ChemPath Flashcards
What is inosinic acid (IMP)?
An intermediate metabolite of AMP (adenylic acid) and GMP (guanylic acid)
Also a product of de novo purine synthesis
Describe the inhibitory and stimulatory controls on this enzyme.
AMP and GMP negatively regulate the activity of PAT PPRP positively regulates the activity of PAT
What inborn error of purine metabolism is characterised by HPRT deficiency?
Lesch-Nyhan syndrome
Describe the inheritance pattern of Lesch-Nyhan syndrome.
X-linked recessive
Outline the clinical features of Lesch-Nyhan syndrome.
Normal at birth Developmental delay at 6 months Hyperuricaemia
Choreiform movements at 1 year
Spasticity and mental retardation
Self-mutilation present in 85% (e.g. biting lips very hard)
Describe the biochemical basis of Lesch-Nyhan syndrome.
It is caused by absolute deficiency of HPRT (Hypoxanthine Phosphoribosyltransferase)
This reduces the production of IMP and GMP by the salvage pathway
This reduces the inhibitory effect of IMP and GMP on PAT, thereby increasing the activity of the de novo pathway This leads to the production of vast amounts of IMP, which will be shunted down the catabolic pathway to produce urate (which accumulates)
Less conversion of guanine –> GMP leads to a build-up of PPRP (which stimulates PAT)
What are the two mechanisms of hyperuricaemia? List some examples.
Increased urate production (e.g. rapid cells turnover in myeloproliferative diseases and psoriasis)
Decreased urate excretion (e.g. saturnine gout (caused by lead poisoning) and diuretic use)
What is birefringence?
The ability of a crystal to rotate the axis of the polarised light
NEGATIVE – appear blue at 90 degrees to the axis of the red compensator
POSITIVE – appear blue in the axis of the red compensator
Describe the management of gout after the acute phase is over.
Encourage fluid intake
Reverse factors that may increase the concentration of uric acid (e.g. stopping diuretics)
Allopurinol – reduces synthesis of urate by inhibiting xanthine oxidase
Probenecid – increases renal excretion of urate (increases FEUA)
Describe the uptake of cholesterol by the intestinal epithelium.
Cholesterol entering the intestines will come from the diet and bile
Cholesterol will be solubilised in mixed micelles It is then transported across the intestinal epithelium by NPC1L1 (this is the main determinant of cholesterol transport)
Name two transporters that transport cholesterol back into the intestinal lumen.
ABC G5
ABC G8
ABC = ATP-binding casette transporter
What are the two fates of cholesterol that is either produced by or transported to the liver?
Hydroxylation by 7-hydroxylase to produce bile acids
Esterification by ACAT to produce cholesterol ester which is incorporated into VLDLs along with triglycerides and ApoB
ACAT: Acyl-CoA cholesterol acyltransferase
Which transfer protein is important in the packaging of VLDLs?
MTP (microsomal triglyceride transfer protein)
Which transfer protein is important in the packaging of HDLs?
ABC A1
Which receptor is responsible for the uptake of some HDLs by the liver?
SR-B1
Describe the transport and metabolism of triglycerides.
Triglycerides from fatty foods are hydrolysed to fatty acids, absorbed, and resynthesized into triglycerides which are transported by chylomicrons into the plasma
Chylomicrons are hydrolysed by lipoprotein lipase into free fatty acids
Some free fatty acids are taken up by the liver, and some by adipose tissue
The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs
VLDLs are acted upon by lipoprotein lipase to liberate free fatty acids
List the three causes of familial hypercholesterolaemia (type II).
Caused by autosomal dominant gene mutations in:
LDL receptor
ApoB
PCSK9 (Proprotein convertase subtilisin/kexin type 9)
List the key features of the following forms of familial hypertriglyceridaemia: a. Familial Type I b. Familial Type IV c. Familial Type V
a. Familial Type I Caused by deficiency of lipoprotein lipase and ApoC II NOTE: lipoprotein lipase degrades chylomicrons and ApoC II is an activator of lipoprotein lipase
b. Familial Type IV Characterised by increased synthesis of triglycerides
c. Familial Type V Characterised by deficiency of ApoA V NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate
What is familial dysbetalipoproteinaemia (type III)?
