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Laz questions > Chem Path > Flashcards

Chem Path Flashcards

1
Q

<p></p>

<p>List 3 roles of purines</p>

A

<p></p>

<p>Genetic code, 2nd messengers for hormone action (e.g. cAMP), energy transfer (e.g. ATP)</p>

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2
Q

<p></p>

<p>Describe pathway of purine catabolism (include enzymes & substrate names)</p>

A

<p></p>

<p>Purines -> hypoxanthine -> xanthine -> urate -> allantoin
<br></br>
<br></br>- Xanthine oxidase: hypoxanthine -> urate
<br></br>- Uricase: urate -> allantoin</p>

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3
Q

<p></p>

<p>Which enzyme typically leads to build-up of uric acid?</p>

A

<p></p>

<p>Uricase
<br></br>N.B: Allantoin (product of uricase) = soluble & rapidly excreted in urine</p>

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4
Q

<p></p>

<p>Why are M more susceptible to gout than F?</p>

A

<p></p>

<p>Higher average urate plasma concentrations</p>

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5
Q

<p></p>

<p>Which joint is most commonly affected by gout & why?</p>

A

<p></p>

<p>1st metatarsophalangeal joint - found at periphery so likely to be cooler (lower temperatures reduce concentration at which urate precipitates out of solution)</p>

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6
Q

<p></p>

<p>Describe how kidneys handle urate.</p>

A

<p></p>

<p>Proximal convoluted tubule reabsorbs & secretes urate
<br></br>N.B: Reason urate reabsorbed probably because it's an important antioxidant that protects from oxidative stress</p>

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7
Q

<p></p>

<p>Roughly what proportion of filtered urate will be found in urine? What term is used to describe this?</p>

A

<p></p>

<p>10%
<br></br>Fractional excretion of uric acid (FEUA)</p>

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8
Q

<p></p>

<p>What are the 2 methods of purine synthesis? Which is predominant in most tissues?</p>

A

<p></p>

<p>De novo synthesis
<br></br>Salvage pathway (predominant)</p>

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9
Q

<p></p>

<p>Describe de novo purine synthesis. In which tissue is this dominant?</p>

A

<p></p>

<p>Metabolically demanding & inefficient.
<br></br>Only occurs when high demand for purines (e.g. bone marrow)</p>

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10
Q

<p></p>

<p>What is rate limiting step in de novo purine synthesis pathway?</p>

A

<p></p>

<p>PAT (polar auxin transport)</p>

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11
Q

<p></p>

<p>Describe the inhibitory & stimulatory controls on this enzyme</p>

A

<p></p>

<p>AMP & GMP negatively regulate PAT activity
<br></br>PPRP positively regulates PAT activity</p>

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12
Q

<p></p>

<p>What is the main enzyme in the salvage pathway? Describe its role.</p>

A

<p></p>

<p>HPRT (aka HGPRT)
<br></br>Mops up partially catabolised purines & brings them back up metabolic pathway to produce IMP & GMP
<br></br>N.B: Hypoxanthine -> IMP; guanine -> GMP</p>

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13
Q

<p></p>

<p>What inborn error of purine metabolism is characterised by HPRT deficiency?</p>

A

<p></p>

<p>Lesch-Nyhan syndrome</p>

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14
Q

<p></p>

<p>Describe Lesch-Nyhan syndrome's inheritance pattern</p>

A

<p></p>

<p>X-linked recessive (must say recessive not just X-linked)</p>

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15
Q

<p></p>

<p>Outline clinical features of Lesch-Nyhan syndrome</p>

A

<p></p>

<p>Normal at birth
<br></br>Developmental delay at 6mths
<br></br>Hyperuricaemia
<br></br>Choreiform movements at 1yr
<br></br>Spasticity & mental retardation
<br></br>Self-multilation present in 85% (e.g. biting lips very hard)</p>

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16
Q

<p></p>

<p>Describe the biochemical basis of Lesch-Nyhan syndrome</p>

A

<p></p>

<p>Caused by absolute deficiency of HPRT
<br></br>Reduces production of AMP & GMP by salvage pathway
<br></br>Reduces inhibitory effect of AMP & GMP on PAT, thereby increasing activity of de novo pathway
<br></br>Leads to production of vast amounts of IMP, which will be shunted down catabolic pathway to produce urate (which accumulates)
<br></br>Less conversion of guanine -> GMP leads to build-up of PPRP (which stimulates PAT)</p>

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17
Q

<p></p>

<p>What are the 2 mechanisms of hyperuricaemia? List some examples</p>

A

<p></p>

<p>Increased urate production
<br></br>- E.g. rapid cell turnover in myeloproliferative diseases & psoriasis
<br></br>
<br></br>Decreased urate excretion
<br></br>- E.g. saturnine gout (caused by lead poisoning e.g. antifreeze) and diuretic use</p>

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18
Q

<p></p>

<p>What are the 2 types of gout?</p>

A

<p></p>

<p>Acute (podagra)
<br></br>Chornic (tophaceous)
<br></br>N.B: Tophi can cause periosteal bone erosion</p>

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19
Q

<p></p>

<p>How can gout be diagnosed if there is still doubt after history, examination, & measurement of uric acid levels?</p>

A

<p></p>

<p>Effusion can be tapped & viewed under polarised light using red light compensator</p>

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20
Q

<p></p>

<p>What is birefringence?</p>

A

<p></p>

<p>Ability of crystal to rotate axis of polarised light
<br></br>-ve = appear blue at 90 degrees to axis of red compensator
<br></br>+ve = appear blue in axis of red compensator</p>

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21
Q

<p></p>

<p>Describe how birefringence/crystals differ between gout & pseudogout?</p>

A

<p></p>

<p>Gout - monosodium urate crystals - needle-shaped & -vely birefringent
<br></br>
<br></br>Pseudogout - calcium pyrophosphate crystals - rhomboid shaped & +vely birefringent</p>

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22
Q

<p></p>

<p>List 3 drug classes used in the acute management of gout</p>

A

<p></p>

<p>NSAIDs
<br></br>Colchicine
<br></br>Glucocorticoids</p>

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23
Q

<p></p>

<p>Describe mechanism of colchicine</p>

A

<p></p>

<p>Inhibits manufacture of tubulin
<br></br>Short-term administration of colchicine inhibits microtubule formation enough to reduce motility of neutrophils (thereby reducing ability to migrate to site of inflammation)</p>

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24
Q

<p></p>

<p>Describe management of gout after acute phase over</p>

A

<p></p>

<p>Encourage fluid intake
<br></br>Reverse factors that may increase concentration of uric acid (e.g. stopping diuretics)
<br></br>
<br></br>Allopurinol - reduces synthesis of urate by inhibiting xanthine oxidase
<br></br>Probenecid - increases renal excretion of urate (increases FEUA)</p>

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25
Q

<p></p>

<p>Which drug is contraindicated with allopurinol?</p>

A

<p></p>

<p>Azathioprine</p>

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26
Q

<p></p>

<p>Describe interaction between allopurinol & azathoioprine</p>

A

<p></p>

<p>Azathioprine = pro-drug that's metabolised to merceptopurine & thioinosate
<br></br>Mercaptopurine (being a purine) metabolised by xanthine oxidase pathway
<br></br>Inhibiting xanthine oxidase with allopurinol leads to build-up of mercaptopurine resulting in bone marrow toxicity</p>

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27
Q

<p></p>

<p>What underlying condition is pseudogout often associated with?</p>

A

<p></p>

<p>Osteoarthritis
<br></br>N.B: Self-limiting & usually resolves after 1-3wks</p>

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28
Q

<p></p>

<p>What are features of atherosclerotic lesion?</p>

A

<p></p>

<p>Fibrous cap
<br></br>Foam cells (macrophages full of cholesteryl ester)
<br></br>Necrotic core (full of cholesterol crystals)</p>

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29
Q

<p></p>

<p>During what time will chylomicrons be most abundunt?</p>

A

<p></p>

<p>After eating (present in very small amounts in fasted state)</p>

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30
Q

<p></p>

<p>Describe uptake of cholesterol by intestinal epithelium</p>

A

<p></p>

<p>Cholesterol entering intestines will come from diet & bile
<br></br>Cholesterol will be solubilised in mixed micelles
<br></br>Then transported across intestinal epithelium by NPC1L1 (this is main determinant of cholesterol transport)</p>

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31
Q

<p></p>

<p>Where are bile acids absorbed?</p>

A

<p></p>

<p>Terminal ileum</p>

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32
Q

<p></p>

<p>What happens when cholesterol arrives at liver?</p>

A

<p></p>

<p>Downregulates activity of HMG CoA reductase
<br></br>N.B: This is responsible for production of cholesterol from acetate & mevalonic acid</p>

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33
Q

<p></p>

<p>What are the 2 fates of cholesterol that either produced by or transported to the liver?</p>

A

<p></p>

<p>Hydroxylation by 7a-hydroxylase to produce bile acids
<br></br>Esterification by ACAT to produce cholesterol ester which is incorporated into VLDLs along with triglycerides & ApoB</p>

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34
Q

<p></p>

<p>What are effects of CETP on movement of substances between lipoproteins?</p>

A

<p></p>

<p>Moves cholesterol from HDL -> VLDL
<br></br>Moves triglycerides from VLDL -> HDL</p>

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35
Q

<p></p>

<p>Describe transport & metabolism of triglycerides</p>

A

<p></p>

<p>Triglycerides from fatty foods hydrolysed to fatty acids, absorbed, & resynthesised into triglycerides which transported by chylomicrons into plasma
<br></br>Chylomicrons hydrolysed by lipoprotein lipase into free fatty acids
<br></br>Some free fatty acids taken up by liver & some by adipose tissue
<br></br>Liver resynthesises fatty acids into triglycerides & packages them into VLDLs
<br></br>VLDLs acted upon by lipoprotein lipase to liberate free fatty acids</p>

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36
Q

<p></p>

<p>List the 3 causes of familial hypercholesterolaemia (type II)</p>

A

<p></p>

<p>Caused by autosomal dominant gene mutations in:
<br></br>- LDL receptor
<br></br>- ApoB
<br></br>- PCSK9</p>

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37
Q

<p></p>

<p>List some mutations implicated in polygenic hypercholesterolaemia</p>

A

<p></p>

<p>NPC1L1
<br></br>HMGCR
<br></br>CYP7A1</p>

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38
Q

<p></p>

<p>What is familial hyperalpha lipoproteinaemia?</p>

A

<p></p>

<p>Increase in HDL caused by deficiency of CETP
<br></br>Associated with longevity</p>

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39
Q

<p></p>

<p>What is phytosterolaemia?</p>

A

<p></p>

<p>Increased plasma concentrations of plant sterols due to mutations in ABC G5 & ABC G8
<br></br>N.B: This condition associated with premature atherosclerosis</p>

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40
Q

<p></p>

<p>Describe function of LDL receptor</p>

A

<p></p>

<p>LDLs bind to LDLR in coated pits which then undergo endocytosis (thereby uptaking LDL into liver)</p>

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41
Q

<p></p>

<p>List some clinical features of familial hypercholesterolaemia</p>

A

<p></p>

<p>Xanthelasma
<br></br>Corneal arcus
<br></br>Tendon xanthomata</p>

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42
Q

<p></p>

<p>What is PCSK9?</p>

A

<p></p>

<p>Protein that binds to LDL receptors & degrades them
<br></br>N.B: Gain of function mutations result in increased breakdown of LDLR & hence increased plasma LDL levles</p>

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43
Q

<p></p>

<p>List key features of the following forms of familial hypertriglyceridaemia:
<br></br>- Familial Type I
<br></br>- Familial Type IV
<br></br>- Familial Type V</p>

A

<p></p>

<p>Familial type I
<br></br>- Caused by deficiency of lipoprotein lipase & ApoCII
<br></br>- N.B: Lipoprotein lipase degrades chylomicrons & ApoCII is an activator of lipoprotein lipase
<br></br>
<br></br>Familial type IV
<br></br>- Characterised by increased synthesis of triglycerides
<br></br>
<br></br>Familial type V
<br></br>- Characterised by deficiency of ApoA V
<br></br>
<br></br>N.B: These hypertriglyceridaemias show different different patterns when plasma left overnight to separate</p>

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44
Q

<p></p>

<p>What is familial combined hyperlipidaemia?</p>

A

<p></p>

<p>Some people in family have high cholesterol & others have high triglycerides</p>

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45
Q

<p></p>

<p>What is familial dysbetalipoproteinaemia (type III)?</p>

A

<p></p>

<p>Due to aberrant form of ApoE (E2/2)
<br></br>N.B: Normal form is ApoE (3/3)
<br></br>Diagnostic clinical feature = yellowing of palmar crease (palmar striae)</p>

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46
Q

<p></p>

<p>List some causes of secondary hyperlipidaemia</p>

A

<p></p>

<p>Pregnancy
<br></br>Hypothyroidism
<br></br>Obesity
<br></br>Nephrotic syndrome</p>

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47
Q

<p></p>

<p>List 4 causes of hypolipidaemia & their underlying genetic defect</p>

A

<p></p>

<p>ab (alpha beta)-lipoproteinaemia
<br></br>- Autosomal recessive
<br></br>- Extremely low levels of cholesterol
<br></br>- Due to deficiency of MTP
<br></br>
<br></br>Hypo-b-lipoproteinaemia
<br></br>- Autosomal dominant
<br></br>- Low LDL
<br></br>- Caused by mutations in ApoB
<br></br>
<br></br>Tangier disease
<br></br>- Low HDL
<br></br>- Caused by mutation of ABC A1
<br></br>
<br></br>Hypo-a-lipoproteinaemia
<br></br>- Sometimes caused by mutation of ApoA1</p>

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48
Q

<p></p>

<p>Describe the role of LDL in atherosclerosis</p>

A

<p></p>

<p>LDL becomes oxidised once it has got through vascular endothelium
<br></br>Once oxidised taken up by macrophages
<br></br>Within the macrophages, the LDLs become esterified & develop foam cells</p>

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49
Q

<p></p>

<p>List some lipid-lowering drugs & their effect on lipid levels</p>

A

<p></p>

<p>Statins - reduce LDLs, increase HDLs, slight increase in triglycerides
<br></br>Fibrates - lower triglycerides, little effects on LDL/HDL
<br></br>Ezetimibe - reduces cholesterol absorption (blocks NPC1L1)
<br></br>Colestyramine - resin that binds to bile acids & reduces their absorption</p>

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50
Q

<p></p>

<p>List some novel form of lipid-lowering drugs</p>

A

<p></p>

<p>Lomitapide - MTP blocker
<br></br>REGN727 - anti-PCSK9 monoclonal Ab
<br></br>Mipomersen - anti-sense ApoB oligonucleotide</p>

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51
Q

<p></p>

<p>What is the definition of success in bariatric surgery?</p>

A

<p></p>

<p>>50% reduction in excess weight</p>

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52
Q

<p></p>

<p>List some beneficial effects of bariatric surgery</p>

A

<p></p>

<p>Reduced diabetes risk
<br></br>Reduced serum triglycerides
<br></br>Increased HDLs
<br></br>Reduced fatty livery
<br></br>Reduced BP</p>

