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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

Which drug is contraindicated with allopurinol?

Azathioprine

26

Describe interaction between allopurinol & azathoioprine

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

27

What underlying condition is pseudogout often associated with?

Osteoarthritis
N.B: Self-limiting & usually resolves after 1-3wks

28

What are features of atherosclerotic lesion?

Fibrous cap
Foam cells (macrophages full of cholesteryl ester)
Necrotic core (full of cholesterol crystals)

29

During what time will chylomicrons be most abundunt?

After eating (present in very small amounts in fasted state)

30

Describe uptake of cholesterol by intestinal epithelium

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

31

Where are bile acids absorbed?

Terminal ileum

32

What happens when cholesterol arrives at liver?

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

33

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

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

34

What are effects of CETP on movement of substances between lipoproteins?

Moves cholesterol from HDL -> VLDL
Moves triglycerides from VLDL -> HDL

35

Describe transport & metabolism of triglycerides

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

36

List the 3 causes of familial hypercholesterolaemia (type II)

Caused by autosomal dominant gene mutations in:
- LDL receptor
- ApoB
- PCSK9

37

List some mutations implicated in polygenic hypercholesterolaemia

NPC1L1
HMGCR
CYP7A1

38

What is familial hyperalpha lipoproteinaemia?

Increase in HDL caused by deficiency of CETP
Associated with longevity

39

What is phytosterolaemia?

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

40

Describe function of LDL receptor

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

41

List some clinical features of familial hypercholesterolaemia

Xanthelasma
Corneal arcus
Tendon xanthomata

42

What is PCSK9?

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

43

List key features of the following forms of familial hypertriglyceridaemia:
- Familial Type I
- Familial Type IV
- Familial Type V

Familial type I
- Caused by deficiency of lipoprotein lipase & ApoCII
- N.B: Lipoprotein lipase degrades chylomicrons & ApoCII is an activator of lipoprotein lipase

Familial type IV
- Characterised by increased synthesis of triglycerides

Familial type V
- Characterised by deficiency of ApoA V

N.B: These hypertriglyceridaemias show different different patterns when plasma left overnight to separate

44

What is familial combined hyperlipidaemia?

Some people in family have high cholesterol & others have high triglycerides

45

What is familial dysbetalipoproteinaemia (type III)?

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

46

List some causes of secondary hyperlipidaemia

Pregnancy
Hypothyroidism
Obesity
Nephrotic syndrome

47

List 4 causes of hypolipidaemia & their underlying genetic defect

ab (alpha beta)-lipoproteinaemia
- Autosomal recessive
- Extremely low levels of cholesterol
- Due to deficiency of MTP

Hypo-b-lipoproteinaemia
- Autosomal dominant
- Low LDL
- Caused by mutations in ApoB

Tangier disease
- Low HDL
- Caused by mutation of ABC A1

Hypo-a-lipoproteinaemia
- Sometimes caused by mutation of ApoA1

48

Describe the role of LDL in atherosclerosis

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

49

List some lipid-lowering drugs & their effect on lipid levels

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

50

List some novel form of lipid-lowering drugs

Lomitapide - MTP blocker
REGN727 - anti-PCSK9 monoclonal Ab
Mipomersen - anti-sense ApoB oligonucleotide

51

What is the definition of success in bariatric surgery?

>50% reduction in excess weight

52

List some beneficial effects of bariatric surgery

Reduced diabetes risk
Reduced serum triglycerides
Increased HDLs
Reduced fatty livery
Reduced BP

53

What is the normal range for H+ concentration in ECF?

35-45mmol/L

54

What equation links H+ to pH

pH = log(1/[H+])

55

What are the 3 main physiological buffers?

Bicarbonate
Haemoglobin
Phosphate
N.B: Also protein & bone

56

What is the rate of production of H+ ions per day?

50-100mmol/day

57

Describe how kidneys excrete H+ ions

HCO3 regenerated through production of carbonic acid

58

Describe how H+ ions pass through renal epithelium membrane

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

59

What is the rate of production of CO2 per day?

20,000-25,000mmol/day

60

Describe respiratory control over CO2

Respiration controlled by chemoreceptors in hypothalamic respiratory centre
Increase in CO2 will stimulate increase in ventilation which then brings down CO2 concentration

61

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

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

62

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

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

63

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

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

64

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

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

65

What derangement of acid-base balance would be caused by pyloric stenosis?

Metabolic alkalosis due to loss of H+ from profuse vomiting

66

Which condition classically causes mixed respiratory alkalosis & metabolic acidosis?

Aspirin overdose
Aspirin stimulates ventilation & reduces renal excretion of H+

67

Describe arrangement of hepatocytes within liver

Hepatocytes arranged in trabeculae with sinusoids between them

68

What are the 3 main components of portal triad?

Portal vein
Hepatic artery
Bile duct

69

Describe arrangement of endothelial cells within hepatic sinusoids

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

70

Describe the differences between zone 1 and zone 3

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

71

Which investigations performed if pre-hepatic cause of jaundice suspected?

FBC
Blood film

72

What reaction is used to measure fractions of bilirubin? Describe how this works

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

73

What is the most common cause of paediatric jaundice?

Physiological jaundice
Neonates have immature livers that cannot conjugate bilirubin fast enough resulting in unconjugated hyperbilirubinaemia

74

Describe how phototherapy for jaundice works

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

75

What is the inheritance pattern of Gilbert's syndrome?

Autosomal recessive

76

Which drug can reduce bilirubin levels in Gilbert's syndrome?

Phenobarbital

77

Outline pathophysiology of Gilbert's syndrome?

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

78

What can worsen bilirubin levels in Gilbert's syndrome?

Fasting

79

Describe how urobilinogen formed. What is the significance of absent urobilinogen into urine?

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

80

Outline how hepatitis A serology changes over time

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)
After a few wks, will start to produce IgG Ab (leading to cure & ongoing protection from Hep A)
N.B: Hep A doesn't recur

81

Name the vaccine for hepatitis A

Havrix (contains some Ags)

82

Outline the features of hepatitis B serology in acute infection

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

83

Outline the features of hepatitis B serology in someone who has been vaccinated

Will have HBsAb but no other Abs
This is because vaccine consists of administering HBsAg only

84

Outline the features of hepatitis B serology in chronic carrier

Pt will mount immune response but will never clear the virus
HBeAg will decline but HBsAg will persist

85

Describe histology of hepatitis

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

86

What are the defining & associated histological features of alcoholic hepatitis?

Defining: Liver cell damage, inflammation, fibrosis
Associated: Fatty change, megamitochondria

87

List differential diagnoses for fatty liver disease

NASH (most common cause of liver disease in the Western world)
Alcoholic hepatitis
Malnourishment (Kwashiorkor)

88

Outline treatment of alcoholic hepatitis

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

89

What is the issue with regeneration of hepatocytes following alcohol-related damage?

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

90

Why is Pabrinex yellow?

Presence of riboflavin (B2)

91

What conditions are caused by the following vitamin deficiencies:
- B1
- B3

B1
- Beri Beri

B3
- Pellagra

92

List some features of chronic alcoholic liver disease

Palmar erythema
Spider naevi
Gynaecomastia (due to failure of liver to break down oestradiol)
Dupuytren's contracture

93

List some features of portal hypertension

Visible veins (oesophageal, rectal, umbilical)
Ascites
Splenomegaly

94

What is flapping tremor caused by?

Hepatic encephalopathy

95

What is liver failure defined by?

Failed synthetic function
Failed clotting factor & albumin production
Failed clearance of bilirubin
Failed clearance of ammonia

96

Which type of cirrhosis is alcohol typically associated with?

Micronodular cirrhosis
N.B: This is because the hepatocytes regenerate within fibrous cuff

97

What is intrahepatic shunting?

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

98

Which type of jaundice associated with itching? What causes the itching?