Due to aberrant form of ApoE (E2/2)
NOTE: normal form is ApoE (3/3) A diagnostic clinical feature of yellowing of the palmar crease (palmar striae)
List four causes of hypolipidaemia and their underlying genetic defect. Abeta-lipoproteinaemia Hypobeta-lipoproteinaemia Tangier disease Hypoalpha-lipoproteinaemia
A-lipoproteinaemia
- Autosomal recessive
- Extremely low levels of cholesterol
- Due to deficiency of MTP
Hypo-lipoproteinaemia
- Autosomal dominant
- Low LDL
- Caused by mutations in ApoB
Tangier disease
- Low HDL
- Caused by mutation of ABC A1
Hypo-lipoproteinaemia
• Sometimes caused by mutation of ApoA1
List some lipid-lowering drugs and 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 and reduces their absorption
What is the rate of production of H+ ions per day?
50-100 mmol/day
Which condition classically causes a mixed respiratory alkalosis and metabolic acidosis?
Aspirin overdose Aspirin stimulates ventilation and reduces renal excretion of H+
What reaction is used to measure fractions of bilirubin? Describe how this works.
Van den Bergh reaction The direct reaction measures conjugated bilirubin Methanol is added which completes the reaction and gives you a value for total bilirubin The difference between these two values is used to measure the unconjugated bilirubin (indirect reaction)
What is the inheritance pattern of Gilbert’s syndrome?
Autosomal recessive
Describe the histology of hepatitis.
Hepatocytes will become fatty and swell (balloon cells), containing a lot of Mallory hyaline
There will also be a lot of neutrophil polymorphs
Collagen around individual liver cells is classic of alcoholic hepatitis
What are the defining and associated histological features of alcoholic hepatitis?
Defining: liver cell damage, inflammation, fibrosis Associated: fatty change, megamitochondria
List a differential diagnosis for fatty liver disease.
NASH (most common cause of liver disease in the Western world) Alcoholic hepatitis Malnourishment (Kwashiorkor)
What is phenylketonuria caused by?
Phenylalanine hydroxylase deficiency This enzyme is responsible for converting phenylalanine to tyrosine Deficiency results in an accumulation of phenylalanine which is toxic (causes blue eyes, fair skin, metnalretardation) NOTE: maple syrup urine disease is also an aminoacidopathy
Which abnormal metabolites are produced in PKU?
Phenylpyruvate Phenylacetic acid (detected in the urine)
Describe the pathophysiology of MCAD deficiency.
This is a fatty acid oxidation disorder The carnitine shuttle transports fats into the mitochondria where it will be broken down into smaller and smaller chains by the process of fatty acid oxidation Without MCAD, you 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 your glucose stores In MCAD deficiency, the patient is unable to break down fats so they become very hypoglycaemic in between meals and this can kill
What is the screening test for MCAD deficiency?
Measuring C6-C10 acylcarnitines by tandem MS
What is homocystinuria caused by?
Failure of remethylation of homocysteine
What are the clinical features of homocystinuria?
Lens dislocation Mental retardation Thromboembolism
Describe the process of screening and diagnosis of cystic fibrosis.
If IRT > 99.5th centile in 3 bloodspots, move on to mutation detection There are > 500 mutations that can cause cystic fibrosis, but FOUR are very common If you detect 2/4 mutations, diagnose CF If you detect 1/4 mutations, extent test to panel of 28 mutations If you detect 0/4 mutations, repeat IRT at day 21-28
How many enzymes are there in the urea cycle?
7
Name three other diseases that count as urea cycle defects.
Lysinuric protein intolerance Hyperornithaemia-hyperammonaemia-homocitrullinuria Citrullinaemia type II
What is the mode of inheritance of all urea cycle disorders? What is the exception?