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53
Q

<p></p>

<p>What is the normal range for H+ concentration in ECF?</p>

A

<p></p>

<p>35-45mmol/L</p>

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54
Q

<p></p>

<p>What equation links H+ to pH</p>

A

<p></p>

<p>pH = log(1/[H+])</p>

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55
Q

<p></p>

<p>What are the 3 main physiological buffers?</p>

A

<p></p>

<p>Bicarbonate
<br></br>Haemoglobin
<br></br>Phosphate
<br></br>N.B: Also protein & bone</p>

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56
Q

<p></p>

<p>What is the rate of production of H+ ions per day?</p>

A

<p></p>

<p>50-100mmol/day</p>

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57
Q

<p></p>

<p>Describe how kidneys excrete H+ ions</p>

A

<p></p>

<p>HCO3 regenerated through production of carbonic acid</p>

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58
Q

<p></p>

<p>Describe how H+ ions pass through renal epithelium membrane</p>

A

<p></p>

<p>H+ ions cannot pass through membrane itself so transport system necessary (Na+/H+ exchange)</p>

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59
Q

<p></p>

<p>What is the rate of production of CO2 per day?</p>

A

<p></p>

<p>20,000-25,000mmol/day</p>

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60
Q

<p></p>

<p>Describe respiratory control over CO2</p>

A

<p></p>

<p>Respiration controlled by chemoreceptors in hypothalamic respiratory centre
<br></br>Increase in CO2 will stimulate increase in ventilation which then brings down CO2 concentration</p>

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61
Q

<p></p>

<p>What is the primary abnormality in metabolic acidosis? List 3 causes with e.g.s</p>

A

<p></p>

<p>Primary abnormality increased H+ (with decreased HCO3)
<br></br>Caused by:
<br></br>- Increased H+ production (e.g. DKA)
<br></br>- Decreased H+ excretion (e.g. renal tubular acidosis)
<br></br>HCO3 loss (e.g. intestinal fistula)</p>

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62
Q

<p></p>

<p>What is the primary abnormality in respiratory acidosis? List 3 causes with e.g.s</p>

A

<p></p>

<p>Primary abnormality increased CO2 (therefore, increased H+) & slight increase in HCO3
<br></br>Caused by:
<br></br>- Decreased ventilation
<br></br>- Poor lung perfusion
<br></br>- Impaired gas exchange
<br></br>N.B: Metabolic compensation slower than respiratory compensation</p>

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63
Q

<p></p>

<p>What is the primary abnormality in metabolic alkalosis? List 3 causes with e.g.s</p>

A

<p></p>

<p>Primary abnormality decreased H+ (with increased HCO3)
<br></br>Caused by:
<br></br>- H+ loss (e.g. pyloric stenosis)
<br></br>- Hypokalaemia
<br></br>- Ingestion of HCO3</p>

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64
Q

<p></p>

<p>What is the primary abnormality in respiratory alkalosis? List 3 causes with e.g.s</p>

A

<p></p>

<p>Primary abnormality reduced CO2
<br></br>If prolonged, can lead to reduced renal H+ excretion & reduced HCO3 generation
<br></br>Can be caused by hyperventilation due to:
<br></br>- Voluntary
<br></br>- Artificial ventilation
<br></br>- Stimulation of respiratory centre</p>

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65
Q

<p></p>

<p>What derangement of acid-base balance would be caused by pyloric stenosis?</p>

A

<p></p>

<p>Metabolic alkalosis due to loss of H+ from profuse vomiting</p>

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66
Q

<p></p>

<p>Which condition classically causes mixed respiratory alkalosis & metabolic acidosis?</p>

A

<p></p>

<p>Aspirin overdose
<br></br>Aspirin stimulates ventilation & reduces renal excretion of H+</p>

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67
Q

<p></p>

<p>Describe arrangement of hepatocytes within liver</p>

A

<p></p>

<p>Hepatocytes arranged in trabeculae with sinusoids between them</p>

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68
Q

<p></p>

<p>What are the 3 main components of portal triad?</p>

A

<p></p>

<p>Portal vein
<br></br>Hepatic artery
<br></br>Bile duct</p>

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69
Q

<p></p>

<p>Describe arrangement of endothelial cells within hepatic sinusoids</p>

A

<p></p>

<p>Endothelial cells discontinous
<br></br>Spaces between hepatocytes & endothelium of sinusoids called space of Disse
<br></br>This space allows blood to come into contact with liver enzymes</p>

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70
Q

<p></p>

<p>Describe the differences between zone 1 and zone 3</p>

A

<p></p>

<p>Zone 1 (closer to portal triad) - receives highest O2 concentration
<br></br>Zone 3 (closer to central vein) - receives lowest O2 concentration, therefore most vulnerable to hypoxia. Most metabolically active zone</p>

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71
Q

<p></p>

<p>Which investigations performed if pre-hepatic cause of jaundice suspected?</p>

A

<p></p>

<p>FBC
<br></br>Blood film</p>

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72
Q

<p></p>

<p>What reaction is used to measure fractions of bilirubin? Describe how this works</p>

A

<p></p>

<p>Van den Bergh reaction
<br></br>Direct reaction measures conjugated bilirubin
<br></br>Methanol added which completes reaction & gives value for total bilirubin
<br></br>Difference between these 2 values used to measure unconjugated bilirubin (indirect reaction)</p>

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73
Q

<p></p>

<p>What is the most common cause of paediatric jaundice?</p>

A

<p></p>

<p>Physiological jaundice
<br></br>Neonates have immature livers that cannot conjugate bilirubin fast enough resulting in unconjugated hyperbilirubinaemia</p>

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74
Q

<p></p>

<p>Describe how phototherapy for jaundice works</p>

A

<p></p>

<p>Phototherapy converts unconjugated bilirubin into lumirubin & photobilirubin which are soluble & don't require conjugation for excretion</p>

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75
Q

<p></p>

<p>What is the inheritance pattern of Gilbert's syndrome?</p>

A

<p></p>

<p>Autosomal recessive</p>

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76
Q

<p></p>

<p>Which drug can reduce bilirubin levels in Gilbert's syndrome?</p>

A

<p></p>

<p>Phenobarbital</p>

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77
Q

<p></p>

<p>Outline pathophysiology of Gilbert's syndrome?</p>

A

<p></p>

<p>UGP glucoronyl transferase activity reduced to 30% of normal
<br></br>Unconjugated bilirubin tightly albumin bound & doesn't enter urine</p>

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78
Q

<p></p>

<p>What can worsen bilirubin levels in Gilbert's syndrome?</p>

A

<p></p>

<p>Fasting</p>

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79
Q

<p></p>

<p>Describe how urobilinogen formed. What is the significance of absent urobilinogen into urine?</p>

A

<p></p>

<p>Bilirubin released into bowels will be converted by bacteria in colon into urobilinogen & stercobilinogen
<br></br>Some urobilinogen will be absorbed & transported via enterohepatic circulation to liver
<br></br>Some of this urobilinogen will then be excreted in urine
<br></br>Presence of urobilinogen in urine is normal
<br></br>Absence of urobilinogen in urine suggestive of biliary obstruction</p>

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80
Q

<p></p>

<p>Outline how hepatitis A serology changes over time</p>

A

<p></p>

<p>As viral titres start to drop following initial infection, there will be a rise in IgM Ab (during this time you will be unwell with jaundice)
<br></br>After a few wks, will start to produce IgG Ab (leading to cure & ongoing protection from Hep A)
<br></br>N.B: Hep A doesn't recur</p>

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81
Q

<p></p>

<p>Name the vaccine for hepatitis A</p>

A

<p></p>

<p>Havrix (contains some Ags)</p>

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82
Q

<p></p>

<p>Outline the features of hepatitis B serology in acute infection</p>

A

<p></p>

<p>Initial rise in HBeAg & HBsAg
<br></br>Eventually will develop HBeAb & HBsAb resulting in decline in HBeAg & HBsAg
<br></br>Will also develop HBcAb which suggests previous infection
<br></br>N.B: There is currently no way of diretly measuring HBcAg</p>

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83
Q

<p></p>

<p>Outline the features of hepatitis B serology in someone who has been vaccinated</p>

A

<p></p>

<p>Will have HBsAb but no other Abs
<br></br>This is because vaccine consists of administering HBsAg only</p>

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84
Q

<p></p>

<p>Outline the features of hepatitis B serology in chronic carrier</p>

A

<p></p>

<p>Pt will mount immune response but will never clear the virus
<br></br>HBeAg will decline but HBsAg will persist</p>

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85
Q

<p></p>

<p>Describe histology of hepatitis</p>

A

<p></p>

<p>Hepatocytes will become fatty & swell (balloon cells), containing a lot of Mallory hyaline
<br></br>There will also be a lot of neutrophil polymorphs</p>

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86
Q

<p></p>

<p>What are the defining & associated histological features of alcoholic hepatitis?</p>

A

<p></p>

<p>Defining: Liver cell damage, inflammation, fibrosis
<br></br>Associated: Fatty change, megamitochondria</p>

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87
Q

<p></p>

<p>List differential diagnoses for fatty liver disease</p>

A

<p></p>

<p>NASH (most common cause of liver disease in the Western world)
<br></br>Alcoholic hepatitis
<br></br>Malnourishment (Kwashiorkor)</p>

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88
Q

<p></p>

<p>Outline treatment of alcoholic hepatitis</p>

A

<p></p>

<p>Supportive
<br></br>Stop alcohol
<br></br>Nutrition (vitamins especially thiamine)
<br></br>Occasionally steroids (controversial but may have useful anti-inflammatory effects)</p>

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89
Q

<p></p>

<p>What is the issue with regeneration of hepatocytes following alcohol-related damage?</p>

A

<p></p>

<p>Regenerate in disorganised manner & produce lots of nodules
<br></br>Disorganised growth interferes with blood flowing through liver leading to rise in portal pressure</p>

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90
Q

<p></p>

<p>Why is Pabrinex yellow?</p>

A

<p></p>

<p>Presence of riboflavin (B2)</p>

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91
Q

<p></p>

<p>What conditions are caused by the following vitamin deficiencies:
<br></br>- B1
<br></br>- B3</p>

A

<p></p>

<p>B1
<br></br>- Beri Beri
<br></br>
<br></br>B3
<br></br>- Pellagra</p>

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92
Q

<p></p>

<p>List some features of chronic alcoholic liver disease</p>

A

<p></p>

<p>Palmar erythema
<br></br>Spider naevi
<br></br>Gynaecomastia (due to failure of liver to break down oestradiol)
<br></br>Dupuytren's contracture</p>

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93
Q

<p></p>

<p>List some features of portal hypertension</p>

A

<p></p>

<p>Visible veins (oesophageal, rectal, umbilical)
<br></br>Ascites
<br></br>Splenomegaly</p>

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94
Q

<p></p>

<p>What is flapping tremor caused by?</p>

A

<p></p>

<p>Hepatic encephalopathy</p>

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95
Q

<p></p>

<p>What is liver failure defined by?</p>

A

<p></p>

<p>Failed synthetic function
<br></br>Failed clotting factor & albumin production
<br></br>Failed clearance of bilirubin
<br></br>Failed clearance of ammonia</p>

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96
Q

<p></p>

<p>Which type of cirrhosis is alcohol typically associated with?</p>

A

<p></p>

<p>Micronodular cirrhosis
<br></br>N.B: This is because the hepatocytes regenerate within fibrous cuff</p>

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97
Q

<p></p>

<p>What is intrahepatic shunting?</p>

A

<p></p>

<p>Bridge of fibrosis between portal tracts & central veins means that blood doesn't come into close contact with hepatocytes & get filtered</p>

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98
Q

<p></p>

<p>Which type of jaundice associated with itching? What causes the itching?</p>

A

<p></p>

<p>Obstructive jaundice
<br></br>Itching caused by bile salts & bile acids</p>

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99
Q

<p></p>

<p>What is Courvoisier's law?</p>

A

<p></p>

<p>If gallbladder palpable in jaundiced patient, cause is unlikely to be gallstones (i.e. more likely to be pancreatic cancer)</p>

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100
Q

<p></p>

<p>Where does pancreatic cancer tend to metastasise to?</p>

A

<p></p>

<p>Liver</p>

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101
Q

<p></p>

<p>What are the main consequences of deficient enzyme activity in the context of inherited metabolic disorders?</p>

A

<p></p>

<p>Lack of end-product
<br></br>Build-up of precursors
<br></br>Abnormal or toxic metabolites</p>

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102
Q

<p></p>

<p>What are the criteria for inherited metabolic disorder screening? (Wilson & Junger criteria)</p>

A

<p></p>

<p>- Important health problem
<br></br>- Accepted treatment
<br></br>- Facilities for diagnosis & treatment
<br></br>- Latent or early symptomatic stage
<br></br>- Suitable test or examination
<br></br>- Test should be acceptable to population
<br></br>- Natural history of disorder is understood
<br></br>- Agreed policy on whom to treat as patients
<br></br>- Economically balanced
<br></br>- Continuing process (keep updating what is screened for)</p>

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103
Q

<p></p>

<p>What is phenylketonuria caused by</p>

A

<p></p>

<p>Phenylalanine hydroxylase deficiency
<br></br>Responsible for converting phenylalanine to tyrosine
<br></br>Deficiency results in accumulation of phenylalanine which is toxic</p>

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104
Q

<p></p>

<p>Which abnormal metabolites are produced in PKU?</p>

A

<p></p>

<p>Phenylpyruvate
<br></br>Phenylacetic acid (detected in urine)</p>

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105
Q

<p></p>

<p>What is the main consequnce of untreated PKU?</p>

A

<p></p>

<p>Low IQ</p>

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106
Q

<p></p>

<p>How is PKU investigated?</p>

A

<p></p>

<p>Blood phenylalanine level</p>

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107
Q

<p></p>

<p>Describe the treatment of PKU</p>

A

<p></p>

<p>Monitor the diet & ensure that the patient is having enough phenylalanine (but not too much)
<br></br>This must be started within the first 6wks of life</p>

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108
Q

<p></p>

<p>When is the Guthrie test performed in the UK?</p>

A

<p></p>

<p>5-8 days after birth</p>

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109
Q

<p></p>

<p>What is congenital hypothyroidism usually caused by?</p>

A

<p></p>

<p>Thyroid dysgenesis or agenesis
<br></br>N.B: Diagnosis based on high TSH</p>

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110
Q

<p></p>

<p>Describe the pathophysiology of MCAD deficiency</p>

A

<p></p>

<p>Fatty acid oxidation disorder
<br></br>The carnitine shuttle transports fats into the mitochondria where it will be broken down into smaller & smaller chains by the process of fatty acid oxidation
<br></br>Without MCAD, will not produce acetyl-CoA from fatty acids, which is necessary in the TCA cycle to produce ketones (which spares glucose)
<br></br>Fat is used when fasting in between meals in order to spare glucose stores
<br></br>In MCAD deficiency, the patient is unable to break down fats so they become very hypoglycaemic (as can't produce ketones) in between meals & thus can die</p>