Obstructive jaundice
Itching caused by bile salts & bile acids

99

What is Courvoisier's law?

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

100

Where does pancreatic cancer tend to metastasise to?

Liver

101

What are the main consequences of deficient enzyme activity in the context of inherited metabolic disorders?

Lack of end-product
Build-up of precursors
Abnormal or toxic metabolites

102

What are the criteria for inherited metabolic disorder screening? (Wilson & Junger criteria)

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

103

What is phenylketonuria caused by

Phenylalanine hydroxylase deficiency
Responsible for converting phenylalanine to tyrosine
Deficiency results in accumulation of phenylalanine which is toxic

104

Which abnormal metabolites are produced in PKU?

Phenylpyruvate
Phenylacetic acid (detected in urine)

105

What is the main consequnce of untreated PKU?

Low IQ

106

How is PKU investigated?

Blood phenylalanine level

107

Describe the treatment of PKU

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

108

When is the Guthrie test performed in the UK?

5-8 days after birth

109

What is congenital hypothyroidism usually caused by?

Thyroid dysgenesis or agenesis
N.B: Diagnosis based on high TSH

110

Describe the pathophysiology of MCAD deficiency

Fatty acid oxidation disorder
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
Without MCAD, will not produce acetyl-CoA from fatty acids, which is necessary in the TCA cycle to produce ketones (which spares glucose)
Fat is used when fasting in between meals in order to spare glucose stores
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

111

What is the screening test for MCAD deficiency?

Measuring C6-C10 acylcarnitines by tandem mass spectrometry

112

Outline the treatment of MCAD deficiency

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

113

What is homocysturia caused by?

Failure of remethylation of homocysteine

114

What are the clinical features of homocystinuria?

Lens dislocation
Mental retardation
Thromboembolism

115

Which conditions are screened for by the Guthrie test?

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

116

Outline the pathophysiology of cystic fibrosis

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

117

What is the screening test for cystic fibrosis?

High serum immune reactive trypsinogen (IRT)

118

Describe the process of screening & diagnosis of cystic fibrosis?

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

119

Why is it difficult to get an ammonia sample?

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

120

What is the main role of the urea cycle

Taking ammonia & producing urea

121

How many enzymes are there in the urea cycle?

7

122

Name 3 other diseases that count as urea cycle defects

Lysinuric protein intolerance
Hyperornithaemia-hyperammonaemia-homocitrullinuria
Citrullinuria type II

123

What do all urea cycle disorders result in?

High ammonia - this is toxic

124

What is the mode of inheritance of almost all of these urea cycle defects? What is the exception?

Autosomal recessive
Ornithine transcarbamylase deficiency (X-linked)

125

How does the body get rid of excess ammonia?

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

126

What is the treatment of urea cycle disorders?

Remove ammonia (using sodium benzoate, sodium phenylacetate, or dialysis)
Remove ammonia production (low protein diet)

127

Why might patients with urea cycle disorders have slight build?

Patients may subconsciously avoid protein because they know it makes them feel ill

128

List the key features of urea cycle disorders

Vomiting without diarrhoea
Respiratory alkalosis
Hyperammonaemia
Encephalopathy
Avoidance or change in diet

129

What tends to cause hyperammonaemia with metabolic acidosis & high anion gap?

Organic acidurias
Also caused by defects in the complex metabolism of branched chain amino acids

130

List 3 branched chain amino acids

Leucine
Isoleucine
Valine

131

Describe the breakdown of leucine

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

132

Describe the presenting features of organic acidurias in neonates

Unusual odour
Lethargy
Feeding problems
Truncal hypotonia/limb hypertonia
Myoclonic jerks

133

Describe the chronic intermittent form of organic acidurias

Recurrent episodes of ketoacidotic coma
Cerebral abnormalities

134

What is Reye's syndrome?

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

135

Describe the features of Reye's syndrome

Vomiting
Lethargy
Increased confusion
Seizures
Decerebration
Respiratory arrest

136

What would constitute the metabolic screen for Reye's syndrome?

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

137

What do defects in mitochondrial fatty acid beta oxidation cause?

Hypoketotic hypoglycaemia
N.B: Means unable to make ketones in between meals as an alternative energy source

138

Which investigations are useful for defects in mitochondrial fatty acid beta oxidation?

Blood ketones
Urine organic acids
Blood spot acylcarnitine profile

139

What is galactosaemia?

Disorder of galactose metabolism resulting in high levels of galactose in the blood

140

What is the most severe & most common form of galactosaemia?

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

141

Describe the presentation of galactosaemia

Vomiting & diarrhoea
Conjugated hyperbilirubinaemia
Hepatomegaly
Hypoglycaemia
Sepsis (galactose-1-phosphate inhibits the immune response)

142

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

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

143

List some investigations for galactosaemia

Urine reducing substances (high levels of galactose)
Red cell Gal-1-PUT

144

What is the treatment for galactosaemia?

Avoid galactose (e.g. milk)

145

Describe the pathophysiology of glycogen storage disease type I

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
N.B: aka von Gierke disease

146

What are the clinical features of glycogen storade disease type I?

Hepatomegaly
Nephromegaly
Hypoglycaemia
Lactic acidosis
Neutropaenia

147

What does 'heteroplasmy' mean with regards to mitochondrial DNA?

Once reach certain load of abnormal mitochondrial DNA, will start to develop symptoms

148

Which organs tend to be affected by mitochondrial disorders?

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

149

List 3 e.g. of mitochondrial diseases & outline their manifestations

Barth syndrome
- Cardiomyopathy, neutropaenia, & myopathy starting at birth

MELAS
- Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes

Kearns-Sayre syndrome
- Chronic progressive external ophthalmoplegia, retinopathy, deafness, & ataxia

150

List some investigations for mitochondrial diseases

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

151

What is the characteristic appearance of mitochondrial myopathy on a muscle biopsy?

Ragged red fibres

152

What are congenital disorders of glycosylation? Give an e.g.

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

153

What is the average birthweight of a baby born at term?

M: 3.3kg
F: 3.2kg

154

List some common problems in LBW babies

Respiratory distress syndrome
Retinopathy of prematurity
Intraventricular haemorrhage
Patent ductus arteriosus
Nectrotising enterocolitis

155

What is necrotising enterocolitis

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

156

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

Nephrons develop
- Wk 6

Start producing urine
- Wk 10

Have fully competent nephrons
- Wk 36

Achieve functional maturity of glomerular function
- 2yrs

157

What are the implications of large SA:V of babies?

Low GFR for SA
Results in slow excretion of solute load
Limited Na+ available for H+ exchange

158

List some key differences of neonatal kidneys compared to adult kidneys & their complications

Short proximal tubule so lower reabsorptive capability
Reduce resorption of HCO3 leading to propensity to acidosis
Loop of Henle & distal collecting ducts short & juxtaglomerular leading to reduced concentrating ability (max urine osmolality = 700mmol/kg)
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)

159

Why does glycosuria occur at lower plasma glucose level in neonates?

Short proximal tubule means that they have lower ability to reabsorb glucose

160

Describe how body water content is different in neonates compared to adults

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

161

What happens to the body water content in 1st wk of life?

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

162

How are daily fluid & electrolyte requirements different in neonates compared to adults?

Na, K, & water requirements higher
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

163

Why do babies have higher insensible water loss?

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

164

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

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

165

What is hypernatraemia usually caused by in neonates?

Dehydration
N.B: Usually uncommon after 2wks
N.B: Food poisoning & osmoregulatory dysfunction are differentials

166

What is hyponatraemia usually caused by in neonates?