Autosomal recessive EXCEPTION: ornithine transcarbamylase deficiency (X-linked)
How does the body get rid of excess ammonia?
An ammonium group is attached to glutamate to make glutamine So, plasma glutamine in hyperammonaemic conditions will be high NOTE: the amino acids within the urea cycle will be high or absent. You can also measure urine orotic acid
List some agents/methods that can be used to remove excess ammonia from the body.
Sodium benzoate Sodium phenylacetate Dialysis
List the key features of urea cycle disorders.
Long-term psychiatric disease
Vomiting without diarrhoea
Respiratory alkalosis
Hyperammonaemia
Encephalopathy (psychiatric manifestations)
Avoidance or change in diet
List three branched chain amino acids.
Leucine Isoleucine Valine
What tends to cause hyperammonaemia with metabolic acidosis and a high anion gap?
Organic acidurias Also caused by defects in the complex metabolism of branched chain amino acids
Describe the breakdown of leucine.
An ammonia group will be broken off using by a transaminase and a high energy protein group will be added This produces a breakdown product called isovaleryl CoA This is then converted by isovaleryl CoA dehydrogenase Molecules with high energy groups cannot traverse the cell membrane, so they need to be converted to other molecules: • Export from cell as: isovaleryl carnitine • Excrete as: 3OH-isovaleric acid (cheesy smell) and isovaleryl glycine
What would constitute the metabolic screen for Reye syndrome?
Plasma ammonia
Plasma/urine amino acid
Urine organic acids
Plasma glucose and lactate
Blood spot carnitine profile (stays abnormal in remission)
NOTE: the top 4 need to be measured during an acute episode because the abnormal metabolites will disappear after a few days
Describe the presentation of galactosaemia.
Vomiting
Diarrhoea
Conjugated hyperbilirubinaemia
Hepatomegaly
Hypoglycaemia
Cataracts
Sepsis (galactose-1-phosphate inhibits the immune response)
Describe the pathophysiology of Glycogen storage disease type I.
Whenever glycogen is broken down, it produces glucose-1-phosphate and glucose-6-phosphate and then the phosphate groups must be removed because it cannot cross the cell membrane with those phosphate groups
A lack of phosphatase means that G1P and G6P cannot be exported
This means that your muscles and liver build up a lot of glycogen that cannot be liberated leading to hypoglycaemia NOTE: also known as von Gierke disease
What are the clinical features of Glycogen storage disease type I?
Hepatomegaly (high hepatoblastoma risk)
Nephromegaly
Hypoglycaemia
Lactic acidosis
Neutropaenia
NOTE: caused by glucose-6-phosphatase deficiency (do NOT confuse with G6PD deficiency)
List three examples of mitochondrial diseases and outline their manifestations.
Barth syndrome – cardiomyopathy, neutropaenia and myopathy starting at birth
MELAS – mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
Kearns-Sayre syndrome – chronic progressive external ophthalmoplegia, retinopathy, deafness and ataxia
List some investigations for mitochondrial diseases.
High lactate (alanine) – especially after periods of fasting (NOTE: in normal people, lactate should go down when fasting)
CSF lactate/pyruvate
CSF protein (elevated in Kearns-Sayre)
CK
Muscle biopsy (ragged red fibres)
Mitochondrial DNA analysis
What are congenital disorders of glycosylation? Give an example.
A defect of post-translational protein glycosylation It is a multisystem disorder associated with cardiomyopathy, osteopaenia and hepatomegaly
Example: CDG type 1a – abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction
List some key differences of the neonatal kidneys compared to adult kidneys and their implications.
Short proximal tubule so lower reabsorptive capability
Reduce reabsorption of bicarbonate leading to a propensity to acidosis
Loop of Henle and distal collecting ducts are short and juxtaglomerular leading to reduced concentrating ability (maximum urine osmolality of 700 mmol/kg)
Distal tubule is relatively unresponsive to aldosterone leading to persistent sodium loss and reduced potassium excretion (sodium loss of 1.8 mmol/kg/day, and upper limit of normal K+ of 6 mmol/L in neonates)
What is hyponatraemia usually caused by in neonates?
