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chempath Flashcards

1
Q

what are porphyrias?

A

diseases due to deficiencies in the enzymes of the Haem biosynthesis pathway. -> overproduction of toxic haem precursors leading to 3 presentations. 1. acute neuro-visceral 2. acute cutaneous 3. chronic cutaneous

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2
Q

ALA Synthase deficiency

A

ALA synthase produces ALA (5-aminolaevulinic acid) from succinyl CoA + glycine).

*not a porphyria

Causes X-linked sideroblastic anaemia

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3
Q

purines e.g.s?

A

adenosine, guanosine, inosine (intermediate)

  • genetic code A & G
  • secondary messengers for hormone action e.g. cAMP

energy transfer e.g. ATP

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4
Q

how does the purine pathway lead to gout?

A

Gout affects up to 3% of males throughout their life.

Allantoin is highly soluble and freely excreted in urine but humans do NOT have working uricase enzyme, hence, we have to excrete urate.

Urate is relatively insoluble and circulates in our bloodstream remarkably close to its limits of solubility, precipitating to gout crystals.

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5
Q

Why does gout precipitate in peripheries/ in the cold?

A

Plasma [Monosodium Urate]:

Men = 0.12-0.42 mmol/L

Women = 0.12- 0.36 mmol/L

Solubility at 37 degrees = 0.40mmol/L

dependent on pH and temp.

Solubility falls at lower pH.

At 30 degrees = 0.27 mmol/L

-> less dissolved at cooler temps.

gout is more likely to precipitate in the big toe/ periphery which is cooler.

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6
Q

what % of uric acid in the excreted in the urine and what % is reasorbed?

A

only 10% of uric acid in the blood is excreted in the urine, the rest is reabsorbed.

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7
Q

In the whole purine pathway involving de novo and salvage pathways, what is the rate limiting step?

What causes negative feedback on this step?

Positive feedback?

A

Rate limiting step is the PAT enzyme (phosphoribosylpyrophosphate amidotransferase).

Negative feedback from GMP and AMP.

Under positive feedback/ control by its PRPP (what PAT acts on)

High [PRPP] drives activity of PAT.

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8
Q

In the salvage pathway, what converts hypoxanthine and guanine back to their precursors?

A

HPRT/ HGPRT (hypoxanthine guanine phosphoribosyl transferase) catalyses hypoxanthine and guanine back to GMP and AMP in the salvage pathway.

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9
Q

Lesch-Nyhan disease

  • what enzyme is affected
  • presentation
A

X linked disease, normal at birth.

complete HGPRT deficiency.

development delay from 6/12, hyperuricaemia, choreiform movements (basal ganglia affected), spasticity, mental retardation, self-mutlitation (85%)

  • bite lips and digits so hard that they seriously injure themselves.
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10
Q

development delay from 6/12, hyperuricaemia, choreiform movements (basal ganglia affected), spasticity, mental retardation, self-mutlitation (85%)

A

Lesch-Nyhan disease

HGPRT deficiency -> uric acid buildup due to lack of salvage pathway activity.

Lack of guanine and hypoxanthine back to GMP and AMP -> less negative feedback to PAT -> massive activity of PAT creating high concentration of INP and uric cid.

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11
Q

what other conditions may cause hyperuricaemia?

A

Increased urate production (secondary):

any excessive cell division.

e.g. myeloproliferative, lymphoproliferative disorders.

Decreased urate excretion:

  • chronic renal failure
  • lead poisoning
  • thiazide diuretics can cause hyperglycaemia, hypoNa, HyperCa, and hyperuricaemia
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12
Q

Metabolic SEs of thiazide diuretics

A

hyperglycaemia

hypoNa

HyperCa

Hyperuricaemia

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13
Q

what condition?

chronic.

may also see deposits in ear lobes/ joints.

looks like hard cottage cheese/ soft chalk.

A

Chronic tophaceous gout.

  • monosodium urate crystals

stimulate intense inflammation in the joint

deposition of gout in the soft tissues, can also be peri-articular.

M 0.5-3% prevalence

F 0.1-0.6%

usually in post pubertal males/ post menopausal females

can be acute. (attacks)

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14
Q

Rapid build up of pain, exquisitely painful affected joint

red, hot and swollen

big toe affected

A

Acute gout

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15
Q

Acute gout

  • what is the most common joint affected?
  • mx?
A

1st MTP joint

Acute Mx: Pain relief!

  • NSAIDs e.g. diclofenac 1st line (except in asthmatics/ previous peptic ulcer disease/ CKD)
  • Colchicine: inhibits microtubule polymerization. Is v useful in acute gout as it also inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect.

Glucocorticoids injected directly into joint (oral prednisolone also good)

Do not attempt to modify plasma [urate] during acute attack, as it can paradoxically lead to further crystallisation of urate.

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16
Q

Chronic Gout

-Mx

A

Lifestyle: drinking plenty of water

- Allopurinol (Xanthine Oxidase inhibitor, thus reducing urate synthesis from xanthine)

Reverse any factors causing hyperuricaemia e.g. thiazide diuretics

Increase renal excretion of uric acid w probenecid.

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17
Q

Side effects of allopurinol?

A
  • interacts with azathioprine (which interferes w purine metabolism), making it more toxic on the BM

Azathioprine -> Mercaptopurine -> Thioinosinate (interferes w purine metabolism)

Allopurinal inhibits XO, which is also in charge of breaking down mercaptopurine.

Thus, [mercaptopurine] increases to dangerous toxic levels, which can render the pt neutropenic.

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18
Q

Dx of Gout

A

Tap effusion

View under polarised light using red filter

Needle shaped, negatively birefringent crystals.

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19
Q

what crystals found in pseudogout?

A

occurs in pts with osteoarthritis

calcium pyrophosphate crystals.

self-limiting 1-3 wks.

rhomboid shaped, positively birefringent.

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20
Q

two main functions of calcium

A
  • Skeletal: important constituent of bone mineralization
  • Metabolic: impt for action potentials and intracellular signalling.

The normal level for calcium is 2.2-2.6mmol/L

Extracellular levels of calcium are affected by gut absorption, renal excretion, intracellular calcium levels and skeletal integrity

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21
Q

normal range for calcium

A

2.2 - 2.6 mmol/L

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22
Q

How is calcium found in the serum?

A

1% of body’s calcium is in the serum, 99% in the bones

Free (“ionised”) ~50% - biologically active

Protein-bound ~40% - albumin

Complexed ~10% - citrate / phosphate

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23
Q

what is the formula to calculate corrected Ca2+?

A

serum Ca2+ + 0.02*(40 – serum albumin(g/L))

*impt because e.g. one has low albumin, bound ca may be low, but free ca still normal.

thus, corrected ca tells you that the problem is w albumin and that the ionised ca is still normal.

tx in this case would be albumin rather than calcium.

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24
Q

circulating calcium: function

A
  • Important for normal nerve and muscle function
  • Plasma concentration must thus be maintained despite calcium and vitamin D deficiency
  • Chronic calcium deficiency thus results in loss of calcium from bone to maintain circulating calcium
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25
Q

why is it impt to know Corrected Calcium and not just the free ionised Ca levels?

A

*impt because e.g. one has low albumin, bound ca may be low, but free ca still normal.

thus, corrected ca tells you that the problem is w albumin and that the ionised ca is still normal.

tx in this case would be albumin rather than calcium.

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26
Q

what happens when there is low Ca detected in the body?

A

Hypocalcaemia detected by parathyroid gland

Parathyroid gland releases PTH activating osteoclasts in bones to release calcium

PTH “obtains” Ca2+ from 3 sources

o Bone

o Gut (increased absorption VIA increased calcitriol produced)

o Kidney (resorption and renal 1 alpha hydroxylase activation)

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27
Q

PTH

  • function
  • where is it secreted from
A
  • Peptide hormone thus cannot be given orally
  • Secreted from parathyroids
  • Bone & renal Ca reabsorption
  • Stimulates vit D synthesis (through 1alpha-hydroxylation)
  • Also stimulates renal phosphate wasting
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28
Q

where is cholecalciferol (D3) synthesized?

A

in the skin.

UV light from sun converts 7-dehydrocholesterol to cholecalciferol.

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29
Q

What are calcidiol and calcitriol?

A

calcidiol = 25-hydroxycholecalciferol

calcitriol = 1,25-dihydroxycholecalciferol

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30
Q

Where is 25 hydroxylase found?

what does it do?

A

found in the liver.

100% of D3 is converted to 25-OH D3 in the liver.

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31
Q

where is 1 alpha hydroxylase found?

what does it do?

A

in the kidney.

rate limiting step regulated by PTH!

converts 25-OH D3 to 1,25-(OH)2 D3

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32
Q

what is ergocalciferol

A

D2 - a plant pased product.

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33
Q

what is the rate limiting step in the calcitriol pathway?

A

1 alpha hydroxylase, regulated by PTH

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34
Q

Calcitriol function

A

Gut: Intestinal Ca and P absorption which is critical for bone formation

Kidneys: increases ca reabsorption

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35
Q

Role of the skeleton

A
  • Structural framework, strong, lightweight, mobile, protects organs, capable of orderly growth and remodelling
  • Metabolic role in calcium homeostasis
  • Main reservoir of Ca, P and Mg
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36
Q

metabolic bone disease includes?

A

osteoporosis,

osteomalacia,

Paget’s disease,

PTH bone disease,

renal osteodystrophy.

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37
Q

Risk factors for Vit D deficiency

A

lack of sunlight exposure

dark skin

dietary

malabsorption

Vit D deficiency in the UK (>50% of adults, 16% severe deficiency during winter and spring)

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38
Q

how does Vit D deficiency affect bone?

A

defective bone mineralisation

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39
Q

some causes of Vit D deficiency

A

renal failure - no 1a hydroxylase

anticonvulsants which break down Vit D e.g Phenytoin

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40
Q

bone and muscle pain

increased fracture risk

Low Ca & PO4, raised ALP

Loosers zones (pseudofractures)

A

Osteomalacia

  • defective bone mineralisation
  • Loosers zones
  • raised ALP as bones trying to make new osteoids.

Low Ca and PO4 due to Vit D/ calcitriol deficiency

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41
Q

Bowed legs

costochondral swelling

widened epiphyses at the wrists

myopathy when Ca really low

A

Rickets

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42
Q

Features of rickets?

A

Bowed legs

costochondral swelling

widened epiphyses at the wrists

myopathy when Ca really low

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43
Q

Loss of bone mass

residual bone normal in structure

normal biochemistry

cause of pathological fracture

A

Osteoporosis

asymptomatic until first fracture

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44
Q

Typical fracture in Osteoporosis

A

NOF, verterbral, wrist e.g. Colle’s

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45
Q

Dx of osteoporosis?

A

Using DEXA scan.

T-score – sd from mean of young healthy population (useful to determine # risk)

Osteoporosis – T-score <-2.5

* Osteopenia – T-score between -1 & -2.5

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46
Q

when is Z-score useful?

A

Z-score – SD from mean of aged-matched control (useful to identify accelerated bone loss in younger patients)

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47
Q

Causes of osteoporosis

A

Deficient sex steroids (menopause)

old age

childhood illness (failure to achieve peak bone mass)

Lifestyle: sedentary, EtOH, smoking, low BMI/nutritonal

Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings

Drugs: steroids

Others eg genetic, prolonged intercurrent illness

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48
Q

Tx for osteoporosis

lifestyle changes

A

Weight-bearing exercise, stop smoking, reduce EtOH

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49
Q

Medical tx for osteoporosis

A

Vitamin D/Ca

Bisphosphonates (eg alendronate) –↓ bone resorption. Given if T-score <2.5 but vit D is normal. Used by osteoblast to make bone which cannot be biologically broken down.

Teriparatide (PTH derivative) – anabolic

Strontium – anabolic + anti-resorptive (major side effects)

(Oestrogens – HRT) given if patient has early menopause but risk of breast cancer

SERMs eg raloxifene, tamoxifen. Agonist in bone, antagonist in breast. But hot flushes/ increased risk endometrial Ca

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50
Q

Polyuria / polydipsia

Constipation

Neuro – depression/ confusion / seizures / coma

A

hyperCa

symptoms after Ca >3.0 mmol/L

same symptoms as HyperPTH generally.

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51
Q

Normal Hormonal response to high Ca

A

PTH should be zero (completely suppressed)

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52
Q

1st thing to do when u see high Ca

A

is it a genuine result? - repeat

YES - what is the PTH?

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53
Q

If high Ca, PTH not suppressed:

causes?

A

INAPPROPRIATE PTH response to hyperCa

  1. Most common- primary hyperparathyroidism
  2. rare- familial hypocalciuric hyperCa
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54
Q

What is the most common cause of hyperCa

A

primary hyperparathyroidism

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55
Q

Causes of Primary HyperPTH

A

Parathyroid adenoma (80%) / hyperplasia (assoc w MEN1)/ carcinoma (2%)

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56
Q

increased serum Ca, increased/ inappropriately normal PTH,

what is the serum PO4 and urine Ca?

A

Primary HyperPTH

PO4 LOW (phosphate trashing hormone)

Ca in urine HIGH (due to hyperCa)

-> so high ca, low or normal PO4

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57
Q

HyperPTH symptoms

A

BONES (PTH bone disease – become weak and fractures eventually) and STONES (renal calculi)

Hypercalcaemia -> abdominal MOANS (constipation, pancreatitis), psychiatric GROANS (confusion)

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58
Q

Where are Calcium sensing receptors found? (CaSR)

A

Parathyroids: regulates PTH release

Renal: influences Ca2+ resorption (PTH independent)

Familial hypocalciuric (/benign) hypercalcaemia (FHH / FBH): CaSR mutation -> higher set point for PTH release -> mild HyperCa and reduced urine Ca

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59
Q

causes of hyperCa

PTH suppressed

A

In malignancy:

  • Humoral hypercalcaemia of malignancy (eg small cell lung Ca)

– PTHrP (normal in pregnancy to increase Ca levels, as babies will steal Ca from mom)

  • Bone metastases (eg breast Ca)

– Local bone osteolysis

  • Haematological malignancy (eg myeloma)

– cytokines

  • Sarcoidosis (non-renal 1α hydroxylation)
  • Thyrotoxicosis (thyroxine -> bone resorption)
  • Hypoadrenalism (renal Ca2+ transport)
  • Thiazide diuretics (renal Ca2+ transport)
  • Excess vitamin D (eg sunbeds…)
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60
Q

Mx of hyperCa

A

Acute management

Fluids+++ and Fluids+++!