Congenital adrenal hyperplasia

167

Outline the pathophysiology of congenital adrenal hyperplasia

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

168

Outline clinical features of congenital adrenal hyperplasia

Hyponatraemia/hyperkalaemia
Hypoglycaemia
Ambiguous genitalia in F neonates
Growth acceleration

169

List 3 reasons for neonatal hyperbilirubinaemia

High level of bilirubin synthesis
Low rate of transport into liver
Enhanced enterohepatic circulation

170

How much bilirubin can 1g/L of albumin bind?

How much albumin does the average term neonate have? How much bilirubin can this albumin bind?

10mcmol/L/g albumin

34g/L albumin
340mcmol/L of bilirubin

171

What is the issue with free bilirubin?

Can cross the blood-brain barrier leading to kernicterus

172

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

No treatment
Phototherapy
Exchange transfusion

173

List some causes of neonatal jaundice

G6PD deficiency
Haemolytic anaemia (ABO, rhesus)
Crigler-Najjar syndrome

174

What is prolonged jaundice?

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

175

List some causes of prolonged jaundice in neonates

Prenatal infection/sepsis
Hypothyroidism
Breast milk jaundice

176

What level of conjugated hyperbilirubinaemia considered pathological?

>20mcmol/L

177

List some causes of conjugated hyperbilirubinaemia

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

178

At which point during pregnancy is most Ca & PO4 laid down?

Third trimester

179

How are Ca & PO4 levels different in babies?

After birth, Ca levels will fall
PO4 higher in babies (they are good at reabsorbing it)

180

List the main biochemical features of osteopaenia of prematurity

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

181

How is osteopaenia of prematurity treated?

PO4/Ca supplements
1-alpha calcidol

182

List some presenting features of rickets

Frontal bossing
Bowed legs
Muscular hypotonia
Tetany/hypocalcaemic seizure
Hypocalcaemic cardiomyopathy

183

List some genetic causes of rickets

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

184

What is porphyria?

Disorders caused by deficiencies in enzyme sof haem synthesis pathway
Leads to accumulation of toxic haem precursors

185

What are the 2 ways in which porphyria can manifest?

Acute neurovisceral attacks
Acute or chornic cutaneous symptoms

186

List some key features of haem

Organic heterocyclic compound with Fe2+ in centre
Tetrapyrrole ring around the Fe

187

Where is haem found?

Erythroid cells
Liver cytochrome

188

 

Draw the haem synthesis pathway

189

Which component of this pathway is neurotoxic?

5-ALA

190

What types of porphyrin may be produced in absence of Fe

Metal-free protoporphyrins
Zinc protoporphyrin

191

How can porphyrias be classified?

Principle site of enzyme deficiency
- Erythroid
- Hepatic

Clinical presentation
- Acute or non-acute
- Neurovisceral or skin lesions

192

Outline the relationships between UV light & skin lesions

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

193

What is key difference between porphyrinogens & porphyrins?

Porphyrinogens - colourless, unstable, & readily oxidised to porphyrin
Porphyrins - highly coloured

194

Which porphyrins appear in urine & faeces?

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

195

List 4 types of acute porphyria & enzymes involved

Plumboporphyria - PBG synthase
Acute intermittent porphyria - HMB synthase
Hereditary coproporphyria - coproporphyrinogen oxidase
Variegate porphyria - protoporphyrinogen oxidase

196

List 3 types of non-acute porphyria & enzymes involved

Congenital erythropoietic porphyria - uroporphyrinogen III synthase
Porphyria cutanea tarda - uroporphyrinogen decarboxylase
Erythropoietic protoporphyria - ferrochetolase

197

What is most common type of porphyria?

Porphyria cutanea tarda

198

What is most common type of porphyria in children?

Erythropoietic protoporphyria

199

What does ALA synthase deficiency cause?

X-linked sideroblastic anaemia

200

How can mutation in ALA synthase lead to porphyria?

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

201

What are main features of PBG synthase deficiency?

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

202

Which deficiency causes acute intermittent porphyria?

HMB synthase (aka PBG deaminase)

203

Outline clinical features of acute intermittent porphyria

Rise in PBG & ALA
Autosomal dominant
Neurovisceral attacks
- Abdominal pain
- Tachycardia & hypertension
- Constipation, urinary incontinence
- Hyponatraemia & seizures
- Sensory loss/muscle weakness
- Arrhythmias/cardiac arrest

Important: No skin symptoms (because no porphyrinogens produced)
N.B: 90% asymptomatic

204

List some precipitating factors for acute intermittent porphyria

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

205

Describe how acute intermittent porphyria diagnosed

Increased urinary PBG (& ALA)
PBG gets oxidised to porphobilin
Decreased HMB synthase activity in erythrocytes

206

How is acute intermittent porphyria managed?