Congenital adrenal hyperplasia
What level of conjugated hyperbilirubinaemia is considered pathological?
More than 20 µmol/L
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, peroxisomal disorders) NOTE: 20% of biliary atresia is associated with cardiac malformations, polysplenia, situs inversus
List the main biochemical features of osteopaenia of prematurity.
Calcium is usually normal Phosphate < 1 mmol/L ALP > 1200 U/L (10 x adult ULN)
List some genetic causes of rickets.
Pseudo-vitamin D deficiency I (defective renal hydroxylation)
Pseudo-vitamin D deficiency II (receptor defect)
Familial hypophosphataemias (low tubular maximum reabsorption of phosphate, raised urine phosphoethanolamine)
NOTE: top two conditions are treated with 1,25-OH Vitamin D
Outline the relationships between UV light and skin lesions.
Porphyrinogens are oxidised and then activated by UV light into activated porphyrins NOTE: porphyrinogens do NOT oxidise in cells
List four types of acute porphyria and the enzymes involved.
Plumboporphyria – PBG synthase (porphobilinogen)
Acute intermittent porphyria – HMB synthase (hydroxymethylbilane)
Hereditary coproporphyria – coproporphyrinogen oxidase
Variegate porphyria – protoporphyrinogen oxidase
List three types of non-acute porphyria and the enzymes involved.
Congenital erythropoietic porphyria – uroporphyrinogen III synthase Porphyria cutanea tarda – uroporphyginogen decarboxylase Erythropoietic protoporphyria – ferrochetolase
What does ALA synthase deficiency cause?
X-linked sideroblastic anaemia
What are the 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)
Outline the clinical features of acute intermittent porphyria.
Rise in PBG and ALA in urine (Port Wine urine)
Autosomal dominant
Neurovisceral attacks
- Abdominal pain
- Tachycardia and hypertension
- Constipation, urinary incontinence
- Hyponatraemia and seizures
- Sensory loss, muscle weakness, psychosis
- Arrhythmias/cardiac arrest
IMPORTANT: there are NO skin symptoms (because no porphyrinogens are produced) NOTE: 90% will be asymptomatic
Describe how acute intermittent porphyria is diagnosed.
Increased urinary PBG (and ALA) PBG gets oxidised to porphobilin Decreased HMB synthase activity in erythrocytes
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 negative feedback)
What is the negative consequence of accumulation of coproporphyrinogen III and protoporphyrinogen IX?
They are potent inhibitors of HMB synthase
Results in the accumulation of PBG and ALA
What are the main clinical features of hereditary coproporphyria?
Autosomal dominant Acute neurovisceral attacks Skin lesions (blistering, skin fragility, classically on the backs of the hands that tend to appear hours/days after sun exposure)
How is the porphyrin level in the urine and faeces different in hereditary coproporphyria and variegate porphyria compared to acute intermittent porphyria?
AIP - normal HCP and VP – high NOTE: DNA analysis offers a definitive diagnosis
What is the main clinical feature of non-acute porphyria?
Skin blisters, fragility, pigmentations and erosions Occurring hours to days after sun exposure
What is a key investigation for erythropoietic protoporphyria?
RBC protoporphyrin NOTE: only RBCs are affected
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 and pigmentation
Outline the biochemistry features of porphyria cutanea tarda.
Urine/plasma uroporphyrins and coproporphyrins are raised Ferritin is often increased
What haematological condition are erythropoietic protoporphyria and congenital erythropoietic porphyria associated with?
Myelodysplastic syndromes
What does thyroxine bind to in the blood?
Thyroxine binding globulin (TBG) Thyroxine-binding prealbumin (TBPA) Albumin
Why might there be some benefit to treating subclinical hypothyroidism?
Hypothyroidism is associated with hypercholesterolaemia
Outline how thyroid function changes in pregnancy.
hCG has a similar structure to TSH so high hCG levels can cause hyperthyroidism Free T4 levels rise slightly TBG level increase dramatically NOTE: hCG level drops later on in pregnancy
What is struma ovarii?