Bisphosphonates (if cause known to be cancer) otherwise avoid.

Treat underlying cause!

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61
Q

Signs of hypoCa

A

Neuromuscular excitability – Trousseau’s sign, Chvostek’s sign, hyperreflexia, laryngeal spasm (stridor), prolonged QT interval, convulsions

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62
Q

tx of hypoCa

A

Ca + Vit D (give rapidly to avoid convulsions)

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63
Q

hypoCa

  • what to do next?
A

Is it a genuine result? Repeat and adjust for albumin. Secondly, what is the PTH?

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64
Q

Low Ca, PTH raised (secondary hyperPTH)

causes

A

Vit D deficiency - dietary, malabsorption, lack of sunlight

Chronic kidney disease (lack of 1a hydroxylation)

PTH resistance (pseudohypoPTH)

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65
Q

Secondary HyperPTH can progress to?

A

tertiary HyperPTH

chronic low Ca and high PTH -> high Ca and high PTH

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66
Q

Low Ca, Low PTH

causes?

A

surgical - post thyroidectomy

autoimmune hypoPTH

congenital absence of the parathyroids e.g. DiGeorges

Mg deficiency (PTH regulation) - Mg necessary to make PTH

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67
Q

Focal PAIN, warmth, deformity, fracture, SC compression, malignancy, cardiac failure (high output failure as blood needs to be transported rapidly to site of bone remodeling)

affects the Pelvis, femur, skull and tibia most commonly

A

Pagets Disease

focal disorder of bone remodeling

Highly elevated Alk Phos

Nuclear med scan / XR

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68
Q

Mx of pagets

A

Bisphosphonates for pain (good to stop rapid bone turnover)

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69
Q

Primary HyperPTH

effect on bone

A

osteitis fibrosa cystica

loss of cortical bone- > fracture risk

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70
Q

Normal biochemistry (Ca/PO4/ Alk phos etc)?

A

osteoporosis

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71
Q

Ca Low/ N

PO4 Low/ N

PTH (high)

Vit D Low

ALP high

A

Osteomalacia/ Rickets

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72
Q

Ca/PO4/PTH/Vit D Normal

ALP v high

A

Pagets

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73
Q

Ca High

PO4 Low

PTH high/ inappropriately Normal

Vit D normal

ALP high/ normal

A

primary HyperPTH

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74
Q

Ca low/N

PO4 high

PTH high

Vit D N

Alk Phos N/ high

A

Renal osteodystrophy

Vit D normal, but 1a hydroxylation low -> low calcitriol activity.

PO4 retention in renal failuer

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75
Q

why would a pt be unconscious w metabolic acidosis?

A

Brain enzymes cannot function at v acidic pH

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76
Q

How to calculate serum osmolality?

A

2 (Na +K) + Urea + Glucose

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77
Q

How to calculate Anion Gap?

A

Na + K - Cl - bicarb

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78
Q

what is the normal range for anion gap

A

8-16 mEq/L

if high -> suggests high anions causing acidosis

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79
Q

Why is pt unconscious with high osmolality?

A

Brain is v dehydrated

First line tx: gradual fluid replacement

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80
Q

Metformin is assoc w which metabolic acidosis?

A

Lactic Acidosis

  • typically occurs in patients w renal insufficiency

metformin contraindicated in renal impairment!

AKI/ CKD/ metformin overdose-> metformin accumulation.

Cori cycle: Lactate in the liver converted back to glucose to be used by muscle.

Metformin inhibits this conversion -> lactate accumulation

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81
Q

T2DM diagnostic cut offs?

A

Fasting glucose >7.0 mM

OGTT 2h post 75g > 11.1mM

Impaired fasting glucose= 6.1-7.0mM

Impaired Glucose tolerance = 7.8-11.1 mM

Diagnosis = 1 abnormal result + symptomatic. If asymptomatic, diagnosis should be from 2 samples done on different days.

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82
Q

Which deaths are reported to the coroner?

A

Under Section 3 of the Coroner’s Act 1887,

The following deaths are reported to the coroner:

  1. Violent
  2. Unnatural or sudden
  3. Cause of death is unknown

A number of these require analysis for drugs and

alcohol to establish the cause of death

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83
Q

what kind of samples are available to the coroner?

A

Ante-mortem serum / blood (if hospitalised)

* Post-mortem blood - Heart blood, cavity blood (screening), femoral vein blood (screening & quantitation). Heart blood cannot be used for quantitation.

* Urine (shows what was taken yesterday), stomach contents, vitreous humor (if blood not available as in RTC, measure glucose in diabetic deaths as blood can’t be used)

* Hair, liver (for people who have decomposed)

* Others – bile, muscle, powders, syringes (can be misleading as does not prove use)

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84
Q

Cannabis causing death?

A

Never fatal alone, find in RTAs

* Driving after alcohol + cannabis, lethal combi

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85
Q

Ethanol causing death?

A

OD, accidents including RTAs

o Additive effects other resp depressant drugs

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86
Q

Heroin causing death?

A

measured as morphine

iv injection, mix with tobacco, volatilised

o Fatal OD with all routes of ingestion

o Additive effects other resp depressant drugs

o Few rapid deaths, most people die from respiratory depression or aspiration pnuemonitis

o Tolerance

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87
Q

Methadone causing death?

A

Methadone - drug to tx heroin addicts as a substitute.

Tolerance, slow absorbed, taken once every 24h

* After ingestion, fatal amount takes 4-6hours to die

* Additive effects w other resp depressant drugs

* 5 mL can kill a child, 60 mL healthy adult male

* Maintenance dose can vary from 5 to 200 mL, usually 20-40m

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88
Q

BZDs causing death?

A

Addicts usually take these after comedones and heroins for better effect

Additive effects other resp depressant drugs

* Extremely rare to cause death alone

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89
Q

Cocaine causing death?

A

Widely used, injected with heroin, “speedball”

Tolerance which encourages binging

Acute dangers: cardiac dysrhythmias - acute heart failure, myocardial infarction

Slowly developing damage to the myocardium (deaths due to long term use), ventricular arrythmias, sudden death

Lethal syndrome of excited delirium - occurs in regular users within 24 hrs of last dose

Body packers

Effects prolonged if used with ethanol, get cocaethylene formed

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90
Q

Amphetamines / Stimulants causing death?

A

e.g. methamphetamines, MDMA (ecstacy), mephedrone.

Increasing number of deaths

Large OD causes direct toxic effect on heart

Cause hyperthermia, leads to rhabdomyolysis, leads to muscle necrosis and renal failure

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91
Q

Post mortem redistribution of drugs

A

PM blood conc cannot be used to calculate the dose, eg in antidepressants which have high distribution in blood, will have higher [] in PM blood

e.g.

76yrs, male, had been on amitriptyline for 7 years

Told psychiatrist had suicidal thoughts

Daughter could not contact father

Police called, broke it to flat

Stab wounds to chest & stomach (total 7)

Found pair blood stained trouser over a chair

Steak knife had been washed up in kitchen

Specimens: femoral vein blood, urine

Amitriptyline blood : 1.27 ug/ml

Nortriptyline blood : 2.33 ug/ml

Combined blood : 3.60 ug/ml

Combined therapeutic plasma conc: 0.12 to 0.25

Combined potentially fatal conc: >2.0

No ethanol or other drugs detected in general screen blood

Case 1 Interpretation: despite having higher []s of antidepressants, it is not an amitriptyline OD, as amitriptyline has high volumes of distribution. The results show chronic use of antidepressants.

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92
Q

45 male, history of depression

Previously attempted to take own life

Found with paracetamol, brown tablets (COX), ¼ full bottle port. Problems at work

Specimens: femoral vein blood, urine

Amitriptyline blood : 1.63 ug/ml

Nortriptyline blood : 0.23 ug/ml

Combined blood : 1.86 ug/ml

Combined therapeutic plasma conc: 0.12 to 0.25

Combined potentially fatal conc: >2.0

No other drugs detected in general screen blood

No drugs of abuse detected in urine

A

Interpretation:

amitriptyline OD as this patient does not have a drug history of antidepressants as the previous case.

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93
Q

32yrs, male, in residential home

Treatment for depression & schizophrenia

Believed sudden death in epilepsy

Specimens: stomach contents, FVB, urine

Medications included:

Clozapine 450 mg/night (max dose)

(04.01.05, 12.5 mg/night è 15.04.05, 450 mg/night) (died in May)

Zopiclone 15 mg/night

Lithium carbonate 600 mg/night

Clomipramine 200 mg/night

Chlorpromazine 50mg 4x day

Clomipramine blood: 1.35 ug/ml (Therapeutic: 0.10-0.48, Toxic: > 0.40) Potentially fatal : 1.0

desmethylclomipramine blood : 11.62 ug/ml fatal: 0.8 - 2.0

Clozapine blood 2.01 ug/ml Therapeutic : 0.10-0.80, Toxic: > 0.80, Potentially fatal : 3.0 ug/ml

desmethylclozapine 2.33 ug/ml

Ratio clozapine:desmethylclozapine = chronic dosing

Sub-therapeutic Li, neg chlorpromazine & zopiclone

A

extremely high desmethylclomipramine -> OD of clomipramine

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94
Q

Cocaine: what happens in Post mortem distribution?

A

Degrades in pm blood (fluoride oxalate only slows the process)

o pseudocholinesterases -> EME

o Chemical hydrolysis -> BE

* PM blood [] and blood [] at time of death not same

* To interpret cocaine - witness behaviour, cardiovascular pathology, drug use history

* Addict can tolerate high levels

* Causes heart problems, death with low levels

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95
Q

56yrs, female, died following a meal

Slightly heavy heart, natural?

Possibility of amitriptyline OD

(No tablet residue in stomach)

Specimens: femoral vein blood

Ethanol blood: less than 10 mg/100ml

No drugs detected in general screen of blood

A

Case 4 Interpretation: absent due to lack of info

Drugs hx extremely impt!

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96
Q

56yrs, female, at home with husband

Husband believed wife taken some tablets

LAS called, but she refused treatment

Later collapsed, taken to hospital but died

Prescribed medication included: Phyllocontin continus (aminophylline), aspirin, cordura (doxazosin), indur, bendrofluazide, frusemide, amitriptylline, piriton (chlorpheniramine), zirtek (cetirizine), ibuprofen

Samples: AM blood taken shortly after admission

Ethanol am blood: Not detected

Theophylline am blood: 140 ug/ml

Therapeutic range: 8 – 10 Potentially fatal: >63

Ibuprofen am blood: Not detected

Doxazosin am blood: Not detected

No drugs detected in general screen of am blood

A

Case 5 interpretation: with drug history, coroners were able to use tests to find specific drugs in the am blood to determine CoD. This can’t be done if no drug history is available.

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97
Q

What specimen gives info about long term drug use?

A

Hair.

Blood/serum: drugs typically can be detected for no more than 12 hours

Urine, drugs typically detected for 2-3 days

Drugs are incorporated into hair from the blood stream during the growth phase.

Hair growth approx 1cm/month – “tape-recording of drug use”

Can provide valuable evidence which cannot be provided by any other means.

Segmental analysis provides pattern of past use (if present in blood but not in hair, means drug eg. morphine was taken in one dose)

Established technique

Increasingly used in crime investigation

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98
Q

use of hair analysis PROS?

A
  • Demonstrate a history of drug use or lack of it
    e. g. cocaine can be detected in hair but not in other fluids

* avoid the need for a police investigation

* saving valuable resources

* help the family come to terms with the death.

  • Demonstrating tolerance or lack of it

* aid interpretation of drug conc found in post-mortem blood to help establish CoD.

  • Compliance with medication

* question frequently asked by the pathologist

* antidepressants, antipsychotics, anticonvulsants.

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99
Q

death due to chronic cocaine use?

A
  • Depression/suicide

* long term cocaine use → depression → suicidal intention.

  • * Sudden unexplained death

* reliable drug history to distinguish heart disease caused by chronic cocaine use/ naturally occurring heart disease, which saves unnecessary investigations for hyperlipidaemia etc.

  • * Excited delirium

* can be caused by long term use of cocaine

* evidence important if death occurs while being restrained

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100
Q

Hair Analysis CONS?

A

Environmental Contamination

Absorbed from sweat or sebum coating hair

Passive inhalation

Cosmetic treatment - Shampoo washing, perming, dyeing, bleaching

Hair colour – darker hair absorbs more drugs

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101
Q

HypoNa?

A

<135 mmol/L

commonest electrolyte abnormality in hospitalized patients.

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102
Q

Pathogenesis of HypoNa

A

increased extracellular water

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103
Q

ADH / Vasopressin release

  • when does it occur
  • how does it work
A

stimulated by high serum osmolality (mediated by hypothalamic osmoreceptors)

and low blood volume / BP (baroreceptors in the carotids, atria and aorta)

  • > ADH released from posterior pituitary
  • > acts on V2 receptors in the collecting duct

insertion of aquaporin 2 in distal collecting ducts to increase water reabsorption

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104
Q

ADH / Vasopression

  • works on which receptors
A

V2 receptors in the collecting duct

  • insertion of aquaporin 2 to increase water reabsorption

V1 receptors:

  • on vascular SM-> vasoconstriction
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105
Q

what measures serum osmolality and low blood vol/pressure in the body?

A

serum osmolality by hypothalamic osmoreceptors.

low blood volume/ pressure mediated by baroreceptors in carotids, atria and aorta.

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106
Q

ADH is naturally inhibited by which hormone?

A

Inhibited by cortisol!

thus, in Addisons, with low cortisol, less inhibition of ADH and more water reabsorbed leading to HypoNa

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107
Q

if Na LOW,

what to do next?