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

207
Name 2 acute porphyrias that have skin manifestations. State the enzymes affected.
Hereditary coproporphyria - coproporphyrinogen oxidase | Variegate porphyria - protoporphyrinogen oxidase
208
What is the -ve consequence of accumulation of coproporphyrinogen III & protoporphyrinogen IX?
Potent inhibitors of HMB synthase | Results in accumulation of PBG & ALA
209
What are the main clinical features of hereditary coproporphyria?
``` Autosomal dominant Acute neurovisceral attacks Skin lesions (blistering, skin fragility, classically on backs of hands that tend to appear hrs/days after sun exposure) ```
210
What are the main clinical features of variegate porphyria?
Autosomal dominant | Acute attacks with skin lesions
211
How is the porphyrin level in urine & faeces different in hereditary coproporphyria & variegate porphyria compared to acute intermittent porphyria?
AIP - normal HCP & VP - high N.B: DNA analysis offers definitive diagnosis
212
What is a common feature of non-acute porphyria?
Only present with skin lesions with no neurovisceral manifestations
213
List enzymes associated with non-acute porphyria
Uroporphyrinogen III synthase - congenital erythropoietic porphyria Uroporphyrinogen decarboxylase - porphyria cutanea tarda Ferrochetolase - erythropoietic protoporphyria
214
What is the main clinical feature of non-acute porphyria?
Skin blisters, fragility, pigmentations, & erosions, tend to appear hrs/days after sun exposure
215
What are key features of erythropoietic protoporphyria?
Non-blistering & presents with photosensitivity, burning, itching, oedema, following sun exposure
216
What is a key investigation for erythropoietic protoporphyria?
RBC protoporphyrin | N.B: Only RBCs affected
217
What are the key features of porphyria cutanea tarda?
Can be inherited or acquired | Leads to formation of vesicles on sun-exposed areas of skin - crusting, superficial scarring, & pigmentation
218
Outline biochemistry features of porphyria cutanea tarda
Urine/plasma uroporphyrins & coporphyrins raised | Ferritin often increased
219
Which drug can trigger porphyria cutanea tarda?
Hexachlorobenzene
220
What haematalogical condition are erythropoietic protoporphyria & congenital erythropoietic porphyria associated with?
Myelodysplastic syndromes
221
During acute porphyria, what is the most useful sample to send?
Urine
222
What controls the uptake of iodine by thyroid follicular cells?
TSH
223
Which channel is important for the transport of iodide across the cell membrane?
Na/K ATPase
224
Which enzyme converts iodide to iodine?
Thyroid peroxidase
225
How is thyroxine produced?
Iodination of tyrosine residues in thyroglobulin generates MIT & DIT which leads to formation of T3 & T4
226
What percentage of thyroxine is free active T4?
0.03%
227
What does thyroxine bind to in the blood?
Thyroxine binding globulin (TBG) Thyroxine-binding prealbumin (TBPA) Albumin
228
Outline the hypothalamo-pituitary-thyroid axis
Hypothalamus produces TRH which stimulates the release of TSH from anterior pituitary TSH stimulates T3/T4 production T4 feeds back to hypothalamus & pituitary
229
List some causes of hypothyroidism
``` 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
Outline investigation findings that may be seen in hypothyroidism
High TSH Low T4 Thyroid peroxidase Ab Look out for other AI conditions
231
Why important to do ECG in patients with suspected hypothyroidism?
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
How is hypothyroidism treated?
Thyroxine (50-125-200mcg/day titrated to normal TSH)
233
What are some risks of overtreatment with thyroxine?
Osteopaenia | Atrial fibrillation
234
What is subclinical hypothyroidism?
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
Why might there be some benefit to treating subclinical hypothyroidism?
Hypothyroidism associated with hypercholesterolaemia
236
Outline how thyroid function changes in pregnancy
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
How is neonatal hypothyroidism diagnosed?
Guthrie test
238
Why is the timing of neonatal hypothyroidism test important?
Needs to be done at least 48-72hrs after birth to make sure maternal TSH no longer in the baby
239
What is sick euthyroid?
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
What are the TFT findings in sick euthyroid?
Low T4 & T3 Normal/high TSH N.B: These patients don't have symptoms of hypothyroidism
241
What are the 3 main causes of hyperthyroidism?
Graves' disease Toxic multinodular goitre Single toxic adenoma Others: Subacute thyroiditis, post-partum thyroiditis
242
What is postpartum thyroiditis?
During pregnancy, the body may produce Ab that stimulate thyroid gland
243
What is struma ovarii?
Rare form of ovarian tumour (usually teratoma) that contains mostly thyroid tissue & produces thyroxine
244
List some investigation findings of hyperthyroidism
Low TSH High T4 & T3 Technetium scan Thyroid Ab (thyroid microsomal)
245
Outline management of hyperthyroidism
``` Beta-blocker ECG Bone mineral density Radioiodine Thionamides ```
246
What is a major risk of radioiodine treatment for hyperthryoidism?
Can precipitate thyroid storm | Can result in hypothyroidism
247
List some features of Graves' disease
``` Diffuse goitre Thyroid-associated ophthalmopathy Pretibial myxoedema Thyroid acropachy N.B: Radioiodine can make Graves' eye disease worse ```
248
What is the mechanism of action of thionamides?
Prevents the conversion of iodide to iodine by thyroid peroxidase
249
What is a rare but important SE of thionamides?
Agranulocytosis | N.B: Patients should be advised to stop treatment if they develop a sore throat or fever
250
What kind of dosing regimes can be used for thionamides?
Can be titrated to achieve normal T4 levels | Block & replace - high dose given to block thyroid gland & then given thyroxine replacement
251
Which drug can be given to hyperthyroid patients prior to surgery to block uptake of iodide?
Potassium perchlorate
252
What is the long-term treatment of thyroiditis?
Thyroid hormone replacement
253
What are the 2 most common forms of thyroid cancer?
Papillary thyroid cancer | Follicular thyroid cancer
254
How is thyroid cancer treated?
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
Which cells do medullary thyroid cancer arise from?
Calcitonin-producing C cells | N.B: Part of MEN2
256
Name 2 tumour markers used for medullary thyroid cancer?
Calcitonin | CEA
257
Why is the Ca level in the blood so tightly controlled?
Nerves & muscles rely on Ca to cause depolarisation
258
What are the consequences of high & low plasma Ca for nerve conduction?
High Ca - failure of depolarisation | Low Ca - trigger happy neurological system leading to epilepsy
259
What is the normal range for plasma Ca concentration?
2.2-2.6mmol/L
260
What are the 3 forms in which Ca present in plasma?
Free (ionised) - 50% - biologically active Protein-bound - 40% - bound to albumin Complexed - 10% - citrate/phosphate
261
State the equation for corrected Ca
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
What are the main effects of PTH?
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
What is the rate-limiting step in Vit D activation?
1a-hydroxylase
264
What are the 2 forms of Vit D?
``` Vit D2 (ergocalciferol) - from plants Vit D3 (cholecalciferol) - produced when UV hits skin & converts 7-dehydrocholesterol to cholecalciferol N.B: Both active ```
265
Outline how 7-dehydrocholesterol converted to activated Vit D
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
How can sarcoidosis lead to hypercalcaemia?
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
What are main roles of Vit D?
Increased intestinal Ca absorption Increased intestinal PO4 absorption Critical for bone formation
268
What is ALP?
Byproduct of osteoblast activity
269
What is bone a reservoir of?
Ca PO4 Mg
270
What conditions does Vit D deficiency cause?
Osteomalacia | Rickets
271
List some risk factors for Vit D def
Lack of sunlight Dark skin Dietary Malabsorption
272
Outline some clinical features of osteomalacia
Bone & muscle pain Increased fracture risk Looser's zones
273
Outline biochemical changes in osteomalacia
Low Ca Low PO4 High ALP
274
List some clinical features of rickets
Bowed legs Costochondral swelling Widened epiphyses of wrists Myopathy
275
Outline pathophysiology of osteomalacia
Vit D deficiency leads to secondary hyperparathyroidism which stimulates liberation of Ca from bone (leading to demineralisation of bone)
276
How can renal failure cause Vit D deficiency?
Lack of 1a-hydroxylase means unable to activate Vit D
277
Which group of drugs associated with Vit D deficiency?
Anticonvulsants - promote breakdown of Vit D
278
Which component of common foods chelates Vit D in the gut?
Phytic acid - food like chapatis have high level of phytic acid which chelates Vit D in gut & reduces absorption
279
How does acromegaly lead to osteoporosis?
Causes testosterone deficiency
280