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111
Q

<p></p>

<p>What is the screening test for MCAD deficiency?</p>

A

<p></p>

<p>Measuring C6-C10 acylcarnitines by tandem mass spectrometry</p>

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112
Q

<p></p>

<p>Outline the treatment of MCAD deficiency</p>

A

<p></p>

<p>Make sure child never becomes hypoglycaemic, & hence reliant on fats as source of energy</p>

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113
Q

<p></p>

<p>What is homocysturia caused by?</p>

A

<p></p>

<p>Failure of remethylation of homocysteine</p>

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114
Q

<p></p>

<p>What are the clinical features of homocystinuria?</p>

A

<p></p>

<p>Lens dislocation
<br></br>Mental retardation
<br></br>Thromboembolism</p>

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115
Q

<p></p>

<p>Which conditions are screened for by the Guthrie test?</p>

A

<p></p>

<p>Sickle cell disease
<br></br>Cystic fibrosis
<br></br>Congenital hypothyroidism
<br></br>Inherited metabolic diseases:
<br></br>- Phenylketonuria (PKU)
<br></br>- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
<br></br>- Maple syrup urine disease (MSUD)
<br></br>- Isovaleric acidaemia (IVA)
<br></br>- Glutaric aciduria type 1 (GA1)
<br></br>- Homocystinuria (HCU)</p>

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116
Q

<p></p>

<p>Outline the pathophysiology of cystic fibrosis</p>

A

<p></p>

<p>Failure of cystic fibrosis transmembrane conductance regulator (CFTR) means that chloride ions cannot move into lumen from cells, resulting in increased water absorption & very thick secretions</p>

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117
Q

<p></p>

<p>What is the screening test for cystic fibrosis?</p>

A

<p></p>

<p>High serum immune reactive trypsinogen (IRT)</p>

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118
Q

<p></p>

<p>Describe the process of screening & diagnosis of cystic fibrosis?</p>

A

<p></p>

<p>If IRT >99.5th centile in 3 bloodspots, move on to mutation detection
<br></br>>500 mutations that can cause CF, but 4 are very common
<br></br>If detect 2/4 mutations, diagnose CF
<br></br>If detect 1/4 mutations, extend test to panel of 28 mutations
<br></br>If detect 0/4 mutations, repeat IRT at day 21-28</p>

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119
Q

<p></p>

<p>Why is it difficult to get an ammonia sample?</p>

A

<p></p>

<p>Need a free-flowing sample, which needs to be put in ice & rushed to lab</p>

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120
Q

<p></p>

<p>What is the main role of the urea cycle</p>

A

<p></p>

<p>Taking ammonia & producing urea</p>

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121
Q

<p></p>

<p>How many enzymes are there in the urea cycle?</p>

A

<p></p>

<p>7</p>

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122
Q

<p></p>

<p>Name 3 other diseases that count as urea cycle defects</p>

A

<p></p>

<p>Lysinuric protein intolerance
<br></br>Hyperornithaemia-hyperammonaemia-homocitrullinuria
<br></br>Citrullinuria type II</p>

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123
Q

<p></p>

<p>What do all urea cycle disorders result in?</p>

A

<p></p>

<p>High ammonia - this is toxic</p>

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124
Q

<p></p>

<p>What is the mode of inheritance of almost all of these urea cycle defects? What is the exception?</p>

A

<p></p>

<p>Autosomal recessive
<br></br>Ornithine transcarbamylase deficiency (X-linked)</p>

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125
Q

<p></p>

<p>How does the body get rid of excess ammonia?</p>

A

<p></p>

<p>Ammonium group attached to glutamate to make glutamine
<br></br>So, plasma glutamine in hyperammonaemic conditions will be high
<br></br>N.B: The amino acids within the urea cycle will be high or absent. You can also measure urine orotic acid</p>

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126
Q

<p></p>

<p>What is the treatment of urea cycle disorders?</p>

A

<p></p>

<p>Remove ammonia (using sodium benzoate, sodium phenylacetate, or dialysis)
<br></br>Remove ammonia production (low protein diet)</p>

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127
Q

<p></p>

<p>Why might patients with urea cycle disorders have slight build?</p>

A

<p></p>

<p>Patients may subconsciously avoid protein because they know it makes them feel ill</p>

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128
Q

<p></p>

<p>List the key features of urea cycle disorders</p>

A

<p></p>

<p>Vomiting without diarrhoea
<br></br>Respiratory alkalosis
<br></br>Hyperammonaemia
<br></br>Encephalopathy
<br></br>Avoidance or change in diet</p>

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129
Q

<p></p>

<p>What tends to cause hyperammonaemia with metabolic acidosis & high anion gap?</p>

A

<p></p>

<p>Organic acidurias
<br></br>Also caused by defects in the complex metabolism of branched chain amino acids</p>

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130
Q

<p></p>

<p>List 3 branched chain amino acids</p>

A

<p></p>

<p>Leucine
<br></br>Isoleucine
<br></br>Valine</p>

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131
Q

<p></p>

<p>Describe the breakdown of leucine</p>

A

<p></p>

<p>Ammonia group will be broken off using a transaminase & high energy protein group will be added
<br></br>This produces a breakdown product, isovaleryl CoA
<br></br>Then converted by isovaleryl CoA dehydrogenase
<br></br>Molecules with high energy groups cannot cross the cell membrane, so need to be converted to other molecules:
<br></br>- Export from cell as: Isovaleryl carnitine
<br></br>- Excrete as: 3OH-isovaleric acid (cheesy smell) & isovaleryl glycine</p>

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132
Q

<p></p>

<p>Describe the presenting features of organic acidurias in neonates</p>

A

<p></p>

<p>Unusual odour
<br></br>Lethargy
<br></br>Feeding problems
<br></br>Truncal hypotonia/limb hypertonia
<br></br>Myoclonic jerks</p>

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133
Q

<p></p>

<p>Describe the chronic intermittent form of organic acidurias</p>

A

<p></p>

<p>Recurrent episodes of ketoacidotic coma
<br></br>Cerebral abnormalities</p>

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134
Q

<p></p>

<p>What is Reye's syndrome?</p>

A

<p></p>

<p>Rapidly progressive encephalopathy that can be triggered by aspirin use in children (also triggered by antiemetics & valproate)</p>

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135
Q

<p></p>

<p>Describe the features of Reye's syndrome</p>

A

<p></p>

<p>Vomiting
<br></br>Lethargy
<br></br>Increased confusion
<br></br>Seizures
<br></br>Decerebration
<br></br>Respiratory arrest</p>

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136
Q

<p></p>

<p>What would constitute the metabolic screen for Reye's syndrome?</p>

A

<p></p>

<p>Plasma ammonia
<br></br>Plasma/urine amino acids
<br></br>Urine organic acids
<br></br>Plasma glucose & lactate
<br></br>Blood spot carnitine profiles (stays abnormal in remission)
<br></br>N.B: Top 4 need to be measured during an acute episode because the abnormal metabolites will disappear after a few days</p>

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137
Q

<p></p>

<p>What do defects in mitochondrial fatty acid beta oxidation cause?</p>

A

<p></p>

<p>Hypoketotic hypoglycaemia
<br></br>N.B: Means unable to make ketones in between meals as an alternative energy source</p>

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138
Q

<p></p>

<p>Which investigations are useful for defects in mitochondrial fatty acid beta oxidation?</p>

A

<p></p>

<p>Blood ketones
<br></br>Urine organic acids
<br></br>Blood spot acylcarnitine profile</p>

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139
Q

<p></p>

<p>What is galactosaemia?</p>

A

<p></p>

<p>Disorder of galactose metabolism resulting in high levels of galactose in the blood</p>

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140
Q

<p></p>

<p>What is the most severe & most common form of galactosaemia?</p>

A

<p></p>

<p>Galacactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency
<br></br>N.B: High galactose-1-phosphate results in liver & kidney disease</p>

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141
Q

<p></p>

<p>Describe the presentation of galactosaemia</p>

A

<p></p>

<p>Vomiting & diarrhoea
<br></br>Conjugated hyperbilirubinaemia
<br></br>Hepatomegaly
<br></br>Hypoglycaemia
<br></br>Sepsis (galactose-1-phosphate inhibits the immune response)</p>

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142
Q

<p></p>

<p>What is a long-term complication of galactosaemia if it not detected in the neonatal period?</p>

A

<p></p>

<p>Bilateral cataracts
<br></br>High concentration of galactose-1-phosphate end up being substrate for aldolase which is found in the lens of the eye</p>

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143
Q

<p></p>

<p>List some investigations for galactosaemia</p>

A

<p></p>

<p>Urine reducing substances (high levels of galactose)
<br></br>Red cell Gal-1-PUT</p>

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144
Q

<p></p>

<p>What is the treatment for galactosaemia?</p>

A

<p></p>

<p>Avoid galactose (e.g. milk)</p>

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145
Q

<p></p>

<p>Describe the pathophysiology of glycogen storage disease type I</p>

A

<p></p>

<p>Whenever glycogen broken down, it produces glucose-1-phosphate & glucose 6-phosphate. Phosphate groups must be removed so can cross cell membrane. Lack of phosphatase means G1P & G6P cannot be exported. Means muscles & liver build up a lot of glycogen that can't be liberated leading to hypoglycaemia
<br></br>N.B: aka von Gierke disease</p>

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146
Q

<p></p>

<p>What are the clinical features of glycogen storade disease type I?</p>

A

<p></p>

<p>Hepatomegaly
<br></br>Nephromegaly
<br></br>Hypoglycaemia
<br></br>Lactic acidosis
<br></br>Neutropaenia</p>

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147
Q

<p></p>

<p>What does 'heteroplasmy' mean with regards to mitochondrial DNA?</p>

A

<p></p>

<p>Once reach certain load of abnormal mitochondrial DNA, will start to develop symptoms</p>

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148
Q

<p></p>

<p>Which organs tend to be affected by mitochondrial disorders?</p>

A

<p></p>

<p>Defective ATP production leads to issue in organs with high energy demand (e.g. brain, muscle, kidney, retina, endocrine organs)</p>

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149
Q

<p></p>

<p>List 3 e.g. of mitochondrial diseases & outline their manifestations</p>

A

<p></p>

<p>Barth syndrome
<br></br>- Cardiomyopathy, neutropaenia, & myopathy starting at birth
<br></br>
<br></br>MELAS
<br></br>- Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes
<br></br>
<br></br>Kearns-Sayre syndrome
<br></br>- Chronic progressive external ophthalmoplegia, retinopathy, deafness, & ataxia</p>

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150
Q

<p></p>

<p>List some investigations for mitochondrial diseases</p>

A

<p></p>

<p>High lactate (alanine) - especially after periods of fasting (N.B: Normally would expect to decrease when fasting)
<br></br>CSF lactate/pyruvate
<br></br>CSF protein (elevated in Kearns-Sayre)
<br></br>CK
<br></br>Muscle biopsy
<br></br>Mitochondrial DNA analysis</p>

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151
Q

<p></p>

<p>What is the characteristic appearance of mitochondrial myopathy on a muscle biopsy?</p>

A

<p></p>

<p>Ragged red fibres</p>

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152
Q

<p></p>

<p>What are congenital disorders of glycosylation? Give an e.g.</p>

A

<p></p>

<p>Defect of post-translational protein glycosylation
<br></br>Multisystem disorder associated with cardiomyopathy, osteopaenia, & hepatomegaly
<br></br>E.g.: CDG type 1a - abnormal subcutaneous adipose distribution with fat pads & nipple retraction</p>

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153
Q

<p></p>

<p>What is the average birthweight of a baby born at term?</p>

A

<p></p>

<p>M: 3.3kg
<br></br>F: 3.2kg</p>

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154
Q

<p></p>

<p>List some common problems in LBW babies</p>

A

<p></p>

<p>Respiratory distress syndrome
<br></br>Retinopathy of prematurity
<br></br>Intraventricular haemorrhage
<br></br>Patent ductus arteriosus
<br></br>Nectrotising enterocolitis</p>

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155
Q

<p></p>

<p>What is necrotising enterocolitis</p>

A

<p></p>

<p>Inflammation of bowel wall progressing to necrosis & perforation
<br></br>Characterised by bloody stools, abdominal distension, & intramural air (pneumatosis intestinalis)</p>

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156
Q

<p></p>

<p>In developing foetus, when do:
<br></br>- Nephrons develop
<br></br>- Start producing urine
<br></br>- Have fully competent nephrons
<br></br>- Achieve functional maturity of glomerular function</p>

A

<p></p>

<p>Nephrons develop
<br></br>- Wk 6
<br></br>
<br></br>Start producing urine
<br></br>- Wk 10
<br></br>
<br></br>Have fully competent nephrons
<br></br>- Wk 36
<br></br>
<br></br>Achieve functional maturity of glomerular function
<br></br>- 2yrs</p>

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157
Q

<p></p>

<p>What are the implications of large SA:V of babies?</p>

A

<p></p>

<p>Low GFR for SA
<br></br>Results in slow excretion of solute load
<br></br>Limited Na+ available for H+ exchange</p>

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158
Q

<p></p>

<p>List some key differences of neonatal kidneys compared to adult kidneys & their complications</p>

A

<p></p>

<p>Short proximal tubule so lower reabsorptive capability
<br></br>Reduce resorption of HCO3 leading to propensity to acidosis
<br></br>Loop of Henle & distal collecting ducts short & juxtaglomerular leading to reduced concentrating ability (max urine osmolality = 700mmol/kg)
<br></br>Distal tubule relatively unresponsive to aldosterone leading to persistent Na loss & reduced K excretion (Na loss = 1.8mmol/kg/day & upper limit of normal K = 6mmol/L in neonates)</p>

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159
Q

<p></p>

<p>Why does glycosuria occur at lower plasma glucose level in neonates?</p>

A

<p></p>

<p>Short proximal tubule means that they have lower ability to reabsorb glucose</p>

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160
Q

<p></p>

<p>Describe how body water content is different in neonates compared to adults</p>

A

<p></p>

<p>Term neonates 75% water compared to 60% in adults (& 85% in preterm infants)</p>

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161
Q

<p></p>

<p>What happens to the body water content in 1st wk of life?</p>

A

<p></p>

<p>Pulmonary resistance drops & get release of ANP leading to fluid redistribution
<br></br>Can lead to up to 10% weight loss within 1st wk of life
<br></br>Roughly 40mL/kg in preterm infants</p>

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162
Q

<p></p>

<p>How are daily fluid & electrolyte requirements different in neonates compared to adults?</p>

A

<p></p>

<p>Na, K, & water requirements higher
<br></br>N.B: Na requirements particularly high in preterm neonates (<30wks), so plasma Na should be measured daily in these patients. K supplements should be given once urine output >1mL/kg/hr has been achieved</p>

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163
Q

<p></p>

<p>Why do babies have higher insensible water loss?</p>

A

<p></p>

<p>High SA
<br></br>Increased skin blood flow
<br></br>High respiratory rate & metabolic rate
<br></br>Increased transdermal fluid loss
<br></br>N.B: Skin not keratinised in premature infants</p>

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164
Q

<p></p>

<p>Drugs can cause electrolyte disturbances in neonates. Give e.g.s of drugs that can do this & briefly describe the mechanism</p>