A

assess pt’s volume status.

Hypo/Eu/Hypervolaemic?

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108
Q

Clinical signs of hypovolaemia

A

tachycardia, postural hypotension

dry mucous membranes, reduced skin turgor

confusion/ drowsiness

reduced urine output, low urine Na+ (<20)

Decreased blood vol -> renin angiotensin system -> increased aldosterone -> increased Na reabsorption to retain fluids

(cant interpret urine Na if pt is on diuretic)

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109
Q

Causes of hypovolaemic hypoNa

A

Diarrhoea

Vomiting

Diuretics

Salt losing nephropathy

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110
Q

Causes of euvolaemic hypoNa

A

SIADH - so many causes!

Hypothyroidism

Adrenal Insufficiency

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111
Q

Causes of SIADH

A

CNS, lung pathology

e.g. stroke/ bleed, pneumonia

Drugs

e.g. SSRIs, TCA, opiates, PPIs, carbamazepine

Tumours, surgery

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112
Q

Ix for euvolaemic HypoNa

A

TFTs for hypothyroidism

Short SynACTHen test for Addisons

Plasma and urine osmolality for SIADH

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113
Q

what should the plasma and urine osmolality be in SIADH

A

Reduce Plasma Osmolality

and

High Urine osmolality

Inappropriate ADH -> increased water reabsorption (but not solute) so excess water.

this causes the hypoosmolality (dilution of blood) and in turn decreases [solutes] -> HypoNa and also low

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114
Q

Dx of SIADH

A

no hypovolaemia

no hypothyroidism/ adrenal insufficiency

Reduced plasma osmolality AND increased urine osmolality (>100)

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115
Q

Mx of HypoNa

A

Hypovolaemia: Volume replacement w 0.9% saline

Euvolaemia: Fluid restriction, treat the underlying cause

Hypervolaemia: Fluid restriction, tx underlying cause

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116
Q

Severe hypoNa

Reduced GCS, seizures

mx?

A

Seek expert help!

Tx w hypertonic 3% saline (3%NaCl)

(if reduced GCS/ seizures)

*Serum Na must not be corrected >8-10mmol/L in the first 24 h

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117
Q

When correcting Na levels, what to ALWAYS rmb

A

Dont correct it >8-10mmol/L in the first 24 h

Risk of osmotic demyelination (Central Pontine myelinolysis) - quadriplegia, dysarthria, dysphagia, seizures, coma and death

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118
Q

Central Pontine Myelinolysis

A

most commonly overly rapid correction of low blood sodium

(also assoc w refeeding in anorexia/ burns victims/ dialysis pt)

w correction of HypoNa w IV fluids, if serum Na rises too rapidly, water will be driven out of the brain’s cells.

-> cellular dysfunction

and CPM characterized by acute paralysis, dysarthria, dysphagia etc.

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119
Q

Mx of SIADH

A

Tx underlying cause

Water resriction (750ml - 1L/day)

Drugs:

  • demeclocycline

(reduces responsiveness of collecting tubule to ADH- monitor U+Es due to risk of nephrotoxicity)

  • tolvaptan (V2R antagonist)
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120
Q

What is demeclocycline and what is it used for?

A

Reduces responsiveness of collecting tubule cells to ADH

used in SIADH when fluid restriction is insufficient.

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121
Q

What is Tolvaptan and what is it used for?

A

V2R antagonist.

used in SIADH to reduce ADH binding to V2R and triggering insertion of aquaporin-2

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122
Q

definition of HyperNa?

A

Serum [Na+] >145 mmol/L

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123
Q

main causes of hyperNa

A

unreplaced water loss

  • GI loss, sweat loss,
  • renal loss: osmotic diuresis, reduced ADH release/ action (DI)

Pt cannot control water intake - children/ elderly

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124
Q

Mx of HyperNa

A

Correct water deficit - 5% dextrose

Correct ECF volume depletion - 0.9% saline

Serial Na+ measurements every 4-6 h

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125
Q

Effect of diabetes mellitus on serum Na

A

hyperglycaemia draws water out of cells leading to hypoNa

Osmotic diuresis in uncontrolled diabetes leads to loss of water and hyperNa

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126
Q

Ix in suspected Diabetes insipidus

A

Serum Glucose (to exclude DM)

Serum K (exclude hypoK)

Serum Ca (exclude HyperCa)

Plasma and urine osmolality

Water deprivation test (dilute urine)

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127
Q

what ion is the main intracellular cation?

A

K+

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128
Q

Normal range of K+

A

3.5 -5.0 mmol/L

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129
Q

What is K+ regulated by

A

Renin-Angiotensin system (AgII)

and

Aldosterone

(High K+ stimulates release of aldosterone to increase Na reabsorption and K+ excretion)

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130
Q

How does the renin-angiotensin-aldosterone system work?

A

Aldosterone stimulates Na reabsorption and K excretion in the urine, through the principal cells in the cortical collecting tubule.

Even though Na is reabsorbed, serum [Na] does not change as water is reabsorbed as well.

Aldosterone thus, only affects [K+]

Aldosterone increases no of open Na channels in the luminal membrane, increasing Na reabsorption. This makes the lumen electronegative and creates an electrical gradient. Thus, K+ is secreted into the lumen.

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131
Q

Main causes of hyperK

A

Renal impairment: reduced renal excretion

Drugs: ACEi, ARB, spironolactone

Low Aldosterone: Addison’s disease, Type 4 renal tubular acidosis (low renin, low aldosterone)

Release from cells: rhabdomyolysis, acidosis (H+ taken up into cells, K+ out)

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132
Q

What are the ECG changes assoc w hyperK

A

tall tented T waves

loss of p wave

broad QRS complex

will lead to arrhythmia (VF/ asystole) and needs urgent tx

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133
Q

Mx of HyperK

A

10ml 10% calcium gluconate - if K+> 6.5

(to reduce the risk of cardiac arrhythmias)

50ml 50% dextrose +

10 units insulin

(insulin will drive K+ into cells, but will also drive in glucose -> making pt hypoglycaemic so give dextrose)

Nebulised salbutamol

Tx the underlying cause

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134
Q

Causes of HypoK

A

GI loss - D+V, fistula

Renal loss - Hyperaldosteronism (Conns), increased sodium delivery to distal nephron due to diuretics/ thiazides/ Bartter or Gitelman syndrome, osmotic diuresis in diabetics

redistribution into cells - insulin, b agonists e.g. salbutamol, alkalosis

Rare causes- renal tubular acidosis types 1 &2, hypoMg

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135
Q

HypoK and how it leads to alkalosis?

and how alkalosis leads to hypoK

A

Loss of K+ outside, causes K+ from the intracellular stores to move out. -> H+ moves into cells to maintain charge.

(-> extracellular alkalosis)

Low K+ also leads to increased H+ secretion in the kidneys. Increased excretion of H+ in exchange for Na+ leading to production of acidic urine and bicarbonates.

Low H+ outside due to alkalosis causes H+ to move out of cells and thus K+ to move into cells.

-> HypoK

Alkalosis also causes increased K+ secretion in the kidneys

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136
Q

HypoK clinical features

A

muscle weakness

-> cramping, paralysis, parasthesiae

cardiac arrhythmia

polyuria and polydipsia (nephrogenic DI)

ECG changes - flattened T waves, U wave elevation, ST segment sagging

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137
Q

Ix for a pt with hypoK and HTN?

A

Aldosterone:renin ratio

conns

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138
Q

Mx of HypoK if serum K between 3.0-3.5

A

Oral KCl (two SandoK tablets tds for 48h)

Recheck serum K

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139
Q

Mx of hypoK if serum K <3.0

A

IV KCl, max rate 10mmol/hr

Rates > 20mmol/hr are highly irritating to peripheral veins, and need to be given via central line

Tx underlying cause e.g. spironolactone

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140
Q

mx of hypoglycaemia if pt is alert and oriented

A

oral carbohydrates

rapid acting e.g. juice/ sweets

longer acting e.g. sandwich

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141
Q

Mx of hypoglycaemia if drowsy/ confused but swallow intake

A

Buccal glucose e.g. hypostop/ glucogel

Start thinking about IV access

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142
Q

Mx of hypoglycaemia if unconscious or concerned about swallow

A

IV access

50ml 50% glucose

OR

100ml 20% glucose

Deteriorating/ refractory/ insulin induced/ difficult IV access: consider IM/SC 1mg Glucagon

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143
Q

Caveats regarding IV glucose to treat hypoglycaemia?

and w Glucagon?

A

Beware extravasation of IV glucose: irritant-> phlebitis

Glucagon mobilises glycogen stores so takes 15-20 mins to work

  • are there glycogen stores to mobilize? e.g. anorexia
  • danger of rebound hypoglycaemia as it will also cause insulin release
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144
Q

Hypoglycaemia definition?

A

Whipple’s triad: low blood glucose, symptoms and relief of symptoms with glucose

adrenergic symptoms: tremors, palpitations, sweating, hunger

Neuroglycopaenic symptoms: somnolence, confusion, incoordination, seizures, coma

Relief of symptoms w glucose administration

Careful of patients with autonomic instability-> hypo without the adrenergic symtoms

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145
Q

When glucose is low in the body, what happens?

A

decreased insulin and increased glucagon -> increased glycogenolysis, gluconeogenesis, lipolysis and reduced peripheral uptake of glucose.

  • > increase glucose in serum and also increased FFAs
  • beta oxidation of FFAs and increased ketone body production

also

low neuronal glucose sensed in the hypothalamus

  • > sympathetic activation - release of catecholamines
  • > ACTH, cortisol and GH production
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146
Q

what is the first response to hypoglycaemia?

A

suppression of insulin!

to allow production of ketones as secondary supply of energy.

*Insulin is a potent inhibitor of ketone production

hence, T1DM with no insulin have DKA. whereas T2DM with high peripheral insulin (resistance) usually have Hyperosmolar Hyperglycaemic Nonketotic syndrome

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147
Q

where is low glucose sensed in the brain?

effects?

A

Low neuronal glucose sensed by the hypothalamus

  1. sympathetic activation - release of catecholamines
  2. ACTH, cortisol and GH production

these are late responses, occuring hours later

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148
Q

2nd thing you see with hypoglycaemia, after suppression of insulin?

A

release of glucagon

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149
Q

Ix of hypoglycaemia

A

confirm with blood glucose test (*gold standard)

(grey top- fluoride oxalate - inhibit glycolysis)

-capillary blood glucose less sensitive at low levels.

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150
Q

Causes of hypoglycaemia

A

commonest in diabetes

  • impaired awareness regarding medications
  • inadequate CHO intake/ missed meal
  • excessive alcohol, strenuous exercise
  • coexisting autoimmune conditions

in non diabetics:

  • critically unwell, organ failure, hyperinsulinism
  • extreme weight loss, post gastric bypass, drugs
  • factitious
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151
Q

Diabetic Medications

Oral Hypoglycaemics

A

Sulphonylureas

e. g. tolbutamide, glibenclamide, gliclazide, gli___,
- increase insulin release from Beta cells in the pancreas

SE: weight gain, hypos

meglitinides

(same MOA as sulphonylureas, but much shorter-acting)

e.g. repaglinide, nateglinide

GLP-1 agents (glucagon like peptide 1 receptor agonists)

e.g. exenatide, liraglutide, ____-glutide, lixisenatide

aka incretin mimetics

decreases blood sugar levels in a glucose-dependent manner by enhancing secretion of insulin

SEs: weight LOSS, lower risk of hypos

DPP4- inhibitors

e.g. ____gliptins

increase incretin levels

eventually increases insulin secretion and decreases blood glucose levels.

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152
Q

liraglutide, exenatide

  • what class of drugs?
  • how does it work?
A

GLP-1 agonist (glucagon like peptide-1 receptor agonist)

aka incretin mimetics

decreases blood sugar levels in a glucose-dependent manner by enhancing secretion of insulin

SEs: weight LOSS, lower risk of hypos

But is still w sulphonylureas and meglitinides in the group of oral hypoglycaemics

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153
Q

Gliclazide, tolbutamide glibenclamide, glipizide

what class of drugs?

A

Sulphonylureas

e. g. tolbutamide, glibenclamide, gliclazide, gli___,
- increase insulin release from Beta cells in the pancreas

SE: weight gain, hypos

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154
Q

oral hypoglycaemic

repaglinide, nateglinide

  • what class of drugs?
A

meglitinides

(same MOA as sulphonylureas, but much shorter-acting)

e.g. repaglinide, nateglinide

stimulates insulin release from beta cells

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155
Q

Diabetes medications

insulin preparations

A

Rapid acting with meals - hypos if they occur, most likely due to a missed meal

e.g. Humalog (insulin lispro), Novorapid (insulin aspart)

Long acting - hypos often occur at night

e.g. Lantus (insuline glargine), Levemir (insulin detemir)

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156
Q

Comorbidities in diabetes

A

co existing renal/ liver failure alters drug clearance, and reduced doses of insulin/ oral hypoglcaemics are needed.

autonomic neuropathy - impairs awareness

hypo may occur when pt is asleep at night and unaware

*be aware a very good HbA1c in a diabetic could be due to recurrent hypos.

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157
Q

What is C peptide?

A

C peptide is a good marker of endogenous insulin production.

Proinsulin breaks down into insulin and c-peptide.

*good to differentiate between exogenous / endogenous insulin production

also good to help differentiate the cause of hypoglycaemia

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158
Q

Anorexia with poor liver glycogen stores

what are the insulin/ C peptide levels

A

low insulin and low c-peptide

Hypoinsulinaemic hypoglycaemia

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159
Q

Hypoinsulinaemic hypoglycaemia

causes?

A

appropriate response to hypolgycaemia

  • fasting/ starvation
  • strenous exercise (catabolic activities)
  • critical illness, liver failure, anorexia nervosa
  • endocrine deficiencies - hypopituitarism, adrenal failure
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160
Q

Hypoglycaemia and Absence of ketones?

A

e.g. of ketone bodies: beta hydroxybutyrate, acetoacetate, acetone

absence of ketones suggests a FFA oxidation defect.