Describe the changes in serum biochemistry in osteoporosis
Normal
281
What is the main investigation used for osteoporosis?
DEXA scan
282
# Define: - T-score | - Z-score
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
List some causes of osteoporosis
``` Age-related decline in bone mass Early menopause Sedentary lifestyle Alcohol Low BMI Thyrotoxicosis Hyperprolactinaemia Cushing's syndrome Prolonged recurrent illness ```
284
List some lifestyle changes that are recommended in the treatment of osteoporosis
Weight-bearing exercise Stop smoking Reduce alcohol consumption
285
List some drugs that may be used in the treatment of osteoporosis
``` Vit D Bisphosphonates Teriparitide (PTH-derivative) Strontium (anabolic & antiresorptive) HRT SERMs (e.g. raloxifene) ```
286
List some symptoms of hypercalcaemia
Polyuria/polydipsia Constipation Confusion, seizures, coma N.B: These tend to occur when Ca level >3mmol/L
287
What are the main causes of primary hyperparathyroidism?
Parathyroid adenoma Parathyroid hyperplasia (associated with MEN1) Parathyroid carcinoma
288
Outline the serum biochemistry features of primary hyperparathyroidism
``` High Ca Inappropriately raised PTH Low phosphate ('phosphate thrashing hormone) ```
289
Outline the pathophysiology of familial benign hypercalcaemia
Mutation in Ca-sensing receptor (CaSR) leads to increase in set-point for PTH release (leads to mild hypercalcaemia)
290
Why don't patients with familial benign hypercalcaemia get kidney stones?
PTH causes increased renal Ca absorption, thereby reducing urine Ca
291
What are the 3 types of hypercalcaemia in malignancy?
``` 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
List some other non-PTH driven causes of hypercalcaemia
``` Sarcoidosis Thyrotoxicosis (increases bone resorption) Hydroadrenalism (renal Ca transport) Thiazide diuretics (renal Ca transport) Excess Vit D (e.g. sunbeds) ```
293
Outline management of hypercalcaemia
Fluids, fluids, & more fluids Bisphosphonates (stops cancer from eating bone) Treat underlying cause
294
What is the definition of hyponatraemia?
Na concentration <135mmol/L
295
What is the underlying pathogenes of hyponatraemia?
Increased extracellular water
296
Describe action of ADH
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
What are the 2 main stimuli for ADH release?
Increased serum osmolality (via hypothalamic osmoreceptors) | Blood vol/BP (via baroreceptors)
298
What is the first step in the management of hyponatraemia?
Assess their volume status
299
List some clinical features of hypovolaemia
``` Tachycardia Postural hypotension Dry mucous membranes Reduced skin turgor Confusion Reduced urine output ```
300
What is the most reliable clinical sign of hypovolaemia?
Low urine Na (suggests trying to retain fluid) | N.B: May be high in patients on diuretics
301
List some clinical features of hypervolaemia
Raised JVP Bibasal crackles Peripheral oedema
302
List some cause of hyponatraemia - Hypovolaemic - Euvolaemic - Hypervolaemic
Hypovolaemic (Losses) - Diarrhoea - Vomiting - Diuretics - Salt-losing nephropathy Euvolaemic (endocrine) - Adrenal insufficiency - Hypothyroidism - SIADH Hypervolaemic (Failures) - Cirrhosis - Cardiac failure - Nephrotic syndrome
303
Explain how patients with hypovolaemic hyponatraemia have too much water
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
How does cirrhosis lead to hyponatraemia?
Causes release of various mediators that cause drop in perfusion pressure
305
List some causes of SIADH
``` CNS pathology Lung pathology Drugs (SSRIs, TCAs, opiates, PPIs, carbamazepine) Tumours Surgery ```
306
List main investigative feature of SIADH
Low plasma osmolality | High urine osmolality
307
Which tests would you do for euvolaemic hyponatraemia?
TFTs Short synacthen test Plasma & urine osmolality
308
Outline treatment of: - Hypovolaemic hyponatraemia - Euvolaemic hyponatraemia - Hypervolaemic hyponatraemia
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
What are some clinical features of severe hyponatraemia?
Reduced GCS | Seizures
310
What is the max rate of correction of hyponatraemia?
8-10mmol/L/24hrs
311
What is the main danger of rapidly correcting hyponatraemia?
Can cause central pontine myelinolysis (osmotic demyelination) Can lead to quadriplegia, dysarthria, dysphagia, seizures, coma, & death
312
Name & describe mechanism of action of 2 drugs used to treat SIADH if fluid restriction insufficientt
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
Define hypernatraemia
Serum Na >145mmol/L
314
List some causes of hypernatraemia
GI losses Sweat losses Renal losses (e.g. osmotic diuresis, DI)
315
List some investigations used in suspected DI
``` Plasma glucose (rule out diabetes mellitus) Plasma K (rule out hypokalaemia) Plasma Ca (rule out hypercalcaemia) Plasma & urine osmolality Water deprivation test ```
316
How is hypernatraemia treated?
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
How often should serial Na measurements be taken in someone being treated for hypernatraemia?
4-6hrs
318
How can diabetes mellitus affect serum Na?
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
What is the normal range for serum K?
3.5-5.0mmol/L
320
What are the 2 main hormones involved in regulation of K?
Angiotensin II | Aldosterone
321
Outline how renin-angiotensin-aldosterone system works
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
Outline mechanism of action of aldosterone
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
What are the main stimuli for aldosterone release?
Angiotensin II | Low K
324
List some causes of hyperkalaemia
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
Explain how acidosis leads to hyperkalaemia
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
Outline management of hyperkalaemia
10mL 10% Ca gluconate 50mL 50% dextrose + 10U insulin Nebulised salbutamol Treat cause
327
List some causes of hypokalaemia
``` 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
Name 2 conditions that can block the triple transporter
``` Loop diuretics Bartter syndrome (mutation in triple transporter) ```
329
Name 2 conditions that can block the Na/Cl cotransporter
``` Thiazide diuretics Gitelman syndrome (mutation in Na/Cl cotransporter) ```
330
Explain how increased delivery of Na to distal nephron can cause hypokalaemia
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
What are clinical features of hypokalaemia?
Muscle weakness Arrhythmia Polyuria & polydipsia (due to DI)
332
What screening test should be done in a patient with hypokalaemia & hypertension?
Aldosterone: renin (primary hyperaldosteronism will show high aldosterone & low renin)
333
Outline management of hypokalaemia when: - K = 3-3.5mmol/L - K <3mmol/L
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
Why do acidotic patients become unconscious?
Brain enzymes cannot function at acidic pH
335
State equation for osmolality
Osmolality = 2(Na + K) + urea + glucose
336
What is the anion gap?
Should always be small gap between anions & cations due to contribution of anions that aren't measured Normal ~18mmol
337
List some causes of high anion gap
Ketosis Lactic acidosis Methanol Ethylene glycol poisoning
338
How does increase in plasma pH affect serum Ca levels?
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
Why do patients with hyperosmolar hyperglycaemic state become unconscious?
Causes dehydration of brain
340
What is danger of giving lots of fluids to someone with HHS?
Can cause cerebral oedema, so 0.9% saline should be used to achieve slower reduction in plasma Na
341
What is a major consequence of metformin overdose?
Lactic acidosis
342
What is biochemical definition of diabetes mellitus?
Fasting blood glucose >7.0mmol/L
343
How are results of oral glucose tolerance test (75g glucose) interpreted?
Impaired glucose tolerance = 7.8-11.1mmol at 2hrs | Diabetes => 11.1mmol at 2hrs
344
What can cause adrenal glands to appear wasted?
Addison's disease | Long-term steroid use
345
What can cause adrenal glands to become hyperplastic?
Cushing's disease | Ectopic ACTH
346
What is term used to describe co-existence of primary hypothyroidism & Addison's disease?
Schmidt syndrome
347
What is the differential diagnosis for hypertension with an adrenal mass?
Phaeochromocytoma Conn's syndrome Cushing's syndrome
348
What is a useful investigation for diagnosing phaechromocytoma?
Urine catecholamines
349
What are the disastrous consequences of phaechromocytoma?
Severe hypertension Arrhythmia Death
350
Outline treatment of phaechromocytoma
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
Name 3 genetic syndromes associated with phaechromocytomas
MEN2 von Hippel Lindau syndrome Neurofibromatosis type I
352
What are the levels of aldosterone & renin in Conn's syndrome?
High aldosterone | Low renin
353
Tests for Cushing's syndrome
- 9am cortisol - Midnight cortisol - Low-dose dexamethosone suppression test - Inferior petrosal sinus sampling - Pituitary MRI
354
