR
  • Inadequate glycogen and fat stores
  • Inborn errors of metabolism
294
Q

What are the causes of neonatal hypoglycaemia with low insulin, low C peptide, low ketones but raised FFAs?

A

Inherited metabolic disorders:

  • Fatty Acid Oxidation Disorders (FAOD) = no ketones produced
  • Glycogen Storage Disease (GSD) type 1 (gluconeogenetic disorder)
  • Medium Chain Acyl-CoA
  • Deficiency (MCAD)
  • Carnitine Disorders
295
Q

When would you see hypoglycaemia in a neonate but with elevated insulin levels and a high C peptide?

A

Drugs (sulphonylureas)
Islet cell tumours (e.g. insulinoma)

Islet cell hyperplasia

Infant of a diabetic mother

Beckwith-Wiedemann syndrome (specific body parts overgrowth disorder usually presents at birth)

Nesidioblastosis (hyperinsulinaemic hypoglycaemia caused by excessive function of beta cells with an abnormal microscopic appearance)

296
Q

What is the normal insulin secretion pathway?

A

Glucose crosses membrane and enters glycolysis via glucokinase

Glycolysis produces ATP -> rise in ATP leads to closure of the ATP-sensitive K+ channel (a lot of genetic mutations that affect this channel) -> membrane depolarisation, calcium influx and insulin exocytosis

297
Q

How do sulphonylureas work?

A

Sulphonylureas bind to the ATP-sensitive K+ channel and makes it close, independently of ATP –> insulin release even when there is no ATP around (this is why sulphonylureas can cause hypoglycaemia)

298
Q

What is an insulinoma?

A

Insulinomas = LOW glucose, HIGH insulin, HIGH c-peptide:

1-2 per million per year (rare)
Usually a small solitary adenoma (10% malignant, 8% associated to MEN1)
Diagnosis on biochemistry and localisation
Treatment is simple resection

299
Q

What are some rare causes of hypoglycaemia with undetectable insulin?

A
  • Paraneoplastic syndrome - secretion of big IGF-2 - mesenchymal tumours (mesothelioma, fibroblastoma) and epithelial tumours (carcinoma)
  • Autoimmune - antibodies against insulin or insulin receptor Can be caused by certain drugs (hydralazine, procainamide)
300
Q

What are some genetic causes of hypoglycaemia (LOW glucose, HIGH insulin, HIGH c-peptide)?

A
  • Glucokinase activating mutation

- Congenital hyperinsulinism (KCNJ11 /ABCC8, GLUD-1, HNF4A, HADH)

301
Q

What are the reactive/post-prandial causes of hypoglycaemia?

A
  • Can occur after gastric bypass
  • Hereditary fructose intolerance
  • Early diabetes
  • In insulin-sensitive people post-exercise or large meals
  • True post-prandial hypos are difficult to define

Year 5 Pathology (5 decks)

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