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161
Q

causes of neonatal hypoglycaemia

A

explainable

  • premature, comorbidities
  • inadequate glycogen and fat stores, IUGR, SGA

should improve w feeding

pathological:

inborn metabolic disorders

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162
Q

low glucose but inappropriate insulin levels (high/ not suppressed)

causes?

A

islet cell tumours e.g. insulinoma

drugs: insulin, sulphonylurea abuse

islet cell hyperplasia

e.g. infant of diabetic mother, Beckwith wiedemann syndrome, Nesidioblastosis

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163
Q

low glucose, high insulin and high C-peptide

A

insulinoma or sulphonylurea abuse

sulphonylurea drug screen (urine or serum) needed before diagnosing insulinoma.

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164
Q

insulinoma

A

usually small solitary adenoma, 10% malignant

8% assoc w MEN1

dx based on biochemistry and localisation

tx: resection

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165
Q

low glucose, high insulin, low c peptide

A

factitious insulin

  • especially in patients with access to insulin/ drugs
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166
Q

low glucose, hypoglycaemia persists despite glucose infusion,

insulin, C-peptide, FFA and ketones undetectable/ negative.

A

Non islet cell tumour hypoglycaemia

everything is low!

secretion of ‘big IGF-2’ which binds to IGF-1 receptor and insulin receptor.

This suppresses insulin production from islet cells.

High IGF-2 mimics insulin action thus FFA and ketones low.

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167
Q

Autoimmune insulin syndrome

  • antibodies to?
A

antibodies binding to insulin

may precipitate hypoglycaemia

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168
Q

reactive hypoglycaemia? aka

postprandial hypoglycaemia?

A

hypoglycaemia following food intake

can occur post gastric bypass

hereditary fructose intolerance

early diabetes

in insulin sensitive individuals - after exercise or large meal

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169
Q

T1DM of 5 yrs

previously well controlled

now getting recurrent hypos in the morning

HbA1c 6.0% noted to be tired ++

what would you like to do?

A

review insulin dosing and injection technique, consider pump therapy and perform a short synacthen test.

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170
Q

Ant pituitary releases which hormones?

A

GH, stimulated by GHRH

Prolactin, inhibited by dopamine, stimulated by TRH

TSH, stimulated by TRH

LH, FSH stimulated by LHRH

ACTH, stimulated by CRH

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171
Q

does pituitary failure cause hypotension?

A

no, as hypotension is regulated by aldosterone which is released by adrenal glands.

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172
Q

Prolactinaemia may be due to ?

A
  • hypothyroidism High TSH and high TRH-> prolactinaemia
  • non functioning pituitary tumour -> dopamine cannot inhibit
  • prolactinoma
  • drugs etc
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173
Q

How does breastfeeding work as a contraceptive option?

A

Prolactin suppresses LHRH

-> low LH and FSH

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174
Q

pituitary failure

A

presentation: galactorrhoea, amenorrhoea

commonly causesd by macroadenoma (>1cm)

complications: look for bitemporal hemianopia as pituitary adenoma is pressing on optic chiasm

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175
Q

Prolactin 30, 000

CT scan shows large macroadenoma

A

Prolactinoma

always a prolactinoma if prolactin > 6000

tx: watch and wait, scan yearly to monitor size. prolactinoma rarely grows.

if visual defect loss, then consider surgery

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176
Q

what is the purpose of pituitary function testing?

A

to ensure that the pituitary gland responds adequately to a metabolic stress (ACTH and GH)

to ensure the gonadotrophs and thyrotophs are functional.

Try to increase the levels of anterior pituitary hormones by administering LHRH + TRH + stress (hypoglycaemia)

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177
Q

Pituitary function testing

A
  1. testing the lvls of ant pituitary hormones in response to LHRH + TRH + stress (hypoglycaemia)
    - metabolic stress increases CRF -> ACTH and increases GHRH -> GH

LHRH -> increases LH and FSH

TRH -> increases TSH

Method

fast patient overnight, ensure good IV access

weight patient and calculate dose of insulin required.

Give IV insulin, TRH and LHRH.

Then take blood for glucose, cortisol, GH, LH, FSH, TSH and prolactin every 30 min up to 60 min. (0,30,60)

Check glucose, cortisol and GH up to 120 min

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178
Q

what to ensure before conducting pituitary function test?

A

Ensure no cardiac risk factors, angina and that ECG is normal + no history of epilepsy before introducing hypoglycaemia.

Ensure good IV access before inducing hypoglycaemia as it is harder to put in line during hypoglycaemia. Give insulin to patient.

When glucose is low, first sympathetic activation occurs -> signs that patient is hypo.

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179
Q

Potential complications of pituitary function testing

A

Check blood glucose regularly, patient needs to have adequate hypo (<2.2mmol/L.) When <1.5mM, neuroglycopenia may occur and pt would be aggressive.

  • if >2.2 -> results cannot be interpreted as hypoglycaemia is not sufficient.

if <1.5 (severe hypoglycaemia) or unconsciousness, rescue pt with 50ml of 20% dextrose.

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180
Q

pituitary function testing results

A

Normal response: cortisol reaches 550 nM and

GH reaches 10 IU/l

If tumour pressing pituitary

* GH, cortisol, LH, FSH, TSH are low

* Prolactin is high

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181
Q

Tx of pituitary failure

A

replacement therapy w hormones needed.

most urgent: hydrocortisone (maintains cell integrity when one is in shock)

+ thyroxine, oestrogen and GH replacement

+ dopamine agonist (bromocriptine / cabergoline) for prolactinoma.

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182
Q

Tx for non-functioning adenoma

A

hydrocortisone, thyroxine, oestrogen, GH replacement

surgery usually done.

dexamethasone given for large brain tumours before surgery is done.

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183
Q

Ix of acromegaly

A

Glucose tolerance test

  • failure of GH suppression suggests acromegaly

Pituitary function test usually shows raised GH

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184
Q

Acromegaly Tx

A

1st line: pituitary surgery to remove tumour

Octreotide - Somatostatin analogue

Cabergoline - adjunctive D2R agonist

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185
Q

Low Na, High K, Low Glucose

A

Addisons

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186
Q

Addisons + primary hypothyroidism =?

A

Schmidt’s syndrome

addisons and hypothyroidism occur together more commonly than by chance alone.

Now it is galled Polyglandular autoimmune syndrome type II (PGA type II)

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187
Q

Ix for addisons

A

Short SynACTHen test

Administer 250micrograms of synthetic ACTH by IM injection.

Check cortisol at 30 and 60 mins.

It will still be low in Addisons.

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188
Q

Addisons’ presentation?

Mx?

A

hyperpigmentation, hypotension

addisons causes deficiency of mineralcorticoid and glucocorticoid due to failure of adrenal gland.

Mx: fluids - normal saline.

Hydrocortisone replacement.

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189
Q

Mx of Schmidt’s

A

Give hydrocortisone replacement first!

thyroxine replacement after.

as thyroxine will increase BMR and worsen lack of cortisol -> addisonian crisis worsened.

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190
Q

Hypertension + adrenal mass

DDx?

A

Phaeochromocytoma

Conn’s - adrenal tumour secreting aldosterone

Adrenal medullary secreting adrenaline

Cushings- secreting cortisol

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191
Q

Ix of Phaeochromocytoma

A

Urine catecholamines

(Urine VMA Vanillylmandelic acid)

it will be high in tumours secreting catecholamines.

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192
Q

Mx of phaeochromocytoma

A

Can cause severe HTN, arrhythmias and death.

Medical emergency

  1. alpha blockade e.g. phenoxybenzamine
  2. beta blockade
  3. arrange surgery
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193
Q

e.g of alpha blocker?

A

phenoxybenzamine

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194
Q

HTN, low K, high Na

Plasma aldosterone raised, renin suppressed

A

Conn’s syndrome

195
Q

Mx of Conn’s

A
  1. Spironolactone- aldosterone antagonist
  2. If unilateral disease- surgery to remove tumour. unilateral adrenelectomy
196
Q

Ix of Cushings

A

Dexamethasone suppression test

  • normally suppresses cortisol levels to undetectable lvls.

Low dose - any cause of Cushing’s syndrome

High dose- if it suppresses >50% (will not be completely suppressed), then pituitary dependent Cushings disease

197
Q

Causes of Cushings syndrome

A

Iatrogenic- steroids

pituitary dependent Cushings disease (85%)

ectopic ACTH

Adrenal adenoma

198
Q

Ix of cushings syndrome of indeterminate cause?

A

Pituitary MRI indicated

as pituitaru dependent Cushings disease is the most common cause.

High dose dexamethasone suppression is not specific enough.

199
Q

How does phototherapy help in hyperbilirubinaemia?

A

Phototherapy converts bilirubin into lumirubin and photobilirubin which are isomers that do not need conjugation for excretion.

200
Q

Gilbert’s syndrome

  • inheritance pattern?
  • enzyme affected?
A

Autosomal recessive.

5-6% of the population have this.

Worsened by fasting.
Effects of phenobarbital: reduces jaundice

UDP glucuronosyltransferase 1

activity reduced to 30%

unconjugated Br remains tightly albumin bound and does not enter urine -> high Br, jaundice, normal liver enzymes

201
Q

Best way to measure liver function?

A

PT time.

PT time is the most representative of liver disease. If PT in seconds is longer than overdose in hours (eg PT is 24 seconds for a patient who’s been in overdose for the past 24 hours, this patient has to go to liver unit – it is a serious problem) best marker in terms of survival outcome. This is because clotting factors are not being synthesised by the liver

202
Q

if Br high, AST and ALT high e.g. 1000

A

suggests hepatocyte damage

Alcoholic hepatitis (AST may be higher)

Viral hepaitis (ALT may be higher)

Autoimmune hepatitis

Non-alcoholic steatohepatitis (NASH)

203
Q

NASH vs alcoholic hepatitis - how to differentiate?

A

Same histoloigcal features

e.g. fatty liver, mallory denk bodies and balloonying of hepatocytes

To differentiate the two: clinical history

204
Q

TX of alcoholic hepatitis

A

supportive, stop alcohol

nutrition: vitamins (e.g. B1, thiamine) - B1 deficiency causes beri beri

occasionally steroids

205
Q

signs of chronic liver failure

A

multiple spider naevi

dupuytrens contracture

palmar erythema

gynaecomastia

206
Q

Portal HTN

A

ascites, splenomegaly, varices (oesophageal/ caput medusae)

207
Q

porto systemic anastomoses

where?

A

oesophageal

rectal

umbilical vein recanalising

spleno renal shunt

208
Q

severely jaundiced, cachectic, palpable gall bladder.

multiple scratch marks on skin

Dark urine, pale stools

A

Bile duct obstruction

  • alk phos super high
  • scratch marks due to bile salts in the blood

pale stools: lack of stercobilin

dark urine: lack of urobilin but then high amounts of conj br excreted via kidneys

209
Q

71 year old man presents with jaundice

* No previous history at all, weight loss

* Bilirubin 340, ALP: 1750, AST 50, ALT 45

painless jaundice

A

pancreatic cancer

Courvoisiers law

if gall bladder is palpable in jaundiced pt, the cause is pancreatic ca

210
Q

what is the best measure of renal function?

A

gfr

211
Q

normal serum osmolality

A

275-295 mmol/Kg

212
Q

hypoNa clinical features

A

nausea and vomiting,

confusion (<131 mmol/L)

seizures, non-cardiogenic pulmonary oedema (<125 mmol/L)

coma (<117 mmol/L) and eventual death.

symptomatic hypoNa is a medical emergency

213
Q

What is a true hypoNa?

A

HypoNa + Low serum osmolality

if serum osmolality is normal: consider

spurious sample,

drip arm sample -> pseudo hypoNa as fluids being pumped in (diluted area)

pseudohypoNa (hyperlipidaemia, paraproteinaemia)

If serum osmolality is high: consider

glucose/ mannitol/ ethanol infusion

214
Q

features of hypervolaemia?

A

raised JVP, pulmonary oedema, peripheral oedema.

215
Q

Causes of hypervolaemic hypoNa?

A
  1. Cardiac failure
  2. Liver failure
  3. Renal failure.
    tx. tx underlying cause and fluid restrict!
216
Q

HypoNa: If pt is hypervolaemic, but urinary Na is Low (<20)

A

Non renal cause:

Heart failure,

Cirrhosis

Inappropriate IV fluid

(Cirrhosis causes hypoNa because in liver failure, poor breakdown of vasodilators like Nitric Oxide -> cause Low BP -> ADH release to increase water retention which dilutes the Na.)

(HF-> low cardiac output -> ADH release)

+ BNP / ANP are natriuretic and thought to worsen HypoNa as well

217
Q

HypoNa: if pt is hypervolaemic, and Urinary Na is >20

A

Renal cause!

e.g. AKI, CKD

kidneys are not retaining sodium

218
Q

HypoNa: if pt is hypovolaemic, urinary sodium <20

A

Non renal cause:

diarrhoea,

vomiting

excess sweating

third space losses e.g. burns, ascites

Kidney is doing its job and holding onto Na

219
Q

HypoNa: if pt hypovolaemic and urinary Na >20

A

renal cause

(kidneys NOT holding on to Na)

e.g.

Diuretics

Addisons

Salt losing nephropathies

220
Q

Be aware of hypoNa post surgery due to

A

Oberhydration w hypotonic IV fluids (usually hypervolaemic)

Transient increase in ADH due to stress of the surgery.

221
Q

rapid correction of hyperNa can lead to?

A

cerebral oedema!

222
Q

Ix of diabetes insipidus

A

8 h fluid deprivation test.

clinical features: hyperNa, polyuria, polydipsia, clinically euvolaemic. plasma is extremely dilute despite concentrated plasma.

223
Q

Cranial vs Nephrogenic DI

A

Cranial DI: lack of ADH

causes: surgery, trauma, tumours.

Nephrogenic DI:

receptor defect, tx w thiazide diuretics, lithium, demeclocycline, hyperCa, hypoK!

in Cranial DI and nephrogenic DI, urine will fail to concentrate after fluid deprivation.
in cranial DI, after desmopressin is given, will concentrate.