What is pseudo-Cushing's
Obesity can change metabolism of cortisol to produce clinical syndrome that looks like Cushing's syndrome
355
List 3 endoggenous causes of Cushing's syndrome
Pituitary-dependent Cushing's disease (85%) Adrenal adenoma Ectopic ACTH
356
What is the optimal medical therapy for people with coronary heart disease?
``` Intensive lifestyle modification Aspirin High-dose statin (atorvastatin 40-80mg OD) Optimal blood glucose control Thiazides Assessment for probable T2DM ```
357
List some options for people with statin intolerance
Ezetimibe Plasma exchange PCSK9 inhibitors N.B: Nicain no longer available
358
Describe the function of PCSK9 inhibitors | Give an e.g. of a PCSK9 inhibitor
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
Which patient group may benefit from PCSK9 inhibitors?
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
What is the legacy effect of glycaemic control?
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
What are the effects of sudden aggressive blood glucose control in patients with long-standing poor glycaemic control & CVD complications?
Reduce the incidence of complications Increase mortality (due to precipitating tachycardia) N.B: Found in the ACCORD trial
362
Describe how SGLT2 inhibitors can reduce blood glucose | Give an e.g. of an SGLT2 inhibitors
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
What are the effects of SGLT2 inhibitors on incidence of CVD events & mortality?
Reduces incidence of CVD events Reduces mortality Reduces incidence of renal failure
364
What is the physiological role of GLP1? | What is GLP1 broken down by?
Produced by the gut & signals to the pancreas to produce more insulin (incretin effect) Also has direct effect on satiety & gastric emptying DPP4
365
Which class of drug inhibits the breakdown of GLP1?
Gliptins (by inhibiting DPP4, & thereby preventing GLP1 breakdown)
366
List 3 e.g. of GLP1 analogues?
Exanatide (synthetic version of exendin 4 (from Gila monster)) Liraglutide (saxenda) Semaglutide
367
Summarise the steps in the pharmacological management of T2DM
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
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
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
What should be considered if a hypoglycaemic patient is deteriorating or doesn't appear to be responding to the 1st step in their management?
IM/SC 1mg glucagon
370
What is the benefit of giving glucose sublingually?
Bypasses hepatic 1st-pass metabolism
371
How long is it likely to take for IM glucagon to cause an increase in blood glucose?
15-20mins
372
Which group of patients may not respond to IM glucagon?
Starving Anorexic Hepatic failure These patients will have poor liver glycogen stores that can be accessed by glucagon
373
What are some possible consequences of extravasation of IV dextrose?
Irritation | Phlebitis
374
What is the triad of features used to define hypoglycaemia?
Low glucose Symptoms Relief of symptoms by administration of glucose
375
List some symptoms of hypoglycaemia
Adrenergic: Tremors, palpitations, sweating Neuroglycopaenic: Confusion, coma
376
What is a consequence of recurrent episodes of hypoglycaemia?
Lack of hypoglycaemic awarenes (loss of adrenergic symptoms with hypoglycaemia)
377
Describe the order in which physiological compensatory changes in response to hypoglycaemia take place
Suppression of insulin Release of glucagon Release of adrenaline Release of cortisol
378
What effect do these physiological changes in response to hypoglycaemia have on blood glucose & FFA (free fatty acids) production?
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
What is the gold standard for measuring blood glucose?
Lab glucose | N.B: Collected in grey top container that contains fluoride oxalate
380
What is the disadvantage of using BMs to measure blood glucose?
Poor precision at low levels | N.B: Does however produce instant results
381
List some causes of hypoglycaemic in people without diabetes
``` Fasting Paediatric Critically unwell Organ failure Hyperinsulinism Post-gastric bypass Drugs Extreme weight loss Factitious (artifact) ```
382
List some causes of hypoglycaemia in diabetics
``` Medications (inappropriate insulin) Inadequate carbohydrate intake (missed meal) Impaired awareness Excessive alcohol Strenuous exercies Co-existing AI conditions ```
383
List some diabetic medications that cause hypoglycaemia
Oral hypoglycaemics: Sulphonylureas, meglitinides, GLP1 analogues Insulin
384
How could co-morbidities in a diabetic patient lead to increased risk of hypoglycaemia?
Renal/liver failure could lead to impaired drug clearance | Concurrent Addison's disease could result in hypoglycaemia (polyglandular AI syndrome)
385
List some biochemical tests that may help differentiate between causes of hypoglycaemia
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
What would you expect the insulin & C-peptide levels to be in a hypoglycaemic patient with anorexia nervosa but not diabetes?
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
What does hypoglycaemia with a high insulin & low C-peptide suggest?
Exogenous insulin responsible for hypoglycaemia
388
What does hypoglycaemia with high free fatty acids & low ketones suggest?
Fatty acid oxidation defect
389
List some physiologically explicable causes of neonatal hypoglycaemia What is a pathological cause?
Prematurity IUGR Inadequate glycogen/fat stores N.B: Should improve with feeding Pathological: Inborn errors of metabolism
390
List some causes of neonatal hypoglycaemia with: - High FFAs & low ketones - Low FFAs & high ketones
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
List some causes of inappropriately high insulin levels in neonates
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
State 2 causes of hyperinsulinaemic hypoglycaemia with high C-peptide How to distinguish between these 2?
Insulinoma Sulphonylurea abuse Urine or serum sulphonylureas to differentiate
393
Describe the mechanism by which beta cells release insulin in response to blood glucose
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
Describe the mechanism of action of sulphonylureas
Bind to ATP-sensitive K+ channel making it close independently of ATP
395
What proportion of insulinomas are malignant?
10%
396
State 2 causes of hyperinsulinaemic hypoglycaemia with low C-peptide
Factitious result | Oral hypoglycaemic usage (not sulphonylureas)
397
What can cause the following: - Low glucose - Low insulin - Low C-peptide - Low FFAs - Low ketones
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
Describe 2 AI mechanisms of hypoglycaemia
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
List some genetic causes of hypoglycaemia
``` Glucokinase activating mutation Congenital hyperinsulinism (GLUD-1, HNF4A, HADH, KNJJ11) ```
400
What is reactive hypglycaemia?
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
What is normal GFR?
120mL/min (7.2L/hr)
402
Define clearance
Volume of plsama that can be completely cleared of a marker substance per unit time
403
What are the 3 criteria for a marker to be used to measure GFR?
Marker not bound to serum proteins Freely filtered by the glomerulus Not secreted or absorbed by tubular cells
404
State the equation that links clearance with urine & plasma concentration
C = U * V/P
405
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?
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
Describe key features of plasma urea
Byproduct of protein metabolism Variable absorption (30-60%) by tubular cells Dependent on nutritional state, hepatic function, & GI bleeding Limited clinical value
407
Which features of serum creatinine make it a useful marker of GFR?
Freely filtered Produced at constant rate N.B: Actively secreted into urine by tubular cells
408
Name & briefly describe 3 equations that are used to estimate creatinine clearance or GFR
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
What is protein:creatinine (PCR)?
Quantative assessment of proteinurea | Measurement of creatinine corrects for urine concentration
410
How is proteinurea estimated?
Spot urine PCR | N.B: This has superseded 24hr urine collection
411
Aside from blood, what else can cause urine dipstick to be +ve for blood?
Myoglobinuria (from rhabdomyolysis)
412
What is a specific gravity?
Measure of urine concentration
413
How can ethylene glycol poisoning cause AKI?
Gets converted to oxalic acid which precipitates with Ca to form Ca oxalate stones
414
Define AKI
Rapid reduction in kidney function, leading to inability to maintain electrolyte, acid-base, & fluid homeostasis
415
What are the 3 stages of AKI?
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
What is pre-renal AKI?
AKI caused by reduced renal perfusion
417
Describe the normal response to reduced circulating volume
Activation of central baroreceptors & RAS Release of vasopressin Activation of sympathetic system Results in vasoconstriction, increased cardiac output, & renal Na retention