A rare form of ovarian tumour (usually a teratoma) that contains mostly thyroid tissue and produces thyroxine
Which drug can be given to hyperthyroid patients prior to surgery to block uptake of iodide?
Potassium perchlorate
Name two tumour markers used for medullary thyroid cancer?
Calcitonin CEA
What are the three forms in which calcium is present in the plasma?
Free (ionised) – 50% - biologically active Protein-bound – 40% - bound to albumin Complexed – 10% - citrate/phosphate
State the equation for corrected calcium.
Corrected calcium = serum calcium + (0.02 x (40 – serum albumin in g/L)) NOTE: if your albumin level is constant, the total serum calcium will be roughly double the concentration of free calcium
What are the main roles of vitamin D?
Increased intestinal calcium absorption Increased intestinal phosphate absorption Critical for bone formation
List some clinical features of rickets.
Bowed legs
Costochondral swelling
Widened epiphyses of the wrists
Myopathy
NOTE: vitamin D deficiency can also cause Looser’s zones (pseudofractures)
Which group of drugs is associated with vitamin D deficiency?
Anticonvulsants – promote the breakdown of vitamin D
Outline the pathophysiology of familial benign hypercalcaemia.
A mutation in the calcium-sensing receptor (CaSR) leads to an increase in the set-point for PTH release (leads to mild hypercalcaemia)
List some other non-PTH driven causes of hypercalcaemia.
Sarcoidosis Thyrotoxicosis (increases bone resorption) Hypoadrenalism (renal Ca2+ transport) Thiazide diuretics (renal Ca2+ transport) Excess vitamin D (e.g. sun beds)
Describe the consequences of amphetamine overdose.
Causes hyperthermia rhabdomyolysis renal failure Also has a direct toxic effect on the heart
How long can drugs be detected for in the: a. Blood and serum b. Urine
a. Blood and serum 12 hours b. Urine 2-3 days
List some causes of SIADH.
CNS pathology
Lung pathology
Drugs (SSRIs, TCAs, opiates, PPIs, carbamazepine) Tumours Surgery
Name and describe the mechanism of action of two drugs used to treat SIADH if fluid restriction is insufficient.
Demeclocycline – reduces the responsiveness of collecting duct cells to ADH
NOTE: monitor U&E because it can be nephrotoxic
Tolvaptan – V2 receptor antagonist
Alternative: fluid restriction + salt tablets + diuretics
How often should serial Na+ measurements be taken in someone being treated for hypernatraemia?
4-6 hours
Outline the mechanism of action of aldosterone.
Aldosterone binds to MR and stimulates the transcription of ENaC channels
Aldosterone binding to MR also leads to increased Sgk1 which inhibits Nedd4
Nedd4 usually ubiquitinates sodium channels and degrades them
Inhibition of Nedd4 leads to preservation of sodium channels thereby increasing sodium reabsorption
As you reabsorb more sodium, the lumen becomes more negative and K+ will move down the electrochemical gradient into the lumen via ROMK channels
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 Potassium release from cells (rhabdomyolysis, acidosis)
List some causes of hypokalaemia.
GI loss
Renal loss
- Hyperaldosteronism
- Cushing’s syndrome
- Increased sodium delivery to distal nephron
- Osmotic diuresis
Redistribution into cells
- Insulin
- Beta-agonists
- Alkalosis
Rare causes
- Renal tubular acidosis (type 1 and 2)
- Hypomagnesaemia
Name two conditions that can block the triple transporter.
Loop diuretics Bartter syndrome (mutation in triple transporter)
Name two conditions that can block the Na+/Cl- cotransporter.
Thiazide diuretics Gitelman syndrome (mutation in Na+/Cl- cotransporter)
Explain how increased delivery of sodium to the distal nephron can cause hypokalaemia.