A

<p></p>

<p>HCO3 for acidosis (contains high Na)
<br></br>Abx (usually Na salts)
<br></br>Caffeine/theophylline (for apneoa) - increases renal Na loss
<br></br>Indomethacin (for PDA) - causes oliguria
<br></br>N.B: Growth can also cause electrolyte disturbance</p>

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165
Q

<p></p>

<p>What is hypernatraemia usually caused by in neonates?</p>

A

<p></p>

<p>Dehydration
<br></br>N.B: Usually uncommon after 2wks
<br></br>N.B: Food poisoning & osmoregulatory dysfunction are differentials</p>

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166
Q

<p></p>

<p>What is hyponatraemia usually caused by in neonates?</p>

A

<p></p>

<p>Congenital adrenal hyperplasia</p>

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167
Q

<p></p>

<p>Outline the pathophysiology of congenital adrenal hyperplasia</p>

A

<p></p>

<p>Most commonly caused by 21-hydroxylase deficiency
<br></br>Leads to reduced cortisol & aldosterone production & shunting of 17-OH progesterone & 17-OH pregnenolone which goes towards androgen synthesis</p>

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168
Q

<p></p>

<p>Outline clinical features of congenital adrenal hyperplasia</p>

A

<p></p>

<p>Hyponatraemia/hyperkalaemia
<br></br>Hypoglycaemia
<br></br>Ambiguous genitalia in F neonates
<br></br>Growth acceleration</p>

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169
Q

<p></p>

<p>List 3 reasons for neonatal hyperbilirubinaemia</p>

A

<p></p>

<p>High level of bilirubin synthesis
<br></br>Low rate of transport into liver
<br></br>Enhanced enterohepatic circulation</p>

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170
Q

<p></p>

<p>How much bilirubin can 1g/L of albumin bind?
<br></br>
<br></br>How much albumin does the average term neonate have? How much bilirubin can this albumin bind?</p>

A

<p></p>

<p>10mcmol/L/g albumin
<br></br>
<br></br>34g/L albumin
<br></br>340mcmol/L of bilirubin</p>

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171
Q

<p></p>

<p>What is the issue with free bilirubin?</p>

A

<p></p>

<p>Can cross the blood-brain barrier leading to kernicterus</p>

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172
Q

<p></p>

<p>What are the 3 bilirubin thresholds in neonates? (i.e. What treatments are given at these thresholds?)</p>

A

<p></p>

<p>No treatment
<br></br>Phototherapy
<br></br>Exchange transfusion</p>

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173
Q

<p></p>

<p>List some causes of neonatal jaundice</p>

A

<p></p>

<p>G6PD deficiency
<br></br>Haemolytic anaemia (ABO, rhesus)
<br></br>Crigler-Najjar syndrome</p>

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174
Q

<p></p>

<p>What is prolonged jaundice?</p>

A

<p></p>

<p>Jaundice that lasts >14 days in term babies, or >21 days in preterm babies</p>

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175
Q

<p></p>

<p>List some causes of prolonged jaundice in neonates</p>

A

<p></p>

<p>Prenatal infection/sepsis
<br></br>Hypothyroidism
<br></br>Breast milk jaundice</p>

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176
Q

<p></p>

<p>What level of conjugated hyperbilirubinaemia considered pathological?</p>

A

<p></p>

<p>>20mcmol/L</p>

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177
Q

<p></p>

<p>List some causes of conjugated hyperbilirubinaemia</p>

A

<p></p>

<p>Biliary atresia (most common)
<br></br>Choledochal cyst
<br></br>Ascending cholangitis in TPN
<br></br>Inherited metabolic diseases (e.g. galactosaemia, alpha-1 antitrypsin deficiency, tyrosinaemia, peroxismal disorders)
<br></br>N.B: 20% of biliary atresia associated with cardiac malformations, polysplenia, situs inversus</p>

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178
Q

<p></p>

<p>At which point during pregnancy is most Ca & PO4 laid down?</p>

A

<p></p>

<p>Third trimester</p>

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179
Q

<p></p>

<p>How are Ca & PO4 levels different in babies?</p>

A

<p></p>

<p>After birth, Ca levels will fall
<br></br>PO4 higher in babies (they are good at reabsorbing it)</p>

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180
Q

<p></p>

<p>List the main biochemical features of osteopaenia of prematurity</p>

A

<p></p>

<p>Ca usually normal
<br></br>PO4 <1mmol/L
<br></br>ALP >1200U/L (10x adult upper limit of normal)</p>

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181
Q

<p></p>

<p>How is osteopaenia of prematurity treated?</p>

A

<p></p>

<p>PO4/Ca supplements
<br></br>1-alpha calcidol</p>

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182
Q

<p></p>

<p>List some presenting features of rickets</p>

A

<p></p>

<p>Frontal bossing
<br></br>Bowed legs
<br></br>Muscular hypotonia
<br></br>Tetany/hypocalcaemic seizure
<br></br>Hypocalcaemic cardiomyopathy</p>

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183
Q

<p></p>

<p>List some genetic causes of rickets</p>

A

<p></p>

<p>Pseudo-vitamin D deficiency I (defective renal hydroxylation)
<br></br>Pseudo-vitamin D deficiency II (receptor defect)
<br></br>Familial hypophosphataemia (low tubular max reabsorption of phosphate, raised urine phosphoethanolamine)
<br></br>N.B: Top 2 conditions treated with 1,25-OH vitamin D</p>

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184
Q

<p></p>

<p>What is porphyria?</p>

A

<p></p>

<p>Disorders caused by deficiencies in enzyme sof haem synthesis pathway
<br></br>Leads to accumulation of toxic haem precursors</p>

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185
Q

<p></p>

<p>What are the 2 ways in which porphyria can manifest?</p>

A

<p></p>

<p>Acute neurovisceral attacks
<br></br>Acute or chornic cutaneous symptoms</p>

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186
Q

<p></p>

<p>List some key features of haem</p>

A

<p></p>

<p>Organic heterocyclic compound with Fe2+ in centre
<br></br>Tetrapyrrole ring around the Fe</p>

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187
Q

<p></p>

<p>Where is haem found?</p>

A

<p></p>

<p>Erythroid cells
<br></br>Liver cytochrome</p>

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188
Q

<p></p>

<p>Draw the haem synthesis pathway</p>

A
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189
Q

<p></p>

<p>Which component of this pathway is neurotoxic?</p>

A

<p></p>

<p>5-ALA</p>

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190
Q

<p></p>

<p>What types of porphyrin may be produced in absence of Fe</p>

A

<p></p>

<p>Metal-free protoporphyrins
<br></br>Zinc protoporphyrin</p>

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191
Q

<p></p>

<p>How can porphyrias be classified?</p>

A

<p></p>

<p>Principle site of enzyme deficiency
<br></br>- Erythroid
<br></br>- Hepatic
<br></br>
<br></br>Clinical presentation
<br></br>- Acute or non-acute
<br></br>- Neurovisceral or skin lesions</p>

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192
Q

<p></p>

<p>Outline the relationships between UV light & skin lesions</p>

A

<p></p>

<p>Porphyrinogens oxidised & activated by UV light into activated porphyrins
<br></br>N.B: Porphyrins don't oxidise in cells</p>

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193
Q

<p></p>

<p>What is key difference between porphyrinogens & porphyrins?</p>

A

<p></p>

<p>Porphyrinogens - colourless, unstable, & readily oxidised to porphyrin
<br></br>Porphyrins - highly coloured</p>

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194
Q

<p></p>

<p>Which porphyrins appear in urine & faeces?</p>

A

<p></p>

<p>Urine - uroporphyrins are water-soluble
<br></br>Faeces - coproporphyrins less soluble & near end of pathway
<br></br>N.B: Someone with porphyria will have colourless/yellow urine which turns red/dark red/purple as porphyrinogens oxidised & activated into porphyrins</p>

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195
Q

<p></p>

<p>List 4 types of acute porphyria & enzymes involved</p>

A

<p></p>

<p>Plumboporphyria - PBG synthase
<br></br>Acute intermittent porphyria - HMB synthase
<br></br>Hereditary coproporphyria - coproporphyrinogen oxidase
<br></br>Variegate porphyria - protoporphyrinogen oxidase</p>

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196
Q

<p></p>

<p>List 3 types of non-acute porphyria & enzymes involved</p>

A

<p></p>

<p>Congenital erythropoietic porphyria - uroporphyrinogen III synthase
<br></br>Porphyria cutanea tarda - uroporphyrinogen decarboxylase
<br></br>Erythropoietic protoporphyria - ferrochetolase</p>

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197
Q

<p></p>

<p>What is most common type of porphyria?</p>

A

<p></p>

<p>Porphyria cutanea tarda</p>

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198
Q

<p></p>

<p>What is most common type of porphyria in children?</p>

A

<p></p>

<p>Erythropoietic protoporphyria</p>

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199
Q

<p></p>

<p>What does ALA synthase deficiency cause?</p>

A

<p></p>

<p>X-linked sideroblastic anaemia</p>

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200
Q

<p></p>

<p>How can mutation in ALA synthase lead to porphyria?</p>

A

<p></p>

<p>Gain-of-function mutation will result in increased throughput through pathway leading to build-up in protoporphyrin IX as overwhelms ability of ferrochetolase to convert into haem</p>

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201
Q

<p></p>

<p>What are main features of PBG synthase deficiency?</p>

A

<p></p>

<p>Causes acute porphyria
<br></br>Leads to accumulation of ALA
<br></br>Abdominal pain (most important feature)
<br></br>Neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)</p>

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202
Q

<p></p>

<p>Which deficiency causes acute intermittent porphyria?</p>

A

<p></p>

<p>HMB synthase (aka PBG deaminase)</p>

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203
Q

<p>Outline clinical features of acute intermittent porphyria</p>

A

<p>Rise in PBG & ALA
<br></br>Autosomal dominant
<br></br>Neurovisceral attacks
<br></br>- Abdominal pain
<br></br>- Tachycardia & hypertension
<br></br>- Constipation, urinary incontinence
<br></br>- Hyponatraemia & seizures
<br></br>- Sensory loss/muscle weakness
<br></br>- Arrhythmias/cardiac arrest
<br></br>
<br></br>Important: No skin symptoms (because no porphyrinogens produced)
<br></br>N.B: 90% asymptomatic</p>

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204
Q

<p>List some precipitating factors for acute intermittent porphyria</p>

A

<p>ALA synthase inhibitors (e.g. steroids, ethanol, anticonvulsants (CYP450 inducers))
<br></br>Stress (infection, surgery)
<br></br>Reduced caloric intake
<br></br>Endocrine factors</p>

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205
Q

<p>Describe how acute intermittent porphyria diagnosed</p>

A

<p>Increased urinary PBG (& ALA)
<br></br>PBG gets oxidised to porphobilin
<br></br>Decreased HMB synthase activity in erythrocytes</p>

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206
Q

<p>How is acute intermittent porphyria managed?</p>

A

<p>Avoid attacks (adequate nutrition, avoid precipitant drug, prompt treatment of other illnesses)
<br></br>IV carbohydrate (inhibits ALA synthase)
<br></br>IV haem arginate (switches off haem synthesis through -ve feedback)</p>

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207
Q

Name 2 acute porphyrias that have skin manifestations. State the enzymes affected.

A

Hereditary coproporphyria - coproporphyrinogen oxidase

Variegate porphyria - protoporphyrinogen oxidase

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208
Q

What is the -ve consequence of accumulation of coproporphyrinogen III & protoporphyrinogen IX?

A

Potent inhibitors of HMB synthase

Results in accumulation of PBG & ALA

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209
Q

What are the main clinical features of hereditary coproporphyria?

A 
Autosomal dominant
Acute neurovisceral attacks
Skin lesions (blistering, skin fragility, classically on backs of hands that tend to appear hrs/days after sun exposure)
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210
Q

What are the main clinical features of variegate porphyria?

A

Autosomal dominant

Acute attacks with skin lesions

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211
Q

How is the porphyrin level in urine & faeces different in hereditary coproporphyria & variegate porphyria compared to acute intermittent porphyria?

A

AIP - normal
HCP & VP - high
N.B: DNA analysis offers definitive diagnosis

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212
Q

What is a common feature of non-acute porphyria?

A

Only present with skin lesions with no neurovisceral manifestations

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213
Q

List enzymes associated with non-acute porphyria

A

Uroporphyrinogen III synthase - congenital erythropoietic porphyria
Uroporphyrinogen decarboxylase - porphyria cutanea tarda
Ferrochetolase - erythropoietic protoporphyria

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214
Q

What is the main clinical feature of non-acute porphyria?

A

Skin blisters, fragility, pigmentations, & erosions, tend to appear hrs/days after sun exposure

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215
Q

What are key features of erythropoietic protoporphyria?

A

Non-blistering & presents with photosensitivity, burning, itching, oedema, following sun exposure

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216
Q

What is a key investigation for erythropoietic protoporphyria?

A

RBC protoporphyrin

N.B: Only RBCs affected

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217
Q

What are the key features of porphyria cutanea tarda?

A

Can be inherited or acquired

Leads to formation of vesicles on sun-exposed areas of skin - crusting, superficial scarring, & pigmentation

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218
Q

Outline biochemistry features of porphyria cutanea tarda

A

Urine/plasma uroporphyrins & coporphyrins raised

Ferritin often increased

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219
Q

Which drug can trigger porphyria cutanea tarda?

A

Hexachlorobenzene

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220
Q

What haematalogical condition are erythropoietic protoporphyria & congenital erythropoietic porphyria associated with?

A

Myelodysplastic syndromes

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221
Q

During acute porphyria, what is the most useful sample to send?

A

Urine

222
Q

What controls the uptake of iodine by thyroid follicular cells?

A

TSH

223
Q

Which channel is important for the transport of iodide across the cell membrane?

A

Na/K ATPase

224
Q

Which enzyme converts iodide to iodine?

A

Thyroid peroxidase

225
Q

How is thyroxine produced?

A

Iodination of tyrosine residues in thyroglobulin generates MIT & DIT which leads to formation of T3 & T4

226
Q

What percentage of thyroxine is free active T4?

A

0.03%

227
Q

What does thyroxine bind to in the blood?

A

Thyroxine binding globulin (TBG)
Thyroxine-binding prealbumin (TBPA)
Albumin

228
Q

Outline the hypothalamo-pituitary-thyroid axis

A

Hypothalamus produces TRH which stimulates the release of TSH from anterior pituitary
TSH stimulates T3/T4 production
T4 feeds back to hypothalamus & pituitary

229
Q

List some causes of hypothyroidism

A 
Hashimoto's thyroiditis (AI)
Atrophic thyroid gland
Post-Graves' disease (after treatment)
Post-thyroiditis
Drugs (e.g. amiodarone, lithium)
Iodine deficiency
Pituitary disease
Peripheral thyroid hormone resistance
230
Q

Outline investigation findings that may be seen in hypothyroidism

A

High TSH
Low T4
Thyroid peroxidase Ab
Look out for other AI conditions

231
Q

Why important to do ECG in patients with suspected hypothyroidism?

A

If someone with hypothyroidism has underlying CVD, giving them thyroxine may induce ischaemia
N.B: So would start on a low dose of thyroxine & escalate

232
Q

How is hypothyroidism treated?