418
Name & describe the 2 mechanisms that maintain renal blood flow despite changes in systemic BP
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
List some causes of pre-renal AKI
True volume depletion Hypotension Oedematous state Selective renal ischaemia (e.g. renal artery stenosis) Drugs affecting renal blood flow e.g.: - ACEi - reduce efferent arteriolar constriction - NSAIDs - decrease afferent arteriolar constriction - Calcineurin inhibitors - decrease afferent arteriolar constriction - Diuretics - affect tubular function & decrease preload
420
What is a consequence of prolonged pre-renal insult? | What might be seen on urine microscopy of a patient with this?
Acute tubular necrosis (ATN) Epithelial cell casts
421
What causes post-renal AKI?
Physical obstruction of urine flow
422
Outline the pathophysiology of post-renal AKI
GFR dependent on hydraulic pressure gradient Obstruction results in increased tubular pressure Results in immediate decline in GFR
423
What are some consequences of prolonged urine obstruction?
Glomerular ischaemia Tubular damage Long-term interstitial scarring
424
What can cause direct tubular kidney injury?
``` Ischaemia (most common) Endogenous toxins (e.g. myoglobin, immunoglobulin) Exogenous toxins (e.g. aminoglycosides, amphotereicin, aciclovir) ```
425
Which diseases can cause AKI due to infiltration/abnormal protein deposition?
Amyloidosis (associated with nephrotic syndrome) Lymphoma Myeloma
426
What are the biochemical definitions of AKI?
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
What are the 4 processes of acute wound healing?
Haemostasis Inflammation Proliferation Remodelling
428
What are the stages of CKD?
``` Stage 1: eGFR >90 Stage 2: eGFR 60-89 Stage 3: eGFR 30-59 Stage 4: eGFR 15-29 Stage 5: eGFR <15 ```
429
List some causes of CKD
``` Diabetes mellitus Hypertension Chronic glomerulonephritis Atherosclerotic renal disease Infective or obstructive uropathy Polycystic kidney disease ```
430
Outline the consequences of CKD
Progressive failure of homeostatic function (acidosis, hyperkalaemia) Progressive failure of hormonal function (anaemia, renal bone disease) CVD (vascular calcification, uraemic cardiomyopathy) most important & most likely to cause death Uraemia & death
431
What are the consequences of renal acidosis? | How is it treated?
Muscle & protein degradation Osteopaenia due to mobilisation of bone Ca Cardiac dysfunction Oral NaHCO3
432
What are the consequences of hyperkalaemia? | What medications can treat it?
``` Cardiac dysfunction (arrhythmia) Muscle dysfunction N.B: Hyperkalaemia causes membrane depolarisation ``` ACEi Spironolactone K-sparing diuretics
433
What type of anaemia does CKD cause? | How is it treated?
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
List some types of renal bone disease
Osteitis fibrosa cystica Osteomalacia Adynamic bone disease Mixed osteodystrophy
435
Outline the pathophysiology of renal bone disease
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
What is osteitis fibrosa cystica?
Caused by osteoclastic resorption of calcified bone & replacement by fibrous tissue (feature of hyperparathyroidism)
437
What is adynamic bone disease?
Overtreatment leading to excessive suppression of PTH result in low bone turnover & reduced osteoid
438
Outline treatment of renal bone disease
PO4 control - dietary, PO4 binders | Vit D activators - 1-a calcidol, paricalcitol
439
What are the 3 phases of uraemic cardiomyopathy?
LV hypertrophy LV distension LV dysfunction
440
What are the treatment options for patients with CKD?
Transplantation Haemodialysis Peritoneal dialysis
441
Describe the cardiac consequences of plasma K being too high or low
Too high - Asystole (unstable rhythm) Too low - Ventricular fibrillation
442
What is the difference between a Colles' fracture & a Smith's fracture?
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
What is a Pott's fracture?
Ankle fracture involving the tibia & fibula
444
What would you expect to see on the urine dipstick of someone with subacute bacterial endocarditis?
Microscopic haematuria
445
What is the differential diagnosis for hypercalcaemia?
Cancer Primary hyperparathyroidism Sarcoidosis
446
What is the physiological role of PTHrP?
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
What are 2 main mechanisms of hypercalcaemia of malignancy?
PTHrP | Cancer invading bone
448
What are the main actions of PTH?
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
Name & describe an eye sign of hypercalcaemia
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
List some complications of hypercalcaemia
Renal stones (radio-opaque) Pancreatitis Peptic ulcer disease Skeletal changes (osteitis fibrosa cystica)
451
List some RFs for hypercalcaemia
Family history Dehydration Hyperparathyroidism
452
Which bacterium has predilection to infect urinary tract stones?
Proteus mirabilis
453
What are the main investigations & management options for urinary tract stones?
CT-KUB Stone analysis Urine & serum biochemistry Lithotripsy Cystoscopy Lithotomy
454
How can urinary stones be prevented?
Drink more water Treat hypercalciurea (thiazides) Treat hypercalcaemia N.B: Loop diuretics increase urine Ca
455
At what point would you use emergency management of hypercalcaemia? Outline the emergency management of hypercalcaemia
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
Which other drug would you consider using to manage hypercalcaemia particularly in hypercalcaemia of malignancy?
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
In which group of patients would you use dextrose to treat hypercalcaemia rather than saline?
Liver failure - tend to have tendency to retain salt
458
Outline the treatment of non-emergency hypercalcaemia
Keep well hydrated Avoid thiazides (reduce hypercalciurea but increase plasma Ca concentration) Surgery
459
What feature may you see on X-ray of the hands in a patient with primary hyperparathyroidism?
Cystic changes in radial aspect
460
What is a characteristic histological feature of long-standing undiagnosed hyperparathyroidism?
Brown tumours - multinucleated giant cells (activated osteoclasts) in bone
461
What is the mainstay of treatment of sarcoidosis?
Steroids
462
What is the histological hallmark of sarcoidosis?
Non-caseating granulomas
463
Outline the mechanism of hypercalcaemia in sarcoidosis
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
# Define diabetes based on: - Fasting plasma glucose - 2hr oral glucose tolerance test - HbA1c
Fasting plasma glucose - >7.7mmol/L 2hr OGTT - >11.1mmol/L HbA1c - >48mmol/mol (6.5%)
465
Outline the relationship between hypokalaemia & alkalosis
Low K leads to shift of H+ into cells Causes alkalosis Similarly, low H+ results in shift of K into cells
466
Which cause of Cushing's syndrome is most commonly associated with hypokalaemia?
Ectopic ACTH
467
Why might a patient with Cushing's syndrome be hypotensive?
Diuresis can lead to dehydration & hypotension
468
What is the only definitive way of distinguishing acute renal failure from chronic renal failure?
Renal biopsy
469
How might ATN due to dehydration be treated?
3wks of dialysis
470
What does slow-onset upper motor neuron lesions in a cancer patient suggest?
Brain metastases
471
Why doesn't hypopituitarism cause low BP?
Adrenals still produce aldosterone
472
Which hypothalamic hormones affect prolactin release?
Dopamine -ve TRH +ve N.B: Hypothyroidism causes hyperprolactinaemia
473
How might pituitary failure present in F?
Amenorrhoea & galactorrhoea
474
What physical manifestation might macroadenoma of pituitary gland (>1cm) cause?
Bitemporal hemianopia | N.B: Can be tested using visual field test
475
What is the main problem with prolactinomas?
Might reduce/stop the production of other pituitary hormones (e.g. ACTH, TSH, GH) High prolactin itself not much of an issue
476
What is CPFT? Which 3 stimuli of pituitary hormone secretion are used?
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
What safety precautions must you take before subjecting a patient to hypoglycaemia?
No cardiac risk factors (needs normal ECG) No history of epilepsy Ensure good IV access
478
Describe manifestations of increasing hypoglycaemia
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
Describe the normal response from pituitary gland during CPFT?
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
List order of hormone replacement in someone with panhypopituitarism
Hydrocortisone - 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
How should prolactinoma be treated?
``` Dopamine agonists (e.g. cabergoline) Reduces size of tumours & can avoid surgery ```
482
What is disconnection hyperprolactinaemia?
Compression of pituitary stalk by tumour cuts off -ve effect of dopamine on pituitary prolactin secretion Results in hyperprolactinaemia
483
How should you investigate a child with poor growth who is suspected of having GH deficiency?
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