224
Q

normal urine concentration after water deprivation test

A

Normal: urine conc above 600 mOsmol/kg

Primary polydipsia: urine can concentrate >400-600

225
Q

RMB hypoNa and HIGH urine Na

A

consider a renal problem

e.g. CKD, diuretics, SIADH (anything that acts on the kidney)

226
Q

normal range for urine specific gravity

A

1.000 to 1.030

if urine specific gravity is high, then there are more solutes (high osmolality) and vice versa if it si low.

227
Q

Normal anion gap

A

14-18 mmol/L

228
Q

High anion gap Metabolic Acidosis

KULT

A

Ketoacidosis (DKA, starvation, alcoholic)
Uraemia (renal failure)

Lactic acidosis - metformin

Toxins (e.g. salicylate, methanol, paraldehyde, ethylene glycol)

229
Q

Osmolar gap = ?

A

Osmolality - Osmolarity

Normal osmolar gap <10

elevated osmolar gap provides indirect evidence for presence of abnormal solute.

e.g. ethylene glycol, methanol, mannitol.

Helpful in differentiating the cause of elevated anion gap met acidosis

230
Q

Tumour marker of liver cancer

A

alpha fetoprotein

231
Q

Van Der Bergh

A

direct reaction measures conj Br

indirect measures unconj Br

232
Q

GGT elevated

A

normal: 30-150

elevated in chronic alcohol use.

also bile duct disease and metastases.

useful to confirm hepatic source of increased ALP

233
Q

Normal range of AST / ALT

A

<40

raised when hepatocytes die

**AST also assoc w increase in heart/ kidney damage

234
Q

Acute intermittent porphyria

what enzyme is defecient?

A

HMB synthase (hydroxymethylbilane)

aka

PBG deaminase (porphobilinogen deaminase)

-> buildup of ALA and PBG in serum and urine.

235
Q

Acute intermittent porphyria

what inheritance?

A

autosomal dominant

236
Q

What causes the neurovisceral symptoms in porphyria?

A

5-ALA

(5-aminolaevulinic acid)

is neurotoxic

237
Q

what causes the skin lesions in porphyria?

A

porphyrins.

porphyrinogens become oxidised to porphyrins, which under light become activated porphyrins and oxygen.

porphorinogens are colourless while porphyrins are highly coloured.

also, porphyrinogens get oxidised in the circulation where there is high [O2] compared to in the cells where it is made.

238
Q

how to calculate Clearance?

A

At any one time

C = (Ux V)/P

U- urinary conc

P- plasma conc

V- vol of urine

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

Clearance = the volume of plasma that can be completely cleared of a marker substance/ time

239
Q

what is the perfect marker for assessing GFR?

but used as a research tool only

A

inulin clearance

240
Q

Serum creatinine as an endogenous marker of GFR

A

Derived from muscle cells (small amount from intestinal absorption).

Freely filtered, actively secreted into urine by tubular cells

Generation is not equivalent in different individuals. Depends on muscularity, age, sex and ethnicity (higher in black population).

241
Q

what are the properties of an ideal marker of GFR?

A

Not plasma protein bound, freely filtered at glomerulus and not modified by tubules

242
Q

any clinical alternatives to serum creatinine as measure of GFR?

A

Cystatin C

(better than serum cr but not as widely used)

but ultimately,

the most robust value of serum cr measurement is the change within an indiv over time. The trend is more impt than the absolute value.

243
Q

how does urinary protein:creatinine ratio work?

A

spot urine measurement can quantify proteinuria instead of a 24h urinary collection

Measurement of creatinine corrects for urinary concentration

244
Q

Urine dipstick

if leucocyte esterase negative?

A

A negative result for leucocyte on dipstick is signficant.

245
Q

A known alcoholic seemingly intoxicated with acute kidney injury.

Urine microscopy shows calcium oxalate crystals, what is the diagnosis?

A

Ethylene glycol poisoning

antifreeze.

classically calcium oxalate crystals.

go for dialysis immediately.

246
Q

1st line investigation for renal stone?

A

CT-KUB

247
Q

what imaging is useful to differentiate CKD from AKI?

A

KUB USS - if shrunken probably CKD.

Renal biopsy still gold standard for making a diagnosis of CKD.

248
Q

What is Acute kidney injury?

A

rapid reduction in kidney function, leading to inability to maintain electrolyte, acid base and fluid homeostasis.

medical emergency necessitating referral to nephrologist for dx and tx.

abrupt fall in GFR, potentially reversible and tx is targeted to precise diagnosis and reversal of disease

249
Q

Pre-renal AKI

  • why does it cause AKI?
A

reduced renal perfusion w no structural abnormality of the kidney.

  • could be selective renal ischaemia or generalised reduction in tissue perfusion
  • pre renal AKI occurs when normal adaptive mechanisms fail to maintain renal perfusion.
250
Q

Causes of prerenal AKI?

A

True volume depletion (blood/fluid), hypotension, shock

Oedematous states (fluid in wrong compartment, more in interstitium rather than vascular space eg. heart failure)

Selective renal ischaemia – renal artery stenosis

Drugs affecting glomerular blood flow

e.g. NSAIDs, ACEi/ARBs, diuretics, calcineurin inhibitors

251
Q

Pre renal AKI vs ATN?

A

AKI: responds immediately to restoration of circulating volume

Prolonged insult leads to ischaemic injury (acute tubular necrosis)

  • ATN does not respond to restoration of circulating volume
252
Q

Post Renal AKI

causes?

A

characterised by obstruction to urinary flow

GFR is dependent on pressure gradient. obstruction results in increased tubular pressure and decline in pressure gradient. -> immediate decline in gfr.

e.g. ureteric obstruction, prostate (usually causes bilateral hydronephrosis), blocked urinary catheter

253
Q

Post renal AKI

mx

A

remove obstruction.

immediate relief of obstruction fully restores GFR w no structural damage.

But if prolonged obstruction -> structural damage -> glomerular ischaemia, tubular damage and long term interstitial scarring

254
Q

Renal causes of AKI

A

Vascular - vasculitis

glomerular disease - glomerulonephritis

tubular disease - acute tubular necrosis

interstitial disease - analgesic nephropathy

255
Q

most common cause of direct tubular injury in kidneys?

A

ischaemic.

also endogenous toxins - myoglobin (crush injury, statin-induced myositis), immunoglobulins (myeloma, significant paraprotein levels)

and

exogenous toxins - contrast, drugs e.g. aminoglycosides, amphotericin, acyclovir

256
Q

Sitagliptin, ____gliptin?

what kind of drug?

mechanism??

A

DPP-4 inhibitors

dipeptidyl peptidase-4 inhibitor

Class of oral hypoglycaemics used to treat T2DM

Mechanism: to increase incretin levels (GLP-1 and GIP) which inhibits glucagon, increases insulin, decreases gastric emptying and decreases blood glucose levels.

SEs: joint pain, heart failure, acute pancreatitis, IBD (specifically Ulcerative Colitis)

257
Q

what are two measures to determine severity of AKI?

A

urine output and GFR

258
Q

Top cause of AKI

A

decreased renal perfusion

e.g. important causes are predictable - contrast, drugs, postop, sepsis.

259
Q

indications for dialysis?

A

pulmonary oedema

refractory hyperK

metabolic acidosis

uraemic encephalopathy

drug toxicity e.g. lithium

260
Q

Stages of CKD?

A

Stage 1 >90 GFR

Stage 2 60-89

Stage 3 30 - 59

Stage 4 15-29

Stage 5 <15

261
Q

Most common causes of CKD

A

Diabetes, HTN

atherosclerotic renal disease

chronic glomerulonephritis

PCKD

infective or obstructive uropathy

262
Q

Normal roles of the kidney

A

Acid base homeostasis

Endocrine function: EPO, Vit D, RAS

Water, electrolye balance

excretion of water soluble waste

263
Q

Consequences of CKD

A
  1. Progressive failure of homeostatic function
    - Acidosis, hyperkalaemia
  2. Progressive failure of hormonal function
    - Anaemia of chronic disease, renal bone disease
  3. Cardiovascular disease
    - vascular calcification, uraemic cardiomyopathy (ie. LV hypertrophy, LV dilatation, LV dysfunction)
  4. Uraemia and Death
    - need for dialysis/ transplant
264
Q

Renal metabolic acidosis

mx?

A

Failure of renal excretion of protons results in muscle and protein degradation, osteopenia due to mobilization of bone Ca, cardiac dysfunction

tx w Sodium bicarbonate PO when bicarb lvls <20

265
Q

Anaemia of chronic renal disease

what type of anaemia?

mx?

A

Progressive decline in erythropoietin-producing cells with loss of renal parenchyma

Usually noted when GFR<30ml/min

Normochromic, normocytic anaemia

Give EPO/ESA (erythropoietin stimulating agents)

266
Q

Renal bone disease

  • why does it happen?
A

Complex entity resulting in reduced bone density, bone pain and fractures: osteitis fibrosa, osteomalacia, adynamic bone disease, mixed osteodystrophy.

Low Ca, High PTH -> secondary hyperparathyroidism

and causes low bone density

267
Q

osteitis fibrosa in chronic kidney disease

what is it?

A

Osteoclastic resorption of calcified bone and replacement by fibrous tissue

assoc w hyperPTH

268
Q

Adynamic bone disease

assoc w CKD

what is it?

A

Excessive suppression of PTH results in low turnover and reduced osteoid

reduced osteoblasts and osteoclasts, no accumulation of osteoid and markedly low bone turnover

Increasing incidence due to excessive suppression of PTH in current CKD patients

269
Q

Mx of CKD bone disease

A

Phosphate control

  • decreased dietary phosphate intake

phosphate binders

PTH suppression

  • cinacalcet

(but if u overdo it can lead to adynamic bone disease)

Vit D R activators

  • alfacalcidol, paricalcitol
270
Q

what is the most important consequence of CKD?

A

Cardiovascular disease

risk of cardiac event directly predicted by GFR

Lots of people go straight from reduced GFR to death, due to x20 increased risk of CVD

271
Q

Uraemic cardiomyopathy

what are the three phases?

A

in long term pts with uraemia

LV hypertrophy -> dilatation -> dysfunction

272
Q

vascular calcification in CKD

what kind of plaques?

A

renal vascular lesions usually heavily calcified plaques, rather than traditional lipid-rich atheroma

273
Q

Renal replacement therapy options?

A

haemodialysis

peritoneal dialysis

274
Q

contraindications of renal transplantation

A

Should be Free of cancer for at least 2 years

Active sepsis.

275
Q

what do you expect in LFTs in alcoholic hepatitis?

A

AST and ALT elevated but AST>>ALT

276
Q

what LFTs do you expect to see with liver cirrhosis

A

AST / ALT ratio increased

both high

277
Q

GGT

where else is it found?

elevation assoc with?

A

found in liver, kidney, pancreas, spleen, heart, brain, seminal vesicles

in liver found in hepatocytes and epithelium of small bile ducts

elevated in chronic alcohol use, also raised in bile duct disease and hepatic metastasis

278
Q

ALP

  • where else is it found
  • elevation assoc w?
A

liver isoenzyme located in sinusoidal and canalicular membranes thus markedly elevated if obstructive jaundice or bile duct damage

other sources bone, small intestine, kidney, WBC’s, placenta etc

other causes of a rise include bone disease (especially metastatic and pregnancy)

279
Q

albumin

function?

A

synthesized by liver

half life 20 days

contributes to oncotic pressure and binds steroids/ drugs/ br / calcium

280
Q

What is the best acute marker of liver function?

A

PT time

1/2 life in hours.

compared to Albumin (half life 20 days)

281
Q

When is AFP raised?

A

hepatocellular carcinoma

also raised in hepatic damage/ regeneration

raised in pregnancy and testicular cancer

282
Q

Jaundice

high bilirubin

normal liver enzymes

causes?

A

haemolysis

gilberts

283
Q

jaundice

raised br

ALP High

dilated bile ducts

A

gall bladder obstruction e.g. cancer/ gallbladders

284
Q

Jaundice

raised Br

raised ALP

undilated ducts

causes?

A

drugs

PBC

PSC

pregnancy

285
Q

jaundice

raised Br

ALT / AST v high

causes?

A

hepatic cause

acute: toxins, acute hepatitis, paracetamol

chronic

286
Q

Obstructive jaundice

what happens to the urine

A

pale stools dark urine

dark due to high amts of conjugated bilirubin

can be detected on urine dip/ by naked eye if large amts

urobilinogen is normally detected in urine but is absent in obstructive jaundice.

br in urine increased in haemolysis, hepatitis, sepsis.

287
Q

when are bile acids elevated?

A

esp in cholestasis

10-100x in obstetric cholestasis

25 x in PBC/PSC

288
Q

38 year old female secretary

* presented with itch and jaundice, dark urine

* PMH - removal of a benign breast lump, UTI 5/7 earlier treated by GP

* SH single, 21 units of alcohol/week, smokes 15/day O/E no signs of chronic liver disease

* bilirubinuria seen on dipstick of urine. LFT – bilirubin high, ALP 1000, ALT and AST slightly elevated, with preserved synthetic function

A

Diagnosis: drug induced cholestasis (intrahepatic / 2Y to Augmentin) from UTI

289
Q

74 year old retired publican

* 3 week history of itch, pale stools, dark urine, yellow sclera, 2 month weight loss-12 kg’s

* PMH cardiomyopathy, peripheral neuropathy,

* O/E jaundiced, no signs of chronic liver disease but epigastric fullness noted

* bilirubinuria noted on urine dipstick

* O/E displayed Courvoisier’s Sign

* Bilirubin and ALP elevated.

A

Diagnosis: pancreatic adenocarcinoma

290
Q

18 year old female jaundiced art student

* returned from trip to Goa 1 week previously

* felt terrible for the last 10 days, fevers, diarrhoea, joint pain, last 2 days had turned yellow

* admitted to taking “some tablets” in a nightclub + had small tattoo done

no PMH, anti-malarial tablets only

* O/E jaundiced, no signs of CLD or IVDU

* High bilirubin, AST and ALT. liver US showed swollen liver, serum IgM anti-HAV positive

* Only 3 things that can cause ALT > 1000 IU/L: ischaemia, toxins and viruses.