A

Thyroxine (50-125-200mcg/day titrated to normal TSH)

233
Q

What are some risks of overtreatment with thyroxine?

A

Osteopaenia

Atrial fibrillation

234
Q

What is subclinical hypothyroidism?

A

Normal T4 with high TSH
Sometimes referred to as compensated hypothyroidism
N.B: If TPO Ab +ve, patient may go on to develop hypothyroidism

235
Q

Why might there be some benefit to treating subclinical hypothyroidism?

A

Hypothyroidism associated with hypercholesterolaemia

236
Q

Outline how thyroid function changes in pregnancy

A

hCG has similar structure to TSH so high hCG levels can cause hyperthyroidism
Free T4 levels rise slightly
TBG level increase dramatically
N.B: hCG level drops later on in pregnancy

237
Q

How is neonatal hypothyroidism diagnosed?

A

Guthrie test

238
Q

Why is the timing of neonatal hypothyroidism test important?

A

Needs to be done at least 48-72hrs after birth to make sure maternal TSH no longer in the baby

239
Q

What is sick euthyroid?

A

Alteration in pituitary thyroid axis in non-thyroidal illness
In other words, when very sick, thyroid will shut down to try & reduce basal metabolic rate

240
Q

What are the TFT findings in sick euthyroid?

A

Low T4 & T3
Normal/high TSH
N.B: These patients don’t have symptoms of hypothyroidism

241
Q

What are the 3 main causes of hyperthyroidism?

A

Graves’ disease
Toxic multinodular goitre
Single toxic adenoma
Others: Subacute thyroiditis, post-partum thyroiditis

242
Q

What is postpartum thyroiditis?

A

During pregnancy, the body may produce Ab that stimulate thyroid gland

243
Q

What is struma ovarii?

A

Rare form of ovarian tumour (usually teratoma) that contains mostly thyroid tissue & produces thyroxine

244
Q

List some investigation findings of hyperthyroidism

A

Low TSH
High T4 & T3
Technetium scan
Thyroid Ab (thyroid microsomal)

245
Q

Outline management of hyperthyroidism

A 
Beta-blocker
ECG
Bone mineral density
Radioiodine
Thionamides
246
Q

What is a major risk of radioiodine treatment for hyperthryoidism?

A

Can precipitate thyroid storm

Can result in hypothyroidism

247
Q

List some features of Graves’ disease

A 
Diffuse goitre
Thyroid-associated ophthalmopathy
Pretibial myxoedema
Thyroid acropachy
N.B: Radioiodine can make Graves' eye disease worse
248
Q

What is the mechanism of action of thionamides?

A

Prevents the conversion of iodide to iodine by thyroid peroxidase

249
Q

What is a rare but important SE of thionamides?

A

Agranulocytosis

N.B: Patients should be advised to stop treatment if they develop a sore throat or fever

250
Q

What kind of dosing regimes can be used for thionamides?

A

Can be titrated to achieve normal T4 levels

Block & replace - high dose given to block thyroid gland & then given thyroxine replacement

251
Q

Which drug can be given to hyperthyroid patients prior to surgery to block uptake of iodide?

A

Potassium perchlorate

252
Q

What is the long-term treatment of thyroiditis?

A

Thyroid hormone replacement

253
Q

What are the 2 most common forms of thyroid cancer?

A

Papillary thyroid cancer

Follicular thyroid cancer

254
Q

How is thyroid cancer treated?

A

Total thyroidectomy
N.B: Radioiodine treatment may also be given
N.B: High dose thyroxine may be given to suppress TSH levels to prevent TSH from stimulating any remaining cells

255
Q

Which cells do medullary thyroid cancer arise from?

A

Calcitonin-producing C cells

N.B: Part of MEN2

256
Q

Name 2 tumour markers used for medullary thyroid cancer?

A

Calcitonin

CEA

257
Q

Why is the Ca level in the blood so tightly controlled?

A

Nerves & muscles rely on Ca to cause depolarisation

258
Q

What are the consequences of high & low plasma Ca for nerve conduction?

A

High Ca - failure of depolarisation

Low Ca - trigger happy neurological system leading to epilepsy

259
Q

What is the normal range for plasma Ca concentration?

A

2.2-2.6mmol/L

260
Q

What are the 3 forms in which Ca present in plasma?

A

Free (ionised) - 50% - biologically active
Protein-bound - 40% - bound to albumin
Complexed - 10% - citrate/phosphate

261
Q

State the equation for corrected Ca

A

Corrected Ca = serum Ca + (0.02 * (40 - serum albumin in g/L))
N.B: If albumin level constant, total serum Ca will be roughly x2 concentration of free Ca

262
Q

What are the main effects of PTH?

A

Liberation of Ca from bone (increased bone breakdown) & kidneys (increased Ca resorption)
Stimulates 1a-hydroxylase activity resulting in increased activated Vit D
Stimulates renal phosphate excretion

263
Q

What is the rate-limiting step in Vit D activation?

A

1a-hydroxylase

264
Q

What are the 2 forms of Vit D?

A 
Vit D2 (ergocalciferol) - from plants
Vit D3 (cholecalciferol) - produced when UV hits skin & converts 7-dehydrocholesterol to cholecalciferol
N.B: Both active
265
Q

Outline how 7-dehydrocholesterol converted to activated Vit D

A

UV converts 7-dehydrocholesterol to cholecalciferol
Then converted by 25-hydroxylase in liver to 25-hydroxycholecalciferol
Then gets converted by 1a-hydroxylase in kidneys to 1,25-dihydrocholecalciferol
N.B: When measure Vit D levels, actually measuring 25-hydroxy Vit D levels. 25-hydroxy Vit D stored & converted to active form when needed under influence of PTH

266
Q

How can sarcoidosis lead to hypercalcaemia?

A

Lung cells of sarcoid tissue express 1a-hydroxylase
N.B: Hypercalcaemia tends to be seasonal (i.e. during summer months when more sunlight means more Vit D which can be activated)

267
Q

What are main roles of Vit D?

A

Increased intestinal Ca absorption
Increased intestinal PO4 absorption
Critical for bone formation

268
Q

What is ALP?

A

Byproduct of osteoblast activity

269
Q

What is bone a reservoir of?

A

Ca
PO4
Mg

270
Q

What conditions does Vit D deficiency cause?

A

Osteomalacia

Rickets

271
Q

List some risk factors for Vit D def

A

Lack of sunlight
Dark skin
Dietary
Malabsorption

272
Q

Outline some clinical features of osteomalacia

A

Bone & muscle pain
Increased fracture risk
Looser’s zones

273
Q

Outline biochemical changes in osteomalacia

A

Low Ca
Low PO4
High ALP

274
Q

List some clinical features of rickets

A

Bowed legs
Costochondral swelling
Widened epiphyses of wrists
Myopathy

275
Q

Outline pathophysiology of osteomalacia

A

Vit D deficiency leads to secondary hyperparathyroidism which stimulates liberation of Ca from bone (leading to demineralisation of bone)

276
Q

How can renal failure cause Vit D deficiency?

A

Lack of 1a-hydroxylase means unable to activate Vit D

277
Q

Which group of drugs associated with Vit D deficiency?

A

Anticonvulsants - promote breakdown of Vit D

278
Q

Which component of common foods chelates Vit D in the gut?

A

Phytic acid - food like chapatis have high level of phytic acid which chelates Vit D in gut & reduces absorption

279
Q

How does acromegaly lead to osteoporosis?

A

Causes testosterone deficiency

280
Q

Describe the changes in serum biochemistry in osteoporosis

A

Normal

281
Q

What is the main investigation used for osteoporosis?

A

DEXA scan

282
Q

Define:

  • T-score

- Z-score

A

T-score
- Number of standard deviations from the mean of a young healthy population

Z-score
- Number of standard deviations from age-matched control

283
Q

List some causes of osteoporosis

A 
Age-related decline in bone mass
Early menopause
Sedentary lifestyle
Alcohol
Low BMI
Thyrotoxicosis
Hyperprolactinaemia
Cushing's syndrome
Prolonged recurrent illness
284
Q

List some lifestyle changes that are recommended in the treatment of osteoporosis

A

Weight-bearing exercise
Stop smoking
Reduce alcohol consumption

285
Q

List some drugs that may be used in the treatment of osteoporosis

A 
Vit D
Bisphosphonates
Teriparitide (PTH-derivative)
Strontium (anabolic & antiresorptive)
HRT
SERMs (e.g. raloxifene)
286
Q

List some symptoms of hypercalcaemia

A

Polyuria/polydipsia
Constipation
Confusion, seizures, coma
N.B: These tend to occur when Ca level >3mmol/L

287
Q

What are the main causes of primary hyperparathyroidism?

A

Parathyroid adenoma
Parathyroid hyperplasia (associated with MEN1)
Parathyroid carcinoma

288
Q

Outline the serum biochemistry features of primary hyperparathyroidism

A 
High Ca
Inappropriately raised PTH
Low phosphate ('phosphate thrashing hormone)
289
Q

Outline the pathophysiology of familial benign hypercalcaemia

A

Mutation in Ca-sensing receptor (CaSR) leads to increase in set-point for PTH release (leads to mild hypercalcaemia)

290
Q

Why don’t patients with familial benign hypercalcaemia get kidney stones?

A

PTH causes increased renal Ca absorption, thereby reducing urine Ca

291
Q

What are the 3 types of hypercalcaemia in malignancy?

A 
Humoral hypercalcaemia of malignancy (e.g. small cell lung cancer) caused by PTHrP release
Bone metastases (e.g. breast cancer) caused by local bone osteolysis
Haematological malignancy (e.g. myeloma) caused by cytokines
292
Q

List some other non-PTH driven causes of hypercalcaemia

A 
Sarcoidosis
Thyrotoxicosis (increases bone resorption)
Hydroadrenalism (renal Ca transport)
Thiazide diuretics (renal Ca transport)
Excess Vit D (e.g. sunbeds)
293
Q

Outline management of hypercalcaemia

A

Fluids, fluids, & more fluids
Bisphosphonates (stops cancer from eating bone)
Treat underlying cause

294
Q

What is the definition of hyponatraemia?

A

Na concentration <135mmol/L

295
Q

What is the underlying pathogenes of hyponatraemia?

A

Increased extracellular water

296
Q

Describe action of ADH

A

Acts on V2 receptors in collecting duct
Leads to insertion of AQP2 molecules & increase in reabsorption of water
Acts on V1 receptors on vascular smooth muscle leading to vasoconstriction

297
Q

What are the 2 main stimuli for ADH release?

A

Increased serum osmolality (via hypothalamic osmoreceptors)

Blood vol/BP (via baroreceptors)

298
Q

What is the first step in the management of hyponatraemia?

A

Assess their volume status

299
Q

List some clinical features of hypovolaemia

A 
Tachycardia
Postural hypotension
Dry mucous membranes
Reduced skin turgor
Confusion
Reduced urine output
300
Q

What is the most reliable clinical sign of hypovolaemia?

A

Low urine Na (suggests trying to retain fluid)

N.B: May be high in patients on diuretics

301
Q

List some clinical features of hypervolaemia

A

Raised JVP
Bibasal crackles
Peripheral oedema

302
Q

List some cause of hyponatraemia

  • Hypovolaemic
  • Euvolaemic
  • Hypervolaemic
A

Hypovolaemic (Losses)

  • Diarrhoea
  • Vomiting
  • Diuretics
  • Salt-losing nephropathy

Euvolaemic (endocrine)

  • Adrenal insufficiency
  • Hypothyroidism
  • SIADH

Hypervolaemic (Failures)

  • Cirrhosis
  • Cardiac failure
  • Nephrotic syndrome
303
Q

Explain how patients with hypovolaemic hyponatraemia have too much water

A

Diarrhoea & vomiting leads to loss of water & salt

Leads to increased ADH release which causes reabsorption of more water than salt leading to hyponatraemia

304
Q

How does cirrhosis lead to hyponatraemia?

A

Causes release of various mediators that cause drop in perfusion pressure

305
Q

List some causes of SIADH

A 
CNS pathology
Lung pathology
Drugs (SSRIs, TCAs, opiates, PPIs, carbamazepine)
Tumours
Surgery
306
Q

List main investigative feature of SIADH

A

Low plasma osmolality

High urine osmolality

307
Q

Which tests would you do for euvolaemic hyponatraemia?

A

TFTs
Short synacthen test
Plasma & urine osmolality

308
Q

Outline treatment of:

  • Hypovolaemic hyponatraemia
  • Euvolaemic hyponatraemia
  • Hypervolaemic hyponatraemia
A

Hypovolaemic hyponatraemia

  • Vol replacement with 0.9% saline
  • Replenishes circulating fluid volume & switches off stimulus for ADH release

Euvolaemic hyponatraemia

  • Fluid restriction
  • Treat underlying cause

Hypervolaemic hyponatraemia

  • Fluid restriction
  • Treat underlying cause
309
Q

What are some clinical features of severe hyponatraemia?

A

Reduced GCS

Seizures

310
Q

What is the max rate of correction of hyponatraemia?

A

8-10mmol/L/24hrs

311
Q

What is the main danger of rapidly correcting hyponatraemia?

A

Can cause central pontine myelinolysis (osmotic demyelination)
Can lead to quadriplegia, dysarthria, dysphagia, seizures, coma, & death

312
Q

Name & describe mechanism of action of 2 drugs used to treat SIADH if fluid restriction insufficientt

A

Demeclocycline - reduces responsiveness of collecting duct cells to ADH
- N.B: Monitor U&E because can be nephrotoxic
Tolvaptan - V2 receptor antagonist
Alternative: Fluid restriction + salt tablets + diuretics

313
Q

Define hypernatraemia

A

Serum Na >145mmol/L

314
Q

List some causes of hypernatraemia

A

GI losses
Sweat losses
Renal losses (e.g. osmotic diuresis, DI)

315
Q

List some investigations used in suspected DI

A 
Plasma glucose (rule out diabetes mellitus)
Plasma K (rule out hypokalaemia)
Plasma Ca (rule out hypercalcaemia)
Plasma & urine osmolality
Water deprivation test
316
Q

How is hypernatraemia treated?

A

Fluid replacement - use dextrose because will replace fluid without adding to the salt
N.B: If someone hypovolaemic with hypernatraemia, may initially be given 0.9% saline to treat hypovolaemia before switching to dextrose to treat hypernatraemia

317
Q

How often should serial Na measurements be taken in someone being treated for hypernatraemia?

A

4-6hrs

318
Q

How can diabetes mellitus affect serum Na?

A

Hyperglycaemia will draw water out of cells (i.e. into ECF) thereby leading to hypernatraemia
However, high plasma glucose can also lead to an osmotic diuresis (renal losses) which can lead to hypernatraemia

319
Q

What is the normal range for serum K?

A

3.5-5.0mmol/L

320
Q

What are the 2 main hormones involved in regulation of K?