Name 2 tests that may be used to investigate suspected acromegaly
OGTT IGF-1 N.B: Normal IGF-1 ranges not fully resolved & vary with age
485
In which tissues is ALP present in high concentrations?
Liver (sinusoidal & canalicular membranes of bile ducts) Bone Intestines Placenta
486
What is increase in bone ALP caused by?
Increased osteoblast activity
487
List some physiological causes of high ALP
Pregnancy - 3rd trimester (from placenta) | Childhood - growth spurt
488
List some causes of very high ALP (>5x upper limit of normal)
Bone - Paget's disease (as well as osteocalcin), osteomalacia Liver - cholestasis, cirrhosis
489
List some causes of moderately raised ALP (<5x upper limit of normal)
Bone - tumours, fractures, osteomyelitis | Liver - infiltrative disease, hepatitis
490
Which markers are used in acute pancreatitis?
Amylase (also found in salivary glands so also raised in parotitis) Lipase
491
What are the 3 forms of creatine kinase?
CK-MM - skeletal muscle CK-BB - brain CK-MB - cardiac muscle
492
Describe the manifestation of statin-related myopathy
Can range from myalgia to rhabdomyolysis | N.B: Look for recent initiation of statins
493
List some RFs for statin-related myopathy
``` Polypharmacy (particularly fibrates & ciclosporin & other drugs metabolised by CYP3A4) High dose Genetic predisposition Previous history of myopathy Vit D deficiency ```
494
List some other causes of high CK
``` Muscle damage Myopathy (e.g. Duchenne muscular dystrophy) MI Severe exercise Physiological (Afro-Caribbeans) ```
495
List 4 cardiac enzymes that can be used as markers of cardiac damage
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
Describe how troponin levels change with time following an MI
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
Outline diagnostic criteria for MI
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
What are the main biomarkers used in cardiac failure?
ANP - from atria BNP - from ventricles - Used to assess ventricular function & can be used to exclude HF (high -ve predictive value)
499
Define 1IU of enzyme activity
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
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)
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
State the manifestations of an excess of following vitamins: - Vit A (Retinol) - Vit D (Cholecalciferol) - Vit B6 (Pyridoxine) - Vit C
Vit A - Exfoliation, hepatitis Vit D - Hypercalcaemia Vit B6 - Neuropathy Vit C - Renal stones
502
Which tests are used for following vitamin derangements: - Vit K - Vit B1 - Vit B2 - Vit B6 - Folate
Vit K - Prothrombin time Vit B1 - RBC transketolase Vit B2 - RBC glutathione reductase Vit B6 - RBC AST activation Folate - RBC folate
503
What are the 2 forms of Beri Beri? Describe them
Wet - CVD - patients have oedema & other features of HF Dry - Neurological disease - may have Wernicke's syndrome
504
What are the main features of pellagra?
Dementia Diarrhoea Dermatitis
505
State the manifestations of following deficiencies in trace elements - Fe - Iodine - Zn - Cu - Fl
Fe - Anaemia Iodine - Goitre, hypothyroidism Zn - Dermatitis Cu - Anaemia Fl - Dental caries - N.B: Excess causes flourosis
506
What is the recommended division between fats, carbohydrates, & proteins in a normal diet?
Carbohydrates: 50% - 80% of which should be complex carbs Fats: 33% Protein: 17%
507
Describe the adiponectin levels in obese person
Reduced - leads to insulin resistance | N.B: Insulin causes slight increase in satiety & thermogenesis
508
What are the effects of leptin, ghrelin, & PYY?
Leptin - Anti-hunger hormone Ghrelin - Hunger hormone PYY - Satiety hormone produced by intestines
509
What waist circumference is associated with increased risk in M & F?
M >94cm (major risk >102cm) | F >80cm (major risk >88cm)
510
# Define & give an e.g. of: - Indispensable protein - Conditionally indispensable protein - Dispensable protein
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
Describe the relationship between dietary fat & LDL levels
High dietary saturated fat leads to high LDLs
512
Describe effect of alcohol & obesity on lipid levels
Alcohol increases HDLs | Obesity lowers HDLs
513
What are the 5 features that constitute metabolic syndrome?
``` Fasting glucose >6mmol/L HDL <1 (M) or <1.3 (F) Waist circumference >102 (M) >88 (F) Hypertension >135/80 Microalbumin/insulin resistance ```
514
Outline treatment options for obesity
``` 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
Name & describe 2 types of protein energy malnutrition
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
Define intermediary metabolism
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
List some metabolic consequences of liver failure
``` 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
What are the main stages of xenobiotic metabolism in the liver?
Chemical modification Conjugation Excretion
519
Outline the roles of the liver regarding hormone metabolism
``` Vit D hydroxylation Steroid hormones (conjugation & excretion) Peptide hormones (catabolism) ```
520
What are the roles of Kupffer cells?
Main cells of reticuloendothelial system of liver Roles include: - Clearance of infection & lipopolysaccharide (LPS) - Ag presentation - Immune modulation (e.g. cytokine production)
521
What are the main markers of liver synthetic function?
``` Albumin Prothrombin time (normal = 12-14s) - Better acutely as shorter 1/2 life ```
522
Where are ALT & AST found?
``` Liver (cytoplasm of hepatocytes) Muscle Kidney Bone Pancreas ```
523
Describe the rise in ALT & AST seen in alcoholic liver disease and viral hepatitis
Alcoholic liver disease: - AST:ALT > 2 Viral hepatitis - AST:ALT < 1
524
Describe typical ALT & AST levels in cirrhosis
May be raised | May be normal in long-standing chronic liver disease
525
Where is GGT found?
``` Liver (hepatocytes) Biliary system (epithelium of small bile ducts) Kidney Pancreas Spleen Heart Brain Seminal vesicles ```
526
List some causes of raised GGT
Alcohol abuse Bile duct disease (e.g. gallstones) Hepatic metastases
527
How much albumin is produced by the liver/day?
8-14g/day
528
What is the half-life of albumin?
20 days
529
List some causes of low albumin
Low production e.g. CKD, malnutrition Increased loss e.g. gut, kidney Sepsis - 3rd spacing: Endothelium becomes leaky & albumin leaks into tissues
530
What are the main roles of alpha-fetoprotein?
In foetus, plays a role in foetal transport & immune regulation
531
Which tissues produce alpha-fetoprotein in the foetus?
Yolk sac GI epithelium Liver
532
What causes high alpha-fetoprotein?
Hepatocellular carcinoma Pregnancy Testicular cancer
533
List some causes of increased urobilinogen in the urine
Haemolysis Hepatitis Sepsis
534
Name a dye test used to assess liver function
Indocyanine green/bromsulphalein - measures excretory capacity of liver & hepatic blood flow
535
Name a breath test used to assess liver function
Aminopyrine/galactose (C14) - measures residual functioning of liver cell mass
536
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?
Drug-induced cholestasis N.B: Biliary USS will be normal. Usually resolves over 3wks Co-amoxiclav most common cause
537
State 3 causes of ALT>1000
Toxins (paracetamol) Viruses Ischaemia (e.g. post-resuscitation)
538
How often should patients with cirrhosis be followed up to check for hepatocellular carcinoma?
Every 6mths
539
How is paracetamol overdose treated?
Activated charcoal (if still in stomach) N-acetyl cysteine Liver transplant
540
How does rhabdomyolysis lead to AKI?
Myoglobin is very nephrotoxic
541
Under what circumstances will urea rise more than creatinine?
AKI caused by dehydration | N.B: CKD caused by fall in GFR will lead to more prominent rise in creatinine
542
State the indications for dialysis
Hyperkalaemia Acidosis Pulmonary oedema Uraemia (pericarditis, encephalopathy)
543
What is used as a marker of blood glucose control over the last 3wks?
Fructosamine | - Can be used during pregnancy
544
What is a characteristic morphological feature of Paget's disease
Bowed tibia | N.B: Warmth over the affected bone is also a feature
545
How is Paget's disease of the bone treated?
Bisphosphonates (only if painful)
546
Which marker is often used in PET scans looking for cancer deposits?
FDG (fluorodeoxyglucose) | N.B: Cancer cells more active so uptake more glucose. Used to identify abdominal metastases
547
Which radioactive marker can be used to identify neuroendocrine cells?
Gallium 69 stuck to a somatostatin analogue
548
What are MIBG scans used to identify?
Phaeochromocytoma - MIBG = precursor for adrenaline
549
Which scan useful for investigating parathyroid glands?
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
Which score is used to determine fracture risk?
FRAX
551
Which diseases tend to cause low bone density & fractures in the spine?
Cushing's syndrome Hyperthyroidism Postmenopausal

Laz questions (2 decks)

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