A

Diagnosis: acute hepatitis A

291
Q

19 year old student

* split up with boyfriend / exams

* taken 32 g paracetamol / Alcohol++

* PMH nil / no previous psychiatric Hx

* meds nil, denied ever taking any drugs

* O/E alert / vomiting / resps. 28 (acidotic)

A

Diagnosis: paracetamol overdose

* Treatment: N-acetyl cysteine

292
Q

a 54 year old lawyer, abnormal LFTs

* PMH hernia repair. Meds nil, alcohol 2 units/ day, denied ever taking any drugs

* O/E palmar erythema and 5 spider naevei

* US showed coarse liver texture and a large spleen. Hepatitis C confirmed by serology and PCR. Admitted to using heroin once in the seventies.

A

Liver biopsy confirmed cirrhosis

Mx: antiviral therapy

USS/AFP every 6 months for HCC

293
Q

Alkaline phosphatase

  • where is it found
  • when raised most frequently due to?
  • how to differentiate between liver and bone ALP?
A

Present in high concentration in liver, bone, intestine and placenta

Pathological increases most frequently due to liver or bone diseases

Increased in bone diseases associated with increased osteoblastic activity

Liver and bone ALP can be differentiated by:

o GGT measurement

o Electrophoretic separation

o Bone specific ALP immunoassay

294
Q

Physiological causes of raised ALP

A

pregnancy from placenta

childhood esp during growth spurt

295
Q

Will ALP be raised in osteoporosis?

A

NO

unless complicated by fracture.

then yes!

296
Q

Amylase

  • where is it found
  • when is it raised
A

exocrine pancreas, salivary isoenzyme

high serum amylase with acute pancreatitis and mumps (parotitis)

small increases may be seen in other acute abdomen states

297
Q

what are the 3 forms of creatinine kinase and where are they found?

A

CK MM- skeletal muscle

CK-MB (1 &2) - cardiac muscles

CK-BB - brain

CK-MM most widely used marker of muscle damage

CK-BB activity minimal even in severe brain damage.

CK-MB normally around 5% of CK.

298
Q

statin related myopathy

presentation?

risk factors?

A

myalgia -> rhabdomyolysis

Risk factors:

polypharmacy

high dose, genetic predispostion

previous hx of statin related myopathy

299
Q

Causes of raised plasma creatine kinase

A

muscle damage due to any cause

myopathy e.g. Duchenne’s (>10 ULN)

MI (>10 ULN)

Svere exercise (5x ULN)

physiological - afro carribean (<5 x ULN)

300
Q

what is the current marker of choice for MI?

A

troponin (T/I)

rises 4-6 hr post event

and peaks 12-24h post MI

remains elevated for 3-10 days

*measure 6 h and then at 12 h post onset of chest pain

301
Q

Diagnostic criteria of Acute MI

A

typical rise and gradual fall of troponin

or

more rapid rise and fall of CK-MB

+

at least one:

ischaemic symptoms

pathologic Q waves on ECH

ECG changes assoc w ischaemia

coronary artery intervention

pathologic findings of acute MI

302
Q

what natriuretic peptides are raised in heart failiure?

A

ANP - secreted by atria

BNP - secreted by ventricles

BNP can be measured to assess ventricular function, can be used to exclude heart failure in the clinical setting

303
Q

Measuring TMPT activity is important before starting which drug tx?

Thiopurine methyltransferase

A

Azathioprine

+ 6-mercaptopurine and 6-thioguanine

304
Q

what is the unit for measurement of enzyme activity?

A

U/L

one international unit (U)

305
Q

what are the fat soluble vitamins?

A

Vit A, D, E, K

306
Q

Deficiency of Vit A (retinol)?

A

colour blindness

Night blindness

dry skin/ hair + rash

307
Q

Excess Vit A (retinol)?

A

exfoliation

hepatitis

308
Q

Test for Vit A levels?

A

serum Vit A

309
Q

Vit D deficiency?

cholecalciferol

A

osteomalacia

rickets

310
Q

Vit D excess?

A

hypercalcaemia

311
Q

test for Vit D levels?

A

serum Vit D

312
Q

Vit E (tocopherol) deficiency?

A

low in cystic fibrosis, abetalipoproteinaemia

anaemia

neuropathy (ataxia/ areflexia)

IHD

?malignancy

313
Q

Vit K (phytomenadione) deficiency?

A

defective clotting

Test: PT time

314
Q

What are the water soluble vitamins?

A

Vit B1, B2, B3 (niacin), B6, B12, C, Folate

315
Q

Vit B1 (thiamine) deficiency

A

Beri beri - wet: heart failure, SOB, oedema

dry: ascending impairment of nervous function involving sensory and motor components

Neuropathy

Wernickes

  • triad of confusion, opthalmoplegia, ataxia

can lead to Korsakoffs (amnesia and confabulation)

316
Q

Test for Vit B1?

A

RBC transketolase

317
Q

Test for B2 - riboflavin

A

RBC glutathion reductase

318
Q

B2 (riboflavin) deficiency?

A

glossitis,

mucosal damage, corneal ulceration and anaemia

319
Q

Vit B6 deficiency

Pyridoxine

A

Dermatitis with cheilosis (scaling on the lips/ cracks at corners of mouth)/ microcytic anaemia

glossitis

Peripheral neuropathy

sideroblastic anaemia

320
Q

B6 excess

pyridixone

A

neuropathy

321
Q

B6 Pyridoxine test?

A

RBC AST starvation

aspartate amino transferase

322
Q

B12 cobalamin deficiency

A

Pernicious anaemia (macrocytic megaloblastic)

Subacute combined degeneration of cord

Test: serum B12

323
Q

Vit C deficiency

ascorbate

A

Scurvy

  • bleeding of gums, skin, joint

gum disease

  • bone weakness (brittle, micro#s)
324
Q

Vit C excess

ascorbate

A

renal stones

325
Q

test for vit c levels

A

plasma

326
Q

Folate deficiency

A

megaloblastic anaemic

neural tube defect

test: RBC folate

327
Q

B3 (niacin) deficiency

A

Pellagra - 3Ds

Dementia, dermatitis, diarrhoea

*Casal’s necklace

328
Q

Iron deficiency

  • excess?
  • test?
A

hypochromic anaemia

haemochoromatosis

  • FBC, Fe, ferritin
329
Q

Iodine deficiency

A

hypothyroidism

goitre

Test: TFTs

330
Q

Zinc deficiency?

A

dermatitis

331
Q

Copper deficiency?

in excess?

Tests?

A

anaemia

in excess: wilsons

Test: Serum Cu, Caeruloplasmin

332
Q

Fluoride deficiency?

in excess?

A

dental caries

in excess: fluorosis

333
Q

Risk factors for metabolic syndrome

A

Fasting glucose > 6mmol/L

HDL Men <1.0 Women <1.3

Waist circumference men >102 women >88

HTN BP >135/80

Microalbumin

insulin resistance

334
Q

Tx of obesity

A

Exclude endocrine cause (Cushing’s, hypothyroidism, acromegaly) and obesity complications (resp, GI, PCOS, CVD)

* Educate, diet and exercise

* Medical (Orlistat, GLP-1 agonist) and surgical

335
Q

Benefits of weight loss

A

Improvement in PCOS, GORD, osteoarthritis, CVD, liver function, pregnancy, psychological

Health benefits of bariatric surgery

* Resolution/improvement of T2DM, hypertension, sleep apnoea, PCOS and fertility

* Improved lipid profile with resulting in overall reduction in cardiac risk and mortality

336
Q

marasmus

A

shrivelled

growth retarded

severe muscle wasting

no subcut fat

337
Q

kwashiorkor

A

Oedematous, scaling/ulcerated, lethargic

Large liver, s/c fat, protein deficient

338
Q

Dyslipidaemia includes?

A

HIGH cholesterol, triglycerides

High LDL

low HDL

339
Q

signs and symptoms of familial hypercholesterolaemia homozygotes

A

corneal arcus

artheroma in aortic root

xanthelasma

tendon xanthema

e.g. back of achilles tendon

340
Q

familial hyper-alphalipoproteinaemia

A

CETP deficiency

increase in HDL

benign presentations. often assoc w longevity

341
Q

Phytosterolaemia

A

mutations of ABC G5 & G8

allows plant sterols to be absorbed.

increasing risk of premature atherosclerosis as plant sterols more atherogenic than cholesterol

342
Q

Genetic causes of primary hypercholesterolaemia

A

Familial hypercholesterolaemia

Polygenic hypercholesterolaemia

Familial hyper-alphalipoproteinaemia* (not bad for u)

Phytosterolaemia

343
Q

Genetic causes of Primary triglyceridaemia

A

Familial Type I: lipoprotein lipase/ apoC II deficiency

(lack of degradation of TGs-> diet can help)

Familial Type V: sometimes due to ApoA V defic

Familial Type IV: increased synthesis of TG

Types IV and V: diet not as helpful as there is increased production of cholesterol.

344
Q

PCSK9

Proprotein convertase subtilisin/kexin type 9

  • function?
  • relevance?
A

PCSK9: binds LDL receptor and promotes its degradation

Rarely FH caused by gain of function mutations -> increased rate of degradation of LDLRs. -> high LDLs

loss of function mutations -> Low LDL levels

345
Q

signs and symptoms of hypertriglyceridaemia

A

eryptive xanthomas on skin

346
Q

signs and symptoms of primary mixed hyperlipidaemia

A

shiny palmar crease

palmar striae diagnostic of type III

eruptive xanthoma (type III)

type III = familial dys(beta)lipoproteinaemia

347
Q

Causes of hypolipidaemia

A

Abeta-lipoproteinaemia: MTP deficiency

Hypobeta-lipoproteinaemia: truncated apoB protein

Tangier disease: HDL deficiency

Hypoalpha-lipoproteinaemia - apo-I mutation (sometimes)

348
Q

lipid regulating drug that has the biggest effect on LDL-C

A

atorvastatin

349
Q

lipid regulating drug with biggest effect on HDL-C

A

nicotinic acid

but alot of side effects

350
Q

lipid regulating drugs that has biggest effect on triglyceride levels

A

gemfibrozil

351
Q

Novel forms of LDL lowering therapy

A
  • Microsomal Triglyceride Transfer Protein (MTP) inhibitor (lomitapide)
  • * Anti-PCSK9 monoclonal antibody (REGN727)
  • Anti-sense apoB oligonucleotide (mipomersen)
  • Lomitapide reduces LDL absorption however can cause fatty liver (as less is absorbed more is synthesised in the liver). Thus probably would only be used in FH homozygotes.
352
Q

novel HDL based therapies

A

Apolipoprotein A-I or A-1 mimetic infusion therapy

Cholesterol ester transfer protein (CETP) inhibitors (e.g. in familial hyperalpha-lipoproteinaemia)

353
Q

Bariatric surgery options

A

if BMI >40

Gastric banding (small meals feel full)

Roux-en-Y gastric bypass (reduced absorption)

Biliopancreatic diversion (only terminal ileum absorbs nutrients)

354
Q

medical mx of obesity

A

orlistat- malabsorption of TG

side effects of steatorrhoea

355
Q

Drug classes with strongest evidence for reduction in cardiovascular outcomes

A

intensive treatment of controlling BP in patients w previous MI can significantly reduce deaths

  • thiazide type diuretics first line e.g. chlorthialidone
  • loop diuretics (for those w advanced chronic kidney disease)
  • BB (for those w coronary artery disease)

optimal medical therapy postMI

  • intensive lifestyle modification
  • aspirin
  • high dose statin
  • optimal BP control
  • thiazides
356
Q

liraglutide/ semaglutide

A

GLP-1 agonist

  • shown to reduce CV related mortality in diabetic patients
357
Q

Empagliflozin

A

SGLT2 inhibitor

pee more glucose to reduce blood glucose levels

substantial reduction in CV mortality in diabetics

358
Q

Penylketonuria

  • what enzyme is deficient
  • Screening test?
A

Phenylalanine hydroxylase deficiency

Test- blood phenylalanine levels

359
Q

Treatment for phenylketonuria

A

restrictive diet to foods low in phenylanaline + special supplements

to maintain Phe at non-toxic levels

360
Q

sensitive vs specificity?

A

sensitivity = true positive/ total disease (ie. True positives + false negatives)

specificity = true negative / total negatives (true negative + false positive)

361
Q

positive predictive value vs negative predictive value

of a test?

A

PPV = True positive / all those who tested positive ( TP + false positive)

NPV = True negative / all those whoe tested negative (TN + FN)

362
Q

what does guthrie card heel prick test screen for?

A

Screens PKU, congenital hypothyroidism, SCD, CF, medium chain AcylCoA dehydrogenase

done at days 5-8 of life

363
Q

what controls uptake of iodide into the thyroid?

A

TSH

under negative influence by perchlorate.

364
Q

How is thyroxine formed in the thyroid?

A

Iodide uptake into thyroid

iodide-> iodine with thyroid peroxidase

iodine then taken up by thyroglobulin and bind to tyrosine

iodotyrosines join to form thyroxine -> secreted back into the lumen

365
Q

Actions of TSH

A

Stimulates uptake of iodide from capillary lumen into cells, convert iodide into iodine

Uptake of iodotyrosines back into the cell and secreted out into the lumen

366
Q

Medullary carcinoid of the thyroid

A

MTC sporadic/ familial / part of MEN 2

C cells of thyroid that produces calcitonin

Measure calcitonin / carcinoembryonic antigen (CEA) which are tumour markers

367
Q

Hypothyroidism

causes

A

Autoimmune- Hashimotos

Atrophic - congenital/ developed

Post Graves- Radiotherapy, surgery

post de quervains viral thyroiditis, drugs (amiodarone and lithium)

iodide deficiency

secondary hypothyroidism due to pituitary disease (low TSH)

peripheral thyroid hormone resistance

(receptor does not respond)

368
Q

what anaemia would you see in hypothyroidism?