A

Angiotensin II

Aldosterone

321
Q

Outline how renin-angiotensin-aldosterone system works

A

Reduced perfusion or low Na will stimulate renin production from juxtaglomerular cells
Cleaves angiotensin to angiotensin I
Then converted by ACE in lungs to angiotensin II
Angiotensin II stimulates aldosterone production from adrenals
Aldosterone stimulates Na reabsorption & K excretion in principal cells of cortical collecting tubule
N.B: Water will also be drawn in with Na so aldosterone should not greatly affect Na concentration

322
Q

Outline mechanism of action of aldosterone

A

Aldosterone binds to mineralocorticoid receptor & stimulates transcription of ENaC channels
Aldosterone binding also leads to increased Sgk1 which inhibits Nedd4
Nedd4 usually ubiquitinates Na channels & degrades them
Inhibition of Nedd4 leads to preservation of Na channels thereby increasing Na reabsorption
As reabsorb more Na, lumen becomes more -ve & K will move down electrochemical gradient into lumen via ROMK channels

323
Q

What are the main stimuli for aldosterone release?

A

Angiotensin II

Low K

324
Q

List some causes of hyperkalaemia

A

Reduced GFR (renal failure)
Reduced renin activity (renal tubular acidosis type 4, NSAIDs)
ACE inhibitors/ARBs
Addison’s disease
Aldosterone antagonists
K release from cells (rhabdomyolysis, acidosis)

325
Q

Explain how acidosis leads to hyperkalaemia

A

When plasma H+ concentration high, cells try to take in more H+ from plasma
To maintain electrochemical neutrality, K must leave cell when H+ enters
Leads to hyperkalaemia

326
Q

Outline management of hyperkalaemia

A

10mL 10% Ca gluconate
50mL 50% dextrose + 10U insulin
Nebulised salbutamol
Treat cause

327
Q

List some causes of hypokalaemia

A 
GI loss
Renal loss
- Hyperaldosteronism, Cushing's syndrome
- Increased Na delivery to distal nephron
- Osmotic diuresis

Redistribution into cells

  • Insulin
  • Beta-agonists
  • Alkalosis

Rare causes

  • Renal tubular acidosis (type 1 & 2)
  • Hypomagnesaemia
328
Q

Name 2 conditions that can block the triple transporter

A 
Loop diuretics
Bartter syndrome (mutation in triple transporter)
329
Q

Name 2 conditions that can block the Na/Cl cotransporter

A 
Thiazide diuretics
Gitelman syndrome (mutation in Na/Cl cotransporter)
330
Q

Explain how increased delivery of Na to distal nephron can cause hypokalaemia

A

Increased delivery of Na to distal nephron (e.g. because of blocking/ineffective triple transporter or Na/Cl cotransporter) leads to increased reabsorption of Na in distal nephron
Leads to lumen of distal nephron becoming more -ve
Results in movement of K down electrochemical gradient through ROMK channels into lumen

331
Q

What are clinical features of hypokalaemia?

A

Muscle weakness
Arrhythmia
Polyuria & polydipsia (due to DI)

332
Q

What screening test should be done in a patient with hypokalaemia & hypertension?

A

Aldosterone: renin (primary hyperaldosteronism will show high aldosterone & low renin)

333
Q

Outline management of hypokalaemia when:

  • K = 3-3.5mmol/L
  • K <3mmol/L
A

K = 3-3.5mmol/L

  • Oral KCl (2x SandoK TDS for 48hrs)
  • Recheck serum K concentration

K <3mmol/L

  • IV KCl infusion
  • Max rate: 10mmol/hr
  • N.B: Rates >20mmol/hr irritate superficial veins

Treat the cause

334
Q

Why do acidotic patients become unconscious?

A

Brain enzymes cannot function at acidic pH

335
Q

State equation for osmolality

A

Osmolality = 2(Na + K) + urea + glucose

336
Q

What is the anion gap?

A

Should always be small gap between anions & cations due to contribution of anions that aren’t measured
Normal ~18mmol

337
Q

List some causes of high anion gap

A

Ketosis
Lactic acidosis
Methanol
Ethylene glycol poisoning

338
Q

How does increase in plasma pH affect serum Ca levels?

A

As pH increases, plasma proteins start to stick to Ca more than usual
Total plasma Ca levels will remain normal but will be less free ionised Ca (active form)
Leads to tetany (which can make patients hyperventilate even more)

339
Q

Why do patients with hyperosmolar hyperglycaemic state become unconscious?

A

Causes dehydration of brain

340
Q

What is danger of giving lots of fluids to someone with HHS?

A

Can cause cerebral oedema, so 0.9% saline should be used to achieve slower reduction in plasma Na

341
Q

What is a major consequence of metformin overdose?

A

Lactic acidosis

342
Q

What is biochemical definition of diabetes mellitus?

A

Fasting blood glucose >7.0mmol/L

343
Q

How are results of oral glucose tolerance test (75g glucose) interpreted?

A

Impaired glucose tolerance = 7.8-11.1mmol at 2hrs

Diabetes => 11.1mmol at 2hrs

344
Q

What can cause adrenal glands to appear wasted?

A

Addison’s disease

Long-term steroid use

345
Q

What can cause adrenal glands to become hyperplastic?

A

Cushing’s disease

Ectopic ACTH

346
Q

What is term used to describe co-existence of primary hypothyroidism & Addison’s disease?

A

Schmidt syndrome

347
Q

What is the differential diagnosis for hypertension with an adrenal mass?

A

Phaeochromocytoma
Conn’s syndrome
Cushing’s syndrome

348
Q

What is a useful investigation for diagnosing phaechromocytoma?

A

Urine catecholamines

349
Q

What are the disastrous consequences of phaechromocytoma?

A

Severe hypertension
Arrhythmia
Death

350
Q

Outline treatment of phaechromocytoma

A

Urgent alpha blockade (with phenoxybenzamine or phentolamine or doxazocin)
Some fluids may be given before alpha blockade as can cause dramatic drop in BP
Beta-blocker should be given after the alpha-blocker to prevent reflex tachycardia
Patients should receive high-dose alpha & beta-blockade before surgery as action of surgery can cause release of catecholamines from adrenals

351
Q

Name 3 genetic syndromes associated with phaechromocytomas

A

MEN2
von Hippel Lindau syndrome
Neurofibromatosis type I

352
Q

What are the levels of aldosterone & renin in Conn’s syndrome?

A

High aldosterone

Low renin

353
Q

Tests for Cushing’s syndrome

A
  • 9am cortisol
  • Midnight cortisol
  • Low-dose dexamethosone suppression test
  • Inferior petrosal sinus sampling
  • Pituitary MRI
354
Q

What is pseudo-Cushing’s

A

Obesity can change metabolism of cortisol to produce clinical syndrome that looks like Cushing’s syndrome

355
Q

List 3 endoggenous causes of Cushing’s syndrome

A

Pituitary-dependent Cushing’s disease (85%)
Adrenal adenoma
Ectopic ACTH

356
Q

What is the optimal medical therapy for people with coronary heart disease?

A 
Intensive lifestyle modification
Aspirin
High-dose statin (atorvastatin 40-80mg OD)
Optimal blood glucose control
Thiazides
Assessment for probable T2DM
357
Q

List some options for people with statin intolerance

A

Ezetimibe
Plasma exchange
PCSK9 inhibitors
N.B: Nicain no longer available

358
Q

Describe the function of PCSK9 inhibitors

Give an e.g. of a PCSK9 inhibitor

A

Targets LDL receptors leading to endocytosis & degradation
This reduces the ability of the liver to take up cholesterol from the blood

E.g.: Evolocumab

359
Q

Which patient group may benefit from PCSK9 inhibitors?

A

Patients who are very high risk (e.g. familial hypercholesterolaemia)
N.B: PCSK9 inhibitors reduce the incidence of CVD events but have no effect on mortality

360
Q

What is the legacy effect of glycaemic control?

A

A period of good glycaemic control will have a beneficial effect on mortality even if the patient reverts to poor glycaemic control after a certain period of time

361
Q

What are the effects of sudden aggressive blood glucose control in patients with long-standing poor glycaemic control & CVD complications?

A

Reduce the incidence of complications
Increase mortality (due to precipitating tachycardia)
N.B: Found in the ACCORD trial

362
Q

Describe how SGLT2 inhibitors can reduce blood glucose

Give an e.g. of an SGLT2 inhibitors

A

Increases urinary excretion of glucose causing reduction in blood glucose & BP
N.B: Can also be used in HF due to diuretic effect

E.g.: Empagliflozin

363
Q

What are the effects of SGLT2 inhibitors on incidence of CVD events & mortality?

A

Reduces incidence of CVD events
Reduces mortality
Reduces incidence of renal failure

364
Q

What is the physiological role of GLP1?

What is GLP1 broken down by?

A

Produced by the gut & signals to the pancreas to produce more insulin (incretin effect)
Also has direct effect on satiety & gastric emptying
DPP4

365
Q

Which class of drug inhibits the breakdown of GLP1?

A

Gliptins (by inhibiting DPP4, & thereby preventing GLP1 breakdown)

366
Q

List 3 e.g. of GLP1 analogues?

A

Exanatide (synthetic version of exendin 4 (from Gila monster))
Liraglutide (saxenda)
Semaglutide

367
Q

Summarise the steps in the pharmacological management of T2DM

A
  1. Metformin
  2. If non-insulin monotherapy at max tolerated dose doesn’t achieve or maintain HbA1c target after 3mths add either:
    - 2nd oral agent, or
    - GLP1 agonist, or
    - Basal insulin

In patients with long-standing suboptimally controlled T2DM & established CVD, empagliflozin (SGLT2 inhibitor) or liraglutide (GLP1 analogue) should be considered

368
Q

Outline the 1st step in the management of hypoglycaemic patients in the following states:

  • Alert & orientated
  • Drowsy/confused but swallow intact
  • Unconscious or concerned about swallow
A

Alert & orientated
- Oral carbohydrates (e.g. juice/sweets or long-acting forms e.g. sandwich)

Drowsy/confused but swallow intact
- Buccal glucose (e.g. glucogel)

Unconscious or concerned about swallow

  • IV 20% glucose
  • (10% if paediatric)
369
Q

What should be considered if a hypoglycaemic patient is deteriorating or doesn’t appear to be responding to the 1st step in their management?

A

IM/SC 1mg glucagon

370
Q

What is the benefit of giving glucose sublingually?

A

Bypasses hepatic 1st-pass metabolism

371
Q

How long is it likely to take for IM glucagon to cause an increase in blood glucose?

A

15-20mins

372
Q

Which group of patients may not respond to IM glucagon?

A

Starving
Anorexic
Hepatic failure

These patients will have poor liver glycogen stores that can be accessed by glucagon

373
Q

What are some possible consequences of extravasation of IV dextrose?

A

Irritation

Phlebitis

374
Q

What is the triad of features used to define hypoglycaemia?

A

Low glucose
Symptoms
Relief of symptoms by administration of glucose

375
Q

List some symptoms of hypoglycaemia

A

Adrenergic: Tremors, palpitations, sweating
Neuroglycopaenic: Confusion, coma

376
Q

What is a consequence of recurrent episodes of hypoglycaemia?

A

Lack of hypoglycaemic awarenes (loss of adrenergic symptoms with hypoglycaemia)

377
Q

Describe the order in which physiological compensatory changes in response to hypoglycaemia take place

A

Suppression of insulin
Release of glucagon
Release of adrenaline
Release of cortisol

378
Q

What effect do these physiological changes in response to hypoglycaemia have on blood glucose & FFA (free fatty acids) production?

A

Increases blood glucose
Increases FFAs
Not all FFAs can be used to generate ATP by beta-oxidation so some of them will become ketone bodies

379
Q

What is the gold standard for measuring blood glucose?

A

Lab glucose

N.B: Collected in grey top container that contains fluoride oxalate

380
Q

What is the disadvantage of using BMs to measure blood glucose?

A

Poor precision at low levels

N.B: Does however produce instant results

381
Q

List some causes of hypoglycaemic in people without diabetes

A 
Fasting
Paediatric
Critically unwell
Organ failure
Hyperinsulinism
Post-gastric bypass
Drugs
Extreme weight loss
Factitious (artifact)
382
Q

List some causes of hypoglycaemia in diabetics

A 
Medications (inappropriate insulin)
Inadequate carbohydrate intake (missed meal)
Impaired awareness
Excessive alcohol
Strenuous exercies
Co-existing AI conditions
383
Q

List some diabetic medications that cause hypoglycaemia

A

Oral hypoglycaemics: Sulphonylureas, meglitinides, GLP1 analogues
Insulin

384
Q

How could co-morbidities in a diabetic patient lead to increased risk of hypoglycaemia?

A

Renal/liver failure could lead to impaired drug clearance

Concurrent Addison’s disease could result in hypoglycaemia (polyglandular AI syndrome)

385
Q

List some biochemical tests that may help differentiate between causes of hypoglycaemia

A

Insulin levels (N.B: Exogenous insulin can interfere with assays)
C-peptide (marker of endogenous insulin production)
Drug screen
AutoAb
Cortisol/GH
Free fatty acids/ketone bodies
Lactate

In neonates: Hepatomegaly

N.B: Important to perform these tests at the time of the hypo (but try not to delay treatment)

386
Q

What would you expect the insulin & C-peptide levels to be in a hypoglycaemic patient with anorexia nervosa but not diabetes?

A

Low insulin & low C-peptide
Patient is hypoglycaemic because of poor liver glycogen stores (not an issue with insulin) so their insulin response will be normal

387
Q

What does hypoglycaemia with a high insulin & low C-peptide suggest?

A

Exogenous insulin responsible for hypoglycaemia

388
Q

What does hypoglycaemia with high free fatty acids & low ketones suggest?

A

Fatty acid oxidation defect

389
Q

List some physiologically explicable causes of neonatal hypoglycaemia

What is a pathological cause?

A

Prematurity
IUGR
Inadequate glycogen/fat stores

N.B: Should improve with feeding

Pathological: Inborn errors of metabolism

390
Q

List some causes of neonatal hypoglycaemia with:

  • High FFAs & low ketones
  • Low FFAs & high ketones
A

High FFAs & low ketones

  • Fatty acid oxidation defects
  • MCAD deficiency
  • Carnitine disorders
  • HMG-CoA lyase deficiency
  • GSD type 1

Low FFAs & high ketones

  • Galactosaemia
  • Glycogen storage disease
  • Neonatal haemochromatosis
  • GH deficiency
  • Glucocorticoid deficiency
  • Septicaemia
391
Q

List some causes of inappropriately high insulin levels in neonates

A

Islet cell tumours (e.g. insulinoma)
Drugs (e.g. insulin, sulphonylureas)
Islet cell hyperplasia
- Infant with diabetic mother
- Beckwith-Wiedemann syndrome (overgrowth disorder)
- Nesidioblastosis (excessive function of beta cells with abnormal microscopic appearance)

392
Q

State 2 causes of hyperinsulinaemic hypoglycaemia with high C-peptide

How to distinguish between these 2?

A

Insulinoma
Sulphonylurea abuse

Urine or serum sulphonylureas to differentiate

393
Q

Describe the mechanism by which beta cells release insulin in response to blood glucose

A

Glucose crosses the membrane of beta cells & enters glycolysis via glucokinase
Glycolysis produces ATP
Rise in ATP leads to closure of ATP-sensitive K+ channels
Leads to membrane depolarisation, Ca influx, & insulin exocytosis

394
Q

Describe the mechanism of action of sulphonylureas

A

Bind to ATP-sensitive K+ channel making it close independently of ATP

395
Q

What proportion of insulinomas are malignant?

A

10%

396
Q

State 2 causes of hyperinsulinaemic hypoglycaemia with low C-peptide

A

Factitious result

Oral hypoglycaemic usage (not sulphonylureas)

397
Q

What can cause the following:

  • Low glucose
  • Low insulin
  • Low C-peptide
  • Low FFAs
  • Low ketones
A

Suggests something acting like insulin
= Non-islet cell hypoglycaemia caused by secretion of big IGF-2
Big IGF-2 binds to IGF-1 receptors & insulin receptors
It behaves like insulin, so causes hypoglycaemia & suppresses insulin & FFA/ketone production
It is a paraneoplastic syndrome usually caused by mesenchymal tumours (e.g. mesothelioma, fibroblastoma) & epithelial tumours (carcinoma)

398
Q

Describe 2 AI mechanisms of hypoglycaemia

A

AI conditions - Ab against insulin receptors can cause insulin resistance & hypoglycaemia (rarely)
AI insulin syndrome - Ab directed towards insulin so sudden dissociation of Ab can precipitate hypoglycaemia (could be caused by drugs e.g. hydralazine, procainamide)

399
Q

List some genetic causes of hypoglycaemia

A 
Glucokinase activating mutation
Congenital hyperinsulinism (GLUD-1, HNF4A, HADH, KNJJ11)
400
Q

What is reactive hypglycaemia?

A

Hypoglycaemia following food intake (postprandial)
Can occur after gastric bypass
May be suggestive of early diabetes
May occur in insulin-sensitive individuals after exercise or large meals
May be due to hereditary fructose intolerance

401
Q

What is normal GFR?

A

120mL/min (7.2L/hr)

402
Q

Define clearance

A

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

403
Q

What are the 3 criteria for a marker to be used to measure GFR?

A

Marker not bound to serum proteins
Freely filtered by the glomerulus
Not secreted or absorbed by tubular cells

404
Q

State the equation that links clearance with urine & plasma concentration

A

C = U * V/P

405
Q

What is inulin & what is its main purpose with regards to GFR?

Name the marker commonly used in practice as well as an alternative endogenous marker of GFR?

A

Neutral, freely-filtered fructose polymer that is technically the perfect marker
However, measurement of concentrations difficult & requires steady-state infection
So, only used as research tool

Creatinine commonly used in practice to estimate GFR

Cystatin-C is an alternative
N.B: Constitutively produced by all nucleated cells, generated at constant rate, & freely filtered. Almost completely reabsorbed & catabolised by tubular cells

406
Q

Describe key features of plasma urea

A

Byproduct of protein metabolism
Variable absorption (30-60%) by tubular cells
Dependent on nutritional state, hepatic function, & GI bleeding
Limited clinical value

407
Q

Which features of serum creatinine make it a useful marker of GFR?

A

Freely filtered
Produced at constant rate
N.B: Actively secreted into urine by tubular cells

408
Q

Name & briefly describe 3 equations that are used to estimate creatinine clearance or GFR

A

Cockcroft-Gault
- Estimates creatinine clearance by taking into account weight, age, & sex (many overestimate when GFR <30mL/min)

MDRD
- Estimates GFR from creatinine clearance & takes into account age, sex, serum creatinine, & ethnicity (may underestimate in overweight & young people)

CKD-EPI
- Improvement of MDRD & currently recommended

409
Q

What is protein:creatinine (PCR)?

A

Quantative assessment of proteinurea

Measurement of creatinine corrects for urine concentration

410
Q

How is proteinurea estimated?

A

Spot urine PCR

N.B: This has superseded 24hr urine collection

411
Q

Aside from blood, what else can cause urine dipstick to be +ve for blood?

A

Myoglobinuria (from rhabdomyolysis)

412
Q

What is a specific gravity?

A

Measure of urine concentration

413
Q

How can ethylene glycol poisoning cause AKI?

A

Gets converted to oxalic acid which precipitates with Ca to form Ca oxalate stones

414
Q

Define AKI

A

Rapid reduction in kidney function, leading to inability to maintain electrolyte, acid-base, & fluid homeostasis

415
Q

What are the 3 stages of AKI?

A

Stage 1: Increase in serum creatinine by 1.5-1.9x baseline
Stage 2: Increase in serum creatinine by 2-2.9x baseline
Stage 3: Increase in serum creatinine by >3x baseline

416
Q

What is pre-renal AKI?

A

AKI caused by reduced renal perfusion

417
Q

Describe the normal response to reduced circulating volume

A

Activation of central baroreceptors & RAS
Release of vasopressin
Activation of sympathetic system
Results in vasoconstriction, increased cardiac output, & renal Na retention

418
Q

Name & describe the 2 mechanisms that maintain renal blood flow despite changes in systemic BP

A

Myogenic stretch
- If afferent arteriole gets stretched due to high BP, it will constrict to reduce the transmission of that pressure to the glomerulus

Tubuloglomerular feedback
- High Cl concentration in the early distal tubule (suggestive of high GFR) stimulates constriction of the afferent arteriole which lowers GFR, & hence, Cl concentration

419
Q

List some causes of pre-renal AKI

A

True volume depletion
Hypotension
Oedematous state
Selective renal ischaemia (e.g. renal artery stenosis)
Drugs affecting renal blood flow e.g.:
- ACEi - reduce <b>efferent</b> arteriolar constriction
- NSAIDs - decrease afferent arteriolar constriction
- Calcineurin inhibitors - decrease afferent arteriolar constriction
- Diuretics - affect tubular function & decrease preload

420
Q

What is a consequence of prolonged pre-renal insult?

What might be seen on urine microscopy of a patient with this?

A

Acute tubular necrosis (ATN)

Epithelial cell casts

421
Q

What causes post-renal AKI?

A

Physical obstruction of urine flow

422
Q

Outline the pathophysiology of post-renal AKI

A

GFR dependent on hydraulic pressure gradient
Obstruction results in increased tubular pressure
Results in immediate decline in GFR

423
Q

What are some consequences of prolonged urine obstruction?

A

Glomerular ischaemia
Tubular damage
Long-term interstitial scarring

424
Q

What can cause direct tubular kidney injury?

A 
Ischaemia (most common)
Endogenous toxins (e.g. myoglobin, immunoglobulin)
Exogenous toxins (e.g. aminoglycosides, amphotereicin, aciclovir)
425
Q

Which diseases can cause AKI due to infiltration/abnormal protein deposition?

A

Amyloidosis (associated with nephrotic syndrome)
Lymphoma
Myeloma

426
Q

What are the biochemical definitions of AKI?

A

Increase in serum creatinine >26.5mcmol/L within 48hrs
Increase in serum creatinine >1.5x baseline within the previous 7 days
Urine volume <0.5mL/kg/hr for 6hrs

427
Q

What are the 4 processes of acute wound healing?

A

Haemostasis
Inflammation
Proliferation
Remodelling

428
Q

What are the stages of CKD?

A 
Stage 1: eGFR >90
Stage 2: eGFR 60-89
Stage 3: eGFR 30-59
Stage 4: eGFR 15-29
Stage 5: eGFR <15
429
Q

List some causes of CKD

A 
Diabetes mellitus
Hypertension
Chronic glomerulonephritis
Atherosclerotic renal disease
Infective or obstructive uropathy
Polycystic kidney disease
430
Q

Outline the consequences of CKD

A

Progressive failure of homeostatic function (acidosis, hyperkalaemia)
Progressive failure of hormonal function (anaemia, renal bone disease)
CVD (vascular calcification, uraemic cardiomyopathy) <b> most important & most likely to cause death </b>
Uraemia & death

431
Q

What are the consequences of renal acidosis?

How is it treated?

A

Muscle & protein degradation
Osteopaenia due to mobilisation of bone Ca
Cardiac dysfunction

Oral NaHCO3

432
Q

What are the consequences of hyperkalaemia?

What medications can treat it?

A 
Cardiac dysfunction (arrhythmia)
Muscle dysfunction
N.B: Hyperkalaemia causes membrane depolarisation

ACEi
Spironolactone
K-sparing diuretics

433
Q

What type of anaemia does CKD cause?

How is it treated?

A

Normochromic, normocytic anaemia

Erythropoietin alfa (Eprex)
Erythropoietin beta (NeoRecormon)
Darbepoetin (Aranesp)
N.B: If CKD not responding to erythropoiesis stimulating agents, consider Fe deficiency, malignancy, B12 deficiency, etc
434
Q

List some types of renal bone disease

A

Osteitis fibrosa cystica
Osteomalacia
Adynamic bone disease
Mixed osteodystrophy

435
Q

Outline the pathophysiology of renal bone disease

A

Damaged kidneys unable to excrete PO4 & activate Vit D
PO4 retention stimulates FGF23 & Klotho production
This lowers levels of activated Vit D
To try & get rid of excess PO4, body will produce more PTH
Even more PTH produced to try & increase Vit D
High levels of PO4 in blood complex with Ca leading to reduction in free Ca
High levels of PTH will result in bone becoming resistant to PTH

436
Q

What is osteitis fibrosa cystica?

A

Caused by osteoclastic resorption of calcified bone & replacement by fibrous tissue (feature of hyperparathyroidism)

437
Q

What is adynamic bone disease?

A

Overtreatment leading to excessive suppression of PTH result in low bone turnover & reduced osteoid

438
Q

Outline treatment of renal bone disease

A

PO4 control - dietary, PO4 binders

Vit D activators - 1-a calcidol, paricalcitol

439
Q

What are the 3 phases of uraemic cardiomyopathy?

A

LV hypertrophy
LV distension
LV dysfunction

440
Q

What are the treatment options for patients with CKD?

A

Transplantation
Haemodialysis
Peritoneal dialysis

441
Q

Describe the cardiac consequences of plasma K being too high or low

A

Too high
- Asystole (unstable rhythm)

Too low
- Ventricular fibrillation

442
Q

What is the difference between a Colles’ fracture & a Smith’s fracture?

A

Colles’

  • Fracture caused by falling on outstretched hand (FOOSH)
  • Radial head will be displaced backwards, away from palm

Smith’s fracture

  • Caused by falling on flexed wrist
  • Radial head will be displaced forwards, towards palm
443
Q

What is a Pott’s fracture?

A

Ankle fracture involving the tibia & fibula

444
Q

What would you expect to see on the urine dipstick of someone with subacute bacterial endocarditis?

A

Microscopic haematuria

445
Q

What is the differential diagnosis for hypercalcaemia?

A

Cancer
Primary hyperparathyroidism
Sarcoidosis

446
Q

What is the physiological role of PTHrP?

A

Important in foetal life because allows us to steal Ca from our mother to help form our skeleton

N.B: Also produced by lactating breast
N.B: PTHrP stimulates cancer cell to invade bone

447
Q

What are 2 main mechanisms of hypercalcaemia of malignancy?

A

PTHrP

Cancer invading bone

448
Q

What are the main actions of PTH?

A

Increase Ca liberation from bone
Increase Ca reabsorption in kidneys
Increase Ca absorption in intestines (indirectly)
Activates 1a-hydroxylase in kidneys (thereby increasing activation of VitD)
Increase PO4 excretion

449
Q

Name & describe an eye sign of hypercalcaemia

A

Band keratopathy - Ca deposition across front of eye

N.B: Feature of chronic hypercalcaemia (i.e. will not be caused by hypercalcaemia of malignancy)

450
Q

List some complications of hypercalcaemia

A

Renal stones (radio-opaque)
Pancreatitis
Peptic ulcer disease
Skeletal changes (osteitis fibrosa cystica)

451
Q

List some RFs for hypercalcaemia

A

Family history
Dehydration
Hyperparathyroidism

452
Q

Which bacterium has predilection to infect urinary tract stones?

A

Proteus mirabilis

453
Q

What are the main investigations & management options for urinary tract stones?

A

CT-KUB
Stone analysis
Urine & serum biochemistry

Lithotripsy
Cystoscopy
Lithotomy

454
Q

How can urinary stones be prevented?

A

Drink more water
Treat hypercalciurea (thiazides)
Treat hypercalcaemia
N.B: Loop diuretics increase urine Ca

455
Q

At what point would you use emergency management of hypercalcaemia?

Outline the emergency management of hypercalcaemia

A

Serum Ca >3 mmol/L or very unwell (e.g. dehydrated, confused, drowsy, seizures)

IV access
Insert catheter
3-6L 0.9% saline over 24hrs
1st L should be given quickly (over 1hr) to correct dehydration
Elderly patients should be given furosemide (to prevent pulmonary oedema)

456
Q

Which other drug would you consider using to manage hypercalcaemia particularly in hypercalcaemia of malignancy?

A

IV pamidronate

Good at treating bone pain but takes at least 1wk to start working & gets incorporated into bone for a very long time

457
Q

In which group of patients would you use dextrose to treat hypercalcaemia rather than saline?

A

Liver failure - tend to have tendency to retain salt

458
Q

Outline the treatment of non-emergency hypercalcaemia

A

Keep well hydrated
Avoid thiazides (reduce hypercalciurea but increase plasma Ca concentration)
Surgery

459
Q

What feature may you see on X-ray of the hands in a patient with primary hyperparathyroidism?

A

Cystic changes in radial aspect

460
Q

What is a characteristic histological feature of long-standing undiagnosed hyperparathyroidism?

A

Brown tumours - multinucleated giant cells (activated osteoclasts) in bone

461
Q

What is the mainstay of treatment of sarcoidosis?

A

Steroids

462
Q

What is the histological hallmark of sarcoidosis?

A

Non-caseating granulomas

463
Q

Outline the mechanism of hypercalcaemia in sarcoidosis

A

Macrophages in the lungs express 1a-hydroxylase
Activates Vit D

N.B: Patients more likely to become hypercalcaemic in summer because of increased sunlight exposure

464
Q

Define diabetes based on:

  • Fasting plasma glucose
  • 2hr oral glucose tolerance test
  • HbA1c
A

Fasting plasma glucose
- >7.7mmol/L

2hr OGTT
- >11.1mmol/L

HbA1c
- >48mmol/mol (6.5%)

465
Q

Outline the relationship between hypokalaemia & alkalosis

A

Low K leads to shift of H+ into cells
Causes alkalosis
Similarly, low H+ results in shift of K into cells

466
Q

Which cause of Cushing’s syndrome is most commonly associated with hypokalaemia?

A

Ectopic ACTH

467
Q

Why might a patient with Cushing’s syndrome be hypotensive?

A

Diuresis can lead to dehydration & hypotension

468
Q

What is the only definitive way of distinguishing acute renal failure from chronic renal failure?

A

Renal biopsy

469
Q

How might ATN due to dehydration be treated?

A

3wks of dialysis

470
Q

What does slow-onset upper motor neuron lesions in a cancer patient suggest?

A

Brain metastases

471
Q

Why doesn’t hypopituitarism cause low BP?

A

Adrenals still produce aldosterone

472
Q

Which hypothalamic hormones affect prolactin release?

A

Dopamine -ve
TRH +ve
N.B: Hypothyroidism causes hyperprolactinaemia

473
Q

How might pituitary failure present in F?