A

usually macrocytic anaemia

can be normocytic

369
Q

Diagnosis of hypothyroidism

A

TSH high and low T4

antibody screen- anti thyroid peroxidase

370
Q

mx of hypothyroidism

A

T4 levothyroxine

titrated to normal TSH

  • take note of any heart disease

always start w small dose of thyroxine to prevent overworking of heart muscles and subsequently ischaemia

371
Q

Subclinical hyperthyroidism
TFTs?

A

normal T4, T3, high TSH

compensated hypothyroidism.

unlikely to have symptoms.

assoc w hypercholesterolaemia

372
Q

Thyroid function in pregnancy

  • HCG and TSH relation?
A

HCG has same configuration as TSH

Excess HCG-> increased thyroxine released

in first trimester, T4 will be higher than normal.

Thyroid binding globulin also increases in pregnancy due to oestrogen.

at the end of pregnancy, HCG level falls and T4 and TSH goes back to normal.

373
Q

Sick Euthyroidism

TFTs?

A

occurs with any severe illness.

body tries to shut down metabolism and thyroid gland has reduced output

low T3 and low T4 when severe.

slightly high/ normal TSH then later low TSH.

Normal physiological response.

NO hypothyroid symptoms.

* always interpret TFT results in the clinical context of the patients

374
Q

Causes of hyperthyroidism

A

high uptake in technetium scan:

graves

toxic multinodular goitre

single toxic adenoma

Low uptake:

subacute thyroiditis

postpartum thyroiditis

silent thyroiditis

factitious thyroiditis (taking thyroxine)

TSH induced, thyroid cancer induced

trophoblastic tumour and Struma Ovarii-> too much HCG

375
Q

Ix of hyperthyroid

A

TFTs

technetium scan

thyroid autoantibodies (TSHR)

tx dependent on aietiology

376
Q

Mx of low uptake hyperthyroidism

A

symptomatic

BBs

NSAIDs for dequervains

377
Q

Mx of high uptake hyperthyroidism

A

BB if pulse >100

carbimazole/ propylthiouracil (rarely used now due to risks of aplastic anaemia)

Radioiodine/ surgery

378
Q

Signs of Graves Disease

A

smooth diffuse goitre-

smooth palpable thyroid gland

graves opthalmopathy - exophthalmos

pretibial myxoedema

thyroid acropachy

other AI disease or family hx

379
Q

carbimazole and propylthiouracil

  • how do they work
A

inhibits thyroid peroxidase

Propylthiouracil- assoc w aplastic anaemia

titration for 18 months

380
Q

hyperthyroidism + pain in neck+ fever

A

thyroiditis

viral de quervains

tx is actually thyroxine replacement after the thyroid gland stops working

381
Q

Thyroid carcinoma

  • Tx
A

papillary or follicular thyroid cancer

surger +/- radioiodine

thyroxine to lower TSH levels, as TSH can stimulate cancer cells to regrow and relapse.

382
Q

Tumour marker for relapse of thyroid carcinoma?

A

Thyroglobulin

  • indicates functioning thyroid tissue - check for recurrence!
383
Q

Respiratory distress syndrome

A

common before 34 wks

lack surfactant that keeps small air sacs in the lung from collapsing.

Treatment with surfactant helps affected babies breathe more easily. May need additional oxygen and mechanical breathing assistance to keep their lungs expanded.

The sickest babies may temporarily need the help of mechanical ventilation to breathe for them while their lungs mature.

384
Q

Intraventricular haemorrhage

A

Bleeding in the brain occurs in some very LBW premature babies, usually in the 1st 3 days of life.

Brain bleeds usually are diagnosed with an ultrasound

Most brain bleeds are mild and resolve themselves with no lasting problems. Drugs can be used to reduce fluid buildup.

More severe bleeds can cause pressure on the brain that can lead to brain damage. In such cases, tube may be inserted into the brain to drain the fluid and reduce risk of brain damage.

385
Q

Patent ductus arteriosus

A

common in premature babies

Before birth, the ductus arteriosus lets the blood bypass the baby’s nonfunctioning lungs. The ductus normally closes after birth so that blood can travel to the lungs and pick up oxygen. Otherwise, can lead to heart failure.

Diagnosed with echocardiography or other imaging tests. Babies with PDA are treated with NSAIDs (ibuprofen/ indometacin) that helps close the ductus, although surgery may be necessary if the drug doesn’t work.

if severe, complications present -> surgery may be recomended. or catheter procedures in the full term baby

386
Q

Necrotizing enterocolitis

A

common in premies

Inflammation of the bowel wall progressing to necrosis and perforation

Bloody stools, abdominal distension

Can lead to feeding difficulties, abdominal swelling and other complications.

Treated with antibiotics and fed intravenously while the intestine heals. In some cases, surgery is done to remove damaged sections of intestine.

387
Q

at what age if functional maturity of gfr achieved?

A

2 years

388
Q

Rickets

presentation

A

Osteopenia due to deficient activity of Vit D

Presentation: frontal bossing, bowlegs/knock knees, muscular hypotonia

Alternative presentation: tetany / hypocalcaemic seizure, hypocalcaemic cardiomyopathy

  • due to hypoCa
389
Q

Osteopenia of prematurity

A

fraying, splaying and cupping of long bones

Biochemistry of osteopenia – normal Ca, PO4 <1mmol/L, ALP >1200 U/l (10 x adult ULN)

Treatment - PO4/Ca supplements, 1α-calcidol

390
Q

why is hyperbilirubinaemia seen in neonates

A

Extremely common in first 10 days of life due to:

o High level of synthesis (rbc breakdown)

o Low rate of transport into liver

o Enhanced enterohepatic circulation

391
Q

High bilirubin in neonates

complications?

A

Kernicterus

as free bilirubin can cross the BBB

392
Q

What are the thresholds for phototherapy/ exchange transfusion?

A

In full term babies, if bilirubin >350μmol/L, use phototherapy; 450μmol/L, exchange transfusion

In prem, the threshold are 120μmol/L and 230μmol/L, as they have less albumin.

393
Q

renal function in infants

how are they different from an adult?

A
  • not fully mature
  • low gfr compared to their surface area
  • reduced concentrating ability w maximum urine osmolality of 700mmol/kg
  • increased loss of sodium and reduced K excretion
  • > hence, babies need 6x more fluid, 30x more Na and 2x more K+ compared to adult (in terms of body weight ratio)
394
Q

hyperNa in infants?

A

Hypernatraemia after 2 weeks is uncommon and is usually associated with dehydration.

Salt poisoning and osmoregulatory dysfunction are rare but should be considered in cases of repeated hypernatraemia without obvious cause.

Routine measurement of urea, creatinine and electrolytes on paired urine and plasma on admission may differentiate these rare causes.

395
Q

hypoNa in infants

A

Congenital adrenal hyperplasia (1in15000) – missing 21-hydroxylase -> loss of aldosterone and cortisol -> excess loss of salt

Excess androgens due to excess precursors

hypoNa and hyperK with marked volume depletion

hypoglycaemia

ambiguous genitalia in female neonates

396
Q

What causes electrolyte imbalance in infants

A

High insensible water loss - high surface area, skin blood flow, metabolic/respiratory rate and transepidermal fluid loss (skin not keratinised yet)

Drugs

o Bicarbonate (for acidosis) causes high Na content as GFR function not fully developed to excrete the excess Na from Na2CO3

o Antibiotics – almost always Na salts

o Caffeine/theophylline (for apnoea) – increases renal Na loss

o Indomethacin (forPDA) – causes oliguria

397
Q

Cherry red spot

hepatomegaly, cardiomegalt

neuroregression

dysmorphia

A

Lysosomal storage disorders

e.g. Tay Sachs, Fabry’s disease

causes intraorganelle substrate accumulation leading to organomegaly (connective tissue, solid organs, cartilage, bone and nervous tissue), w consequent dysmorphia and regression

398
Q

Lysosomal storage disorder

Intraorganelle substrate accumulation leading to organomagaly, consequent dysmorphia and regression

Ix?

Mx?

A

Ix: Urine mucopolysaccharides and/or oligosaccharides, leucocyte enzyme activity

Mx: BM transplant, exogenous enzyme

399
Q

retinopathy often leading to early blindness, sensorineural deafness, hepatic dysfunction, mental deficiency, FTT, dysmorphic signs.

+

Bony changes involve a large fontanelle which only closes after the first birthday, osteopenia of long bones, and often calcified stippling, especially the patellar region.

in neonate (early presentation): severe muscular hypotonia, seizures, hepatic dysfunction including mixed hyperbilirubinaemia + dysmorphia

A

Peroxismal disorder

  • cannot catabolise very long fatty acids or make bile acids

Test: very long chain fatty acid profile

400
Q

abnormal subcut adipose tissue distribution with fat pads and nipple retraction

+

may be multisustem disorder

A

glycosylation disorder

defect of post translational protein glycosylation

Lab: transferring glycoforms in the serum

mortality: 20% in the first year

401
Q

Hypoglycaemia, Lactic acidosis

Hepatomegaly + nephromegaly

neutropenia

developmental delay

A

Glycogen storage disease

failure to mobilize glucose from glucogen

accumulation of glycogen-> hepatomegaly

high risk of hepatoblastoma

Mx: regular CHO

402
Q

Mitochondrial disorders

  • presentations?
A

affects any organ, age

Birth: barth (cardiomyopathy, neutropenia, myopathy)

5-15: MELAS (mitochondrial encephalopathy, lactic acids and stroke like episodes)

12-30: Kearns-Sayre

(Chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia)

CSF protein raised in Kearns-Sayre

High CK + high lactate -> indiactes mitochondrial disorders

Muscle biopsy

mitochondrial DNA analysis

403
Q

High Gal-1-Phosphate

Liver + kidney disease

presents with vomiting, diarrhoea, conjugated hyperbilirubinaemia, hepatomegaly, hypoglycaemia and sepsis

A

Galactossaemia

most common: deficiency of Gal-1-PUT enzyme.

Raised GAL-1-Phosphate

Tx: galactose- free diet

Galactitiol is formed by the action of aldolase on gal-1-phosphate leading to bilaterial cateracts

404
Q

blue eyes, fair skin/ hair

retardation IQ<50

musty smell

A

phenylketonuria

405
Q

Hypoglycaemia, LOW ketones, raised FFA

hepatomegaly

cardiomyopathy

rhabdomyolysis

A

Fatty acid oxidation disoders

-> Hypoketotic hypoglycaemia

test blood ketones, urine organic acids

Tx w regular carbohydrates

406
Q

often triggered by aspirin, antiemetics, valproate

brain: vomiting, confusion, seizures, LOC
liver: may swell and develop fatty deposits

decerebration, respiratory arrest

A

Reye Syndrome

low blood sugar, raised ammonia

407
Q

E.g.s of organic acidaemias

A

isolvaleric acidaemia

maple syrup urine disease

408
Q

sweaty feet odor

+ cheesy/ sweaty smell of urine

truncal hypotonia/ limb hypertonia + myoclonic jerks

poor feeding, vomiting, seizures, lack of energy -> coma

A

Isovaleric acidaemia

disruption of normal metabolism of leucine

-> buildup of isovaleric acid

hyperammonaemia + metabolic acidosis and high anion gap

Tx: dietary protein restriction especially leucine.

remove ammonia acutely by giving sodium benzoate/ dialysis

409
Q

sweet odor of urine

sweaty feet

poor feeding /FTT/ vomiting

alternating hypo and hypertonia, seizures

A

Maple syrup urine disease

dx: by gas chromaography + mass spec

high ammonia

metabolic acidosis and high anion gap

410
Q

tall thin build resembling marfanoid habitus

high arched feet

lens dislocation - downward dislocation

-> myopia/ cataracts

mental retardation + seizures

thrombosis -> may lead to stroke

A

homocystinuria

fair skin, brittle hair

lens dislocation downwards compared to marfans (upwards)

due to cystathionine beta synthase deficiency -> increased conc of homocysteine

411
Q

precipitating factors of acute intermittent porphyria

A

HMB synthase deficiency - activity of enzyme usually 50% of normal

  • ALA synthase inducers (cytochrome P450 inducers which overwhelms activity of HMB synthase) - barbiturates, steroids, ethanol, anticonvulsants
  • COCP
  • Stress - Infection, surgery
  • Reduced caloric intake
  • Endocrine factors - more common in women and premenstrual
412
Q

Diagnosis of Acute intermittent porphyria

A

Urine sample!

keep it shielded from light

Increased ALA and PBG in urine

‘port wine urine’ as seen by person

when PBG gets oxidised to porphobilin (deep yellow -> purple)

413
Q

Treatment and Mx of acute intermittent porphyria

A

Avoid precipitating factors - adequate nutritional intake, avoid precipitant drugs, prompt treatment of infection/ illness

IV Carbohydrate + IV Haem Arginate (key tx)

  • inhibits ALA synthase, which turns off the pathway and reduces [ALA]
414
Q

Acute intermittent porphyria

symptoms

A

Auto dominant inheritance

HMB synthase deficiency

accumulation of PBG and ALA -> neurovisceral attacks

abdo pain, nausea and vomiting, tachycardia, HTN

constipation and urinary incontinence

hypoNa (SIADH)

seizures, psych distrubances

NO cutaneous manifestations

415
Q

PBG synthase deficiency

symptoms

A

extremely Rare

build up of ALA

neurovisceral symptoms e.g. coma, bulbar palsy, motor neuropathy, 90% present w abdo pain

can have psychiatric symptoms

416
Q

Acute porphyrias with neurovisceral attacks and skin lesions

A

Hereditary coproporphyria

Variegate porphyria

Both produce excess coproporphyrinogen III which can be detected in stool, VP also produces excess protoporphyrinogen IX.

These 2 syndromes have acute neurovisceral attacks as PIX and CIII are both potent inhibitors of HMB synthase. Increased PIX and CIII thus reduces HMB synthase activity, accumulating ALA which causes neuro-visceral attacks.

417
Q

hereditary coproporphyria

  • what enzyme deficiency?
A

coproporphyrinogen oxidase deficiency

excess corprophoryinogen III

418
Q

hereditary coproporphyria and varieta porphyria

presentation

A

acute porphyrias w skin lesions

acute neurovisceral attacks

+ skin lesions - classically sun exposed places like back of hand/ neck)

  • blistering , skin fragility.

both are autosomal dominant

419
Q

variegate porphyria

  • what enzyme is deficient?

what accumulates?

A

protoporphyrinogen oxidase deficiency

accumulation of coprophorphyrinogen III and protoporphyrinogen IX

CPIII and PPIX

420
Q

Ix in acute porphyria w skin lesions

A

urine samples, protected from light - raised PBG (but not ALA like in AIP)

raised porphyrins in faeces/ urine

421
Q

Non acute porphyrias?

presentations

which ones

A

only present w skin lesions e.g. blisters, fragility, pigmentation, erosions

no neuro visceral manifestations

CEP- congenital erythorpoietic porphyria

PCT - porphyria cutanea tarda

EPP - erythropoietic protoporphyria

422
Q

Erythropoietic protophorphyria

  • presentation
A

no blisters

most common in children

burning, itching, oedema following sun exposure

(photosensitivity)

assoc w MDS

423
Q

Erythropoietic protoporphyria

  • what enzyme is deficient
  • what investigations?
A

Ferrochetolase deficiency

Ix: RBC [protophorphyrin]

424
Q

porphyria cutanea tarda

PCT

presentation

A

blistering

inherited/ acquired e.g. liver disease/ drugs

formation of vesicles on sun exposed areas of skin crusting, superficial scarring, pigmentation

425
Q

PCT

porphyria cutanea tarda

which enzyme deficiency?

A

uroporphyrinogen decarboxylase deficiency

Ix: raised urinary uroporphyrins + coproporphyrins + increased ferritin

mx: avoid precipitants (alcohol, hepatic compromise)

426
Q

what does the posterior pituitary secrete?

A

ADH and oxytocin

427
Q

Local mass effects of pituitary tumours

A

compression of optic chiasm -> bitemporal hemianopia

signs and symptoms of raised ICP

obstructive hydrocephalus

428
Q

Calcitonin

  • what function

where is it produced

A

produced in parafollicular cells (C cells) of th thyroid gland

calcitonin involved in opposing the effects of PTH, reducing blood calcium

and promoting absorption of calcium by the skeletal system

429
Q

features of thyroid nodules - what is more often neoplastic

A

Solitary nodules more often neoplastic than multiple nodules (as in multinodular goitre)

Solid nodules more likely to be neoplastic than cystic nodules

Nodules in younger patients/males more likely to be neoplastic than in older patients/females

Nodules that do not take up radioactive iodine (cold nodules) more commonly neoplastic than ‘hot’ nodules

*Ultimately it is the morphology that provides the answer - FNA cytology or core biopsy histology

430
Q

usually solitary, well formed capsule

well circumscribed lesion of the thyroid

that compresses the surrounding parenchyma

A

Thyroid adenoma

431
Q

Types of thyroid carcinoma

A

Papillary (75-85%), follicular (10-20%)

Medullary (5%), anaplastic (<5%)

432
Q

Papillary architecture (connective tissue stalks)

nuclear features- optically clear nuclei and intranuclear inclusions

may have psammoma bodies (little foci of calcification in the cells)

presents as painless mass in neck

may present w metastasis in cervical LN

A

Papillary carcinoma

10yr survival up yo 90%

433
Q

Neuroendocrine neoplasm derived from parafollicular C cells

20% familial - MEN - younger patients

80% sporadic - adults 5-6th decade

Histological characteristic feature – calcitonin broken down and deposited as amyloid within tumour, which can be stained with Congo red and seen in green under polarised light

A

Medullary carcinoma

434
Q

Follicular morphology – similar to original thyroid

May be well demarcated with minimal invasion or clearly infiltrative, usually metastasise via bloodstream to lungs, bone and liver.

A

follicular carcinoma

435
Q

thyroid neoplasm

very aggressive

common in elderly

metastases common

most die within 1 yr due to local invasion

A

Anaplastic carcinoma

436
Q

Causes of primary hyperparathyroidism

A

80-90% - solitary adenoma

10-20% hyperplasia of all 4 glands - sporadic or component of MEN type 1

<1% carcinoma of parathyroid

437
Q

hypoparathyroidism symptoms

A

Neuromuscular irritability - tingling, muscle spasms, tetany

Cardiac arrhythmias, fits, cataracts

438
Q

what part of the adrenal secretes aldosterone?

A

Zona glomerulosa

439
Q

which part of the adrenals secrete glucocorticoids?

A

zona fasciculata

440
Q

what part of the adrenals secrete androgens

A

zona reticularis

441
Q

which part of the adrenal secretes noradrenaline and adrenaline?

A

medulla

442
Q

Phaeochromocytoma

rules of 10s

A

10% arise in association with a familial syndrome inc. MEN 2A and 2B, von Hippel-Lindau disease and Sturge-Weber syndrome

10% are bilateral, 10% are malignant

10% of catecholamine-secreting tumours arise outside the adrenal (paragangliomas)

443
Q

what is produced when porphyrinogens are oxidised by sunlight?

A

porphyrins

444
Q

how does the oxygen dissocian curve shift in pyruvate kinase deficiency?

A

right

445
Q

what protein contributes to the charge barrier of the filtration barrier in the kidneys?

A

heparan sulphate

contributes to the negative charge on the filtration barrier

446
Q

histological sample of breast tissue revealed sheets of markedly atypical cells with a prominent lymphocytic infiltrate.

Immunohistochemically, they were then characterised by positivity for basal cytokeratins CK5/6 and CK14.

what is the most likely condition in this patient?

A

basal like carcinoma

  • often assoc w BRCA mutations and have a propensity to vascular invasion and distant metastatic spread
447
Q

what carcinoma in situ is discovered as an incidental finding because there are never any microcalcifications on mammogram?

A

lobular carcinoma in situ

-ALWAYS incidental finding on biopsy.

cells lack adhesion protein E-cadherin.

RF for subsequent invasive breast carcinoma

448
Q

patient has been treated previously for a fibroadenoma now presents w a mass that has slowly grown over the past few wks. She has no other symptoms, and histology reveals glandular stroma cells arranged in a leaf-like manner.

What is the most likely diagnosis in this patient?

A

Phyllodes tumour.

often arises from pre-existing fibroadenoma

majority are benign.

more stromal cellularity and the presence of atypical cells denote a more malignant process.

449
Q

first line tx in aspiration pneumonia

A

metronidazole

to cover for anaerobes found in the GI tract.

450
Q

what allergic disease is most prevalant among children?

A

food allergy

these allergies resolve as children get older, which is why it is impt that children are retested w the gradual introduction of specific food products into their diet.

451
Q

1st line tx for a pt with nasal discharge and conjunctivitis?

A

intranasal antihistamine (H1 receptor antagonist)

where predominant symptom is nasal blockage -> intranasal corticosteroid is recommended

452
Q

pt treated with cisplatin for confirmed diagnosis of non small cell lung ca did not respond to tx.

what mutation is he most likely to have?

A

ERCC1

453
Q

what structural protein is mutated in hypertrophic cardiomyopathy?

A

Beta-myosin heavy chain

454
Q

hypertrophic cardiomyopathy

A

thickening of septum narrows the L ventricular outflow tract

455
Q

what lung ca secretes PTHrp?

A

squamous cell carcinoma

456
Q

Becks triad of cardiac tamponade

A

low arterial BP

distended neck veins

distant, muffled heart sounds

457
Q

Kussmaul sign in Cardiac tamponade

A

paradoxical rise in JVP on inspiration, or a failure in the appropriate fall of the JVP with inspiration

458
Q

most likely organism to cause infective endocarditis in patients who have undergone dental procedures?

A

streptococcus pyogenes

459
Q

criteria to diagnose SIADH?

A

hypoNa <135

Plasma osmolality <270

Urine osmolality >100

High urine Na >20

Euvolaemia

no adrenal, renal or thyroid dysfunction

460
Q

why could

glucose/ mannitol/ ethanol

cause a hypoNa?

A

not a true hypoNa as serum osmolality is high.

(>295)

just a relative hypoNa

461
Q

baby presenting w hypoK, alkalosis and hypotension. + increased calcium in the urine (hypercalcuria) and the kidneys (nephrocalcinosis)

A

bartter syndrome

462
Q

renal tubular acidosis?

what K?

what ph?

A

hypoK + acidosis.

defect in H ion secretion in renal tubules. K secretion therefore increases to balance sodium reabsorption.

type 1 (distal tubule)

type 2 (proximal tubule)]

type 3 (both distal and proximal)

type 4 (defect in adrenal glands)- metabolic acidosis + hyperK

463
Q

causes of raised anion gap

MUDPILES

A

methanol / metformin

Uraemia

DKA

Paraldehyde

Iron

Lactate

Ethanol

Salicylates

464
Q

Dublin- Johnson syndrome

A

autosomal recessive disorder

results in raised conjugated br level due to reduced secretion of conjugated br into the bile.

AST/ALT are normal.

465
Q

Crigler-Najjar syndrome

A

hereditary disease

either complete (type 1) or partial (type 2) reduction in the conjugating enzyme UDP glucuronosyl transferase

-> unconjugated hyperbilirubinaemia

466
Q

long synACTHen test

A

distinguishes between primary (addisons) and secondary adrenal insufficiency.

In secondary adrenal insufficiency- the defect is in the pituitary gland -> low ACTH -> low cortisol and aldosterone.

Long synACTHen test reveals a high cortisol >900, as there is a delayed rise in production in the adrenal glands.

(would still be low in addisons)

467
Q

A 5 yr old girl who is a known cystic fibrosis sufferer is noted by her mother to have developed poor coordination of her hands and on examination her reflexes are absent. Blood tests also reveal anaemia.

what vitamin is deficient?

A

Vitamin E

tocopherol

is an impt anti-oxidant which acts to scavenge free radicals in the blood stream. Deficiency leads to haemolytic anaemia as RBCs encounter oxidative damage and are consequently broken down in the spleen.

Spino-cerebellar neuropathy is also a manifestation, characterized by ataxia and areflexia.

468
Q

B6 deficiency

what features

A

sideroblastic anaemia

dermatologically - seborrhoeic dermatitis

469
Q

night blindness. + conjunctival Bitot’s spots.

Predisposition to measles and diarrhoeal illnesses.

what vitamin deficiency?

A

Vit A

impairs production of rods and hence causes night blindness.

ocular epithelial changes causes conjunctival Bitot’s spots.

470
Q

metabolic disorder that presents in childhood with v fair skin and brittle hair.

+ developmental delay/ progressive learning difficulties and seizures

A

Homocystinuria

+ skeletal abnormalities

mx: supplement w vitamin B6 or maintaining child on low methionine diet.

471
Q

metabolic disorder

cherry red spot

A

lysosomal storage disorders

fabrys

tay sachs

472
Q

metabolic disorder

sweaty feet

sweet odour

A

maple syrup urine disease

toxic compounds (leucine, isoleucine, valine) accumulate

causing toxic encephalopathy

-> FTT, lethargy, hypotonia, seizures

473
Q

metabolic disorder

fair haired

blue eyes

pale skin

A

phenylketonuria

lack phenylalanine hydroxylase

present w developmental delay, severe IQ impariment

+ seizures/ eczema

474
Q

metabolic disorder

hypoglycaemia

+ liver and kidney enlargement

A

gylcogen storage disorder

e.g

Von Gierke’s

Pompe’s

Cori’s

McArdle’s

475
Q

metabolic disorder

FTT, hypotonia, metabolic acidosis, hyperglycaemia

in a neonate

A

SCAD deficiency

Short chain acyl coenzyme A

476
Q

how does carbamazepine lead to hypoNa?

A

stimulates production of vasopressin (ADH)

so presents similarly to SIADH

477
Q

SIADH diagnosis of exclusion!

rmb diagnostic criteria

2 in the blood

2 in the urine

three exclusions

A

2 low in the blood- hypoNa, hypoosmolality

2 high in the urine - high urinary sodium >20, high urine osmolality

three exclusions - no renal/ adrenal/ thyroid/ cardiac disease, no hypovolaemia and no contributing drugs e.g. carbamazepine

478
Q

Psuedohypoparathyroidism

what Ca/ PO4/ PTH levels?

A

aka Albright’s osteodystrophy

PTHR insensitivity in the kidney

-> HIGH PTH, low Ca and High PO4

+ physical signs e.g. short height, short 4th and 5th metacarpals, reduced intelligence, basal ganglia calcification and endocrinopathies e.g T2DM, obesity, hypothyroid, hypogonadism

479
Q

Pseudopseudohypoparathyroidism

A

similar physical features of pseudohypoPTH (albrights osteodystrophy)

but no biochemical abnromalities

  • genetic imprinting
    e. g. prader willi and angelmans
480
Q

what plasma protein is used for detection of alcohol abuse?

A

carbohydrate deficient transferrin.

Ppl with alcohol abuse have a reduction in bound carbohydrates and increase in their carbohydrate deficient transferrin.

about 70% sensitive but 95% specific for alcohol abuse.

other tests include presence of macrocytic anaemia, raised GGT

481
Q

during the water deprivation test, one cant drink any water in the first 8 h

how much water is the patient allowed to drink after 8h, and after desmopressin is given?

A

allowed to drink 1.5 x the total urine output of the first 8 h

e.g. if 1L was the urine output, allowed to drink 1.5 L

if pt drinks too much water, the test is nullified

482
Q

osmolar gap

A

difference between estimated osmolarity and lab osmolality

usually <10 mmol/L

if higher, then consider presence of additional solutes

e.g. ethanol, methanol, ethylene glycol and acetone

483
Q

newborn with cataracts, poor feeding, lethargy, conjugated hyperbilirubinaemia w hepatomegaly and reducing sugars in the urine after starting milk

A

galactosaemia

galactose-1-phosphate uridyltransferase genn

484
Q

Alk phos in multiple myeloma?

A

normal

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