A

Amenorrhoea & galactorrhoea

474
Q

What physical manifestation might macroadenoma of pituitary gland (>1cm) cause?

A

Bitemporal hemianopia

N.B: Can be tested using visual field test

475
Q

What is the main problem with prolactinomas?

A

Might reduce/stop the production of other pituitary hormones (e.g. ACTH, TSH, GH)
High prolactin itself not much of an issue

476
Q

What is CPFT?

Which 3 stimuli of pituitary hormone secretion are used?

A

Combined Rapid Anterior Pituitary Evaluation Panel
Test for pituitary function

Hypoglycaemia (<2.2mmol using 0.15U/kg insulin) - increases CRF/ACTH & increases GHRH/GH
TRH - increases TSH & prolactin
LHRH - increases LH & FSH

477
Q

What safety precautions must you take before subjecting a patient to hypoglycaemia?

A

No cardiac risk factors (needs normal ECG)
No history of epilepsy
Ensure good IV access

478
Q

Describe manifestations of increasing hypoglycaemia

A

Initially, activation of sympathetic nervous system will result in sweating, tachycardia, etc
When blood glucose reaches <1.5mmol, neuroglycopaenia may occur (loss of consciousness & confusion)

479
Q

Describe the normal response from pituitary gland during CPFT?

A

Blood sugar will go down but then will rise again without any external help
Due to production of GH & ACTH (& hence cortisol) in response to metabolic stress

480
Q

List order of hormone replacement in someone with panhypopituitarism

A

<b> Hydrocortisone </b> - can use prednisolone as has longer half-life so can have OD dosing
Thyroxine
Oestrogen
GH
N.B: Fludrocortisone not necessary because adrenals can still produce aldosterone

481
Q

How should prolactinoma be treated?

A 
Dopamine agonists (e.g. cabergoline)
Reduces size of tumours & can avoid surgery
482
Q

What is disconnection hyperprolactinaemia?

A

Compression of pituitary stalk by tumour cuts off -ve effect of dopamine on pituitary prolactin secretion
Results in hyperprolactinaemia

483
Q

How should you investigate a child with poor growth who is suspected of having GH deficiency?

A

Take random plasma GH measurement (GH pulsatile but if happen to measure during pulse & have detectable GH -> shows producing GH)
Exercise test
Insulin tolerance test (effective but dangerous so shouldn’t be done straight awa)

484
Q

Name 2 tests that may be used to investigate suspected acromegaly

A

OGTT
IGF-1

N.B: Normal IGF-1 ranges not fully resolved & vary with age

485
Q

In which tissues is ALP present in high concentrations?

A

Liver (sinusoidal & canalicular membranes of bile ducts)
Bone
Intestines
Placenta

486
Q

What is increase in bone ALP caused by?

A

Increased osteoblast activity

487
Q

List some physiological causes of high ALP

A

Pregnancy - 3rd trimester (from placenta)

Childhood - growth spurt

488
Q

List some causes of very high ALP (>5x upper limit of normal)

A

Bone - Paget’s disease (as well as osteocalcin), osteomalacia
Liver - cholestasis, cirrhosis

489
Q

List some causes of moderately raised ALP (<5x upper limit of normal)

A

Bone - tumours, fractures, osteomyelitis

Liver - infiltrative disease, hepatitis

490
Q

Which markers are used in acute pancreatitis?

A

Amylase (also found in salivary glands so also raised in parotitis)
Lipase

491
Q

What are the 3 forms of creatine kinase?

A

CK-MM - skeletal muscle
CK-BB - brain
CK-MB - cardiac muscle

492
Q

Describe the manifestation of statin-related myopathy

A

Can range from myalgia to rhabdomyolysis

N.B: Look for recent initiation of statins

493
Q

List some RFs for statin-related myopathy

A 
Polypharmacy (particularly fibrates & ciclosporin & other drugs metabolised by CYP3A4)
High dose
Genetic predisposition
Previous history of myopathy
Vit D deficiency
494
Q

List some other causes of high CK

A 
Muscle damage
Myopathy (e.g. Duchenne muscular dystrophy)
MI
Severe exercise
Physiological (Afro-Caribbeans)
495
Q

List 4 cardiac enzymes that can be used as markers of cardiac damage

A

Troponin (only 1 widely used now)
CK-MB
AST (found in myocytes, rises about 3 days after MI & remains raised for 14 days)
LDH

496
Q

Describe how troponin levels change with time following an MI

A

Rise at 4-6hrs post-MI
Peaks at 12-24hrs
Remains elevated for 3-10 days

So, should be measured at 6 & 12hrs after onset of chest pain in MI

497
Q

Outline diagnostic criteria for MI

A

Typical rise & gradual fall in troponin or more rapid rise & fall in CK-MB with at least 1 of the following:

  • Ischaemic symptoms
  • Pathological Q waves
  • ECG changes suggestive of ischaemia
  • Coronary artery intervention

Pathological findings of acute MI

498
Q

What are the main biomarkers used in cardiac failure?

A

ANP - from atria
BNP - from ventricles
- Used to assess ventricular function & can be used to exclude HF (high -ve predictive value)

499
Q

Define 1IU of enzyme activity

A

Quantity of enzyme required to catalyse reaction of 1mcmol of substrate/min
N.B: Activity affected by assay conditions e.g. pH & temperature (so may differ between labs)

500
Q

State manifestations of following vit deficiencies:

  • Vit A (Retinol)
  • Vit D (Cholecalciferol)
  • Vit E (Tocopherol)
  • Vit K (Phytomenadione)
  • Vit B1 (Thiamine)
  • Vit B2 (Riboflavin)
  • Vit B6 (Pyridoxine)
  • Vit B12 (Cobalamin)
  • Vit C
  • Folate
  • Vit B3 (Niacin)
A

Vit A
- Colour blindness

Vit D
- Osteomalacia/rickets

Vit E
- Anaemia, neuropathy

Vit K
- Defective clotting

Vit B1

  • Beri Beri
  • Neuropathy
  • Wernicke syndrome

Vit B2
- Glossitis

Vit B6
- Dermatitis, anaemia

Vit B12
- Pernicious anaemia

Vit C
- Scurvy

Folate
- Megaloblastic anaemia, NTD

Vit B3
- Pellagra

501
Q

State the manifestations of an excess of following vitamins:

  • Vit A (Retinol)
  • Vit D (Cholecalciferol)
  • Vit B6 (Pyridoxine)
  • Vit C
A

Vit A
- Exfoliation, hepatitis

Vit D
- Hypercalcaemia

Vit B6
- Neuropathy

Vit C
- Renal stones

502
Q

Which tests are used for following vitamin derangements:

  • Vit K
  • Vit B1
  • Vit B2
  • Vit B6
  • Folate
A

Vit K
- Prothrombin time

Vit B1
- RBC transketolase

Vit B2
- RBC glutathione reductase

Vit B6
- RBC AST activation

Folate
- RBC folate

503
Q

What are the 2 forms of Beri Beri? Describe them

A

Wet
- CVD - patients have oedema & other features of HF

Dry
- Neurological disease - may have Wernicke’s syndrome

504
Q

What are the main features of pellagra?

A

Dementia
Diarrhoea
Dermatitis

505
Q

State the manifestations of following deficiencies in trace elements

  • Fe
  • Iodine
  • Zn
  • Cu
  • Fl
A

Fe
- Anaemia

Iodine
- Goitre, hypothyroidism

Zn
- Dermatitis

Cu
- Anaemia

Fl

  • Dental caries
  • N.B: Excess causes flourosis
506
Q

What is the recommended division between fats, carbohydrates, & proteins in a normal diet?

A

Carbohydrates: 50%
- 80% of which should be complex carbs
Fats: 33%
Protein: 17%

507
Q

Describe the adiponectin levels in obese person

A

Reduced - leads to insulin resistance

N.B: Insulin causes slight increase in satiety & thermogenesis

508
Q

What are the effects of leptin, ghrelin, & PYY?

A

Leptin
- Anti-hunger hormone

Ghrelin
- Hunger hormone

PYY
- Satiety hormone produced by intestines

509
Q

What waist circumference is associated with increased risk in M & F?

A

M >94cm (major risk >102cm)

F >80cm (major risk >88cm)

510
Q

Define & give an e.g. of:

  • Indispensable protein
  • Conditionally indispensable protein
  • Dispensable protein
A

Indispensable protein

  • Cannot be made in body & must be obtained from diet
  • E.g. leucine

Conditionally indispensable protein

  • Can be synthesised at certain stages in your life (e.g. very young, pregnancy)
  • E.g. cysteine

Dispensable protein

  • Can be produced by body
  • 6 in humans: Alanine, aspartic acid, asparagine, glutamic acid, serine, & selenocysteine
511
Q

Describe the relationship between dietary fat & LDL levels

A

High dietary saturated fat leads to high LDLs

512
Q

Describe effect of alcohol & obesity on lipid levels

A

Alcohol increases HDLs

Obesity lowers HDLs

513
Q

What are the 5 features that constitute metabolic syndrome?

A 
Fasting glucose >6mmol/L
HDL <1 (M) or <1.3 (F)
Waist circumference >102 (M) >88 (F)
Hypertension >135/80
Microalbumin/insulin resistance
514
Q

Outline treatment options for obesity

A 
Exclude endocrine causes e.g. hypothyroidism
Screen for complications of obesity
Educate
Diet & exercise
Medical: Orlistat, GLP-1 injections
Surgery
- Gastric banding
- Roux-en-Y gastric bypass
- Biliopancreatic diversion
515
Q

Name & describe 2 types of protein energy malnutrition

A

Marasmus

  • Caused by low dietary intake of carbohydrates, lipids, & proteins
  • Shrivelled
  • Growth retardation
  • Severe muscle wasting
  • No subcutaneous fat

Kwashiorkor

  • Caused by protein deficiency
  • Oedematous
  • Scaling/ulcerated
  • Lethargic
  • Large liver
  • Subcutaneous fat
516
Q

Define intermediary metabolism

A

Enzyme-catalysed processes within cells that extract energy from nutrient molecules & use that energy to construct cellular components
e.g. glycolysis, glycogen storage, amino acid & fatty acid synthesis

517
Q

List some metabolic consequences of liver failure

A 
Reduction in blood sugar due to lack of glycogen
Lactic acidosis (reduced ability to metabolise lactic acid)
Increased ammonia (no longer able to process amino acids)
518
Q

What are the main stages of xenobiotic metabolism in the liver?

A

Chemical modification
Conjugation
Excretion

519
Q

Outline the roles of the liver regarding hormone metabolism

A 
Vit D hydroxylation
Steroid hormones (conjugation & excretion)
Peptide hormones (catabolism)
520
Q

What are the roles of Kupffer cells?

A

Main cells of reticuloendothelial system of liver
Roles include:
- Clearance of infection & lipopolysaccharide (LPS)
- Ag presentation
- Immune modulation (e.g. cytokine production)

521
Q

What are the main markers of liver synthetic function?

A 
Albumin
Prothrombin time (normal = 12-14s)
- Better acutely as shorter 1/2 life
522
Q

Where are ALT & AST found?

A 
Liver (cytoplasm of hepatocytes)
Muscle
Kidney
Bone
Pancreas
523
Q

Describe the rise in ALT & AST seen in alcoholic liver disease and viral hepatitis

A

Alcoholic liver disease:
- AST:ALT > 2

Viral hepatitis
- AST:ALT < 1

524
Q

Describe typical ALT & AST levels in cirrhosis

A

May be raised

May be normal in long-standing chronic liver disease

525
Q

Where is GGT found?

A 
Liver (hepatocytes)
Biliary system (epithelium of small bile ducts)
Kidney
Pancreas
Spleen
Heart
Brain
Seminal vesicles
526
Q

List some causes of raised GGT

A

Alcohol abuse
Bile duct disease (e.g. gallstones)
Hepatic metastases

527
Q

How much albumin is produced by the liver/day?

A

8-14g/day

528
Q

What is the half-life of albumin?

A

20 days

529
Q

List some causes of low albumin

A

Low production e.g. CKD, malnutrition
Increased loss e.g. gut, kidney
Sepsis - 3rd spacing: Endothelium becomes leaky & albumin leaks into tissues

530
Q

What are the main roles of alpha-fetoprotein?

A

In foetus, plays a role in foetal transport & immune regulation

531
Q

Which tissues produce alpha-fetoprotein in the foetus?

A

Yolk sac
GI epithelium
Liver

532
Q

What causes high alpha-fetoprotein?

A

Hepatocellular carcinoma
Pregnancy
Testicular cancer

533
Q

List some causes of increased urobilinogen in the urine

A

Haemolysis
Hepatitis
Sepsis

534
Q

Name a dye test used to assess liver function

A

Indocyanine green/bromsulphalein - measures excretory capacity of liver & hepatic blood flow

535
Q

Name a breath test used to assess liver function

A

Aminopyrine/galactose (C14) - measures residual functioning of liver cell mass

536
Q

What is an important cause of jaundice with LFT changes consistent with biliary obstruction that can easily be resolved?
What is the most common cause of this?

A

Drug-induced cholestasis
N.B: Biliary USS will be normal. Usually resolves over 3wks

Co-amoxiclav most common cause

537
Q

State 3 causes of ALT>1000

A

Toxins (paracetamol)
Viruses
Ischaemia (e.g. post-resuscitation)

538
Q

How often should patients with cirrhosis be followed up to check for hepatocellular carcinoma?

A

Every 6mths

539
Q

How is paracetamol overdose treated?

A

Activated charcoal (if still in stomach)
N-acetyl cysteine
Liver transplant

540
Q

How does rhabdomyolysis lead to AKI?

A

Myoglobin is very nephrotoxic

541
Q

Under what circumstances will urea rise more than creatinine?

A

AKI caused by dehydration

N.B: CKD caused by fall in GFR will lead to more prominent rise in creatinine

542
Q

State the indications for dialysis

A

Hyperkalaemia
Acidosis
Pulmonary oedema
Uraemia (pericarditis, encephalopathy)

543
Q

What is used as a marker of blood glucose control over the last 3wks?

A

Fructosamine

- Can be used during pregnancy

544
Q

What is a characteristic morphological feature of Paget’s disease

A

Bowed tibia

N.B: Warmth over the affected bone is also a feature

545
Q

How is Paget’s disease of the bone treated?

A

Bisphosphonates (only if painful)

546
Q

Which marker is often used in PET scans looking for cancer deposits?

A

FDG (fluorodeoxyglucose)

N.B: Cancer cells more active so uptake more glucose. Used to identify abdominal metastases

547
Q

Which radioactive marker can be used to identify neuroendocrine cells?

A

Gallium 69 stuck to a somatostatin analogue

548
Q

What are MIBG scans used to identify?

A

Phaeochromocytoma - MIBG = precursor for adrenaline

549
Q

Which scan useful for investigating parathyroid glands?

A

Sesta MIBI
N.B: MIBI taken up by parathyroid & myocardium
E.g. in myocardial infarction, will be an area that doesn’t take up MIBI

550
Q

Which score is used to determine fracture risk?

A

FRAX

551
Q

Which diseases tend to cause low bone density & fractures in the spine?

A

Cushing’s syndrome
Hyperthyroidism
Postmenopausal

Laz questions (2 decks)

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