Increased delivery of Na+ to the distal nephron (e.g. because of blocking/ineffective triple transporter or Na+/Cl- cotransporter) leads to increased reabsorption of Na+ in the distal nephron This leads to the lumen of the distal nephron becoming more negative This results in the movement of K+ down the electrochemical gradient through ROMK channels into the lumen
How does an increase in plasma pH affect serum calcium levels?
As pH increases, plasma proteins start to stick to calcium more than usual Total plasma calcium levels will remain normal but there will be less free ionised calcium (active form) This leads to tetany (which can make patients hyperventilate even more)
Describe the Cori cycle. How does metformin affect this?
Lactate is produced by anaerobic glycolysis in the muscles This goes to the liver and is converted back to glucose which will then return to the muscle Metformin inhibits hepatic gluconeogenesis (the conversion of lactic acid to glucose in the liver) thereby resulting in lactic acidosis NOTE: excess lactic acid is normally excreted by the kidneys, but in renal failure the kidneys cannot handle the excess lactic acid
Name three genetic syndromes associated with phaeochromocytomas.
MEN2 Von Hippel Lindau syndrome Neurofibromatosis type I
Describe how a low-dose dexamethasone suppression test is performed.
The patient’s baseline ACTH and cortisol is measured at the start
Then they are given 0.5 mg dexamethasone every 6 hours for 48 hours
This should suppress cortisol to < 50 nM
If there is failure of suppression of cortisol, the patient should be sent for inferior petrosal sinus sampling
List some options for people with statin intolerance.
Ezetemibe Plasma exchange PCSK9 inhibitors (e.g. evolocumab) NOTE: niacin is no longer available
Describe how SGLT2 inhibitors can reduce blood glucose.
Increases urinary excretion of glucose causing a reduction in blood glucose and blood pressure NOTE: this can also be used in heart failure because of its diuretic effect
Name an SGLT2 inhibitor.
Empagliflozin
What is the physiological role of GLP1?
Produced by the gut and signals to the pancreas to produce more insulin (incretin effect) Also has a direct effect on satiety and gastric emptying
List three examples of GLP1 analogues.
Exanatide (synthetic version of exendin 4 (from Gila monster)) Liraglutide (saxenda) Semaglutide
Summarise the steps in the pharmacological management of type 2 diabetes mellitus.
Step 1: metformin
Step 2: if non-insulin monotherapy at maximum tolerated dose does not achieve or maintain the HbA1c target after 3 months add either:
- Second oral agent OR
- GLP1 agonist OR
- Basal insulin
In patients with long-standing suboptimally controlled T2DM and established cardiovascular disease, empagliflozin (SGLT2 inhibitor) or liraglutide (GLP1 analogue) should be considered
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
What effect does hypoglycaemia have on blood glucose and FFA 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
List some non-diabetic medications that can cause hypoglycaemia.
Beta-blockers Salicylates Alcohol
List some biochemical tests that may help differentiate between causes of hypoglycaemia.
Insulin levels (NOTE: exogenous insulin can interfere with assays) C-peptide (marker of endogenous insulin production) Drug screen Autoantibodies Cortisol/GH Free fatty acids/ketone bodies Lactate NOTE: it is important to perform these tests at the time of the hypo (but try not to delay treatment)
What would you expect the insulin and C-peptide levels to be in a hypoglycaemic patient who has anorexia nervosa but not diabetes?
Low insulin and low C-peptide The patient is hypoglycaemic because of poor liver glycogen stores (not an issue with insulin) so their insulin response will be normal
List some causes of Hypoinsulinaemic hypoglycaemia.
Fasting/starvation Strenuous exercise Critical illness Endocrine deficiencies (adrenal failure, hypopituitarism) Liver failure Anorexia nervosa NOTE: this is a normal response to hypoglycaemia
Name 3 ketone bodies.
3-hydroxybutyrate Acetone Acetoacetate
List some causes of neonatal hypoglycaemia with high FFAs and low ketones.
Fatty acid oxidation defects MCAD deficiency Carnitine disorders HMG-CoA lyase deficiency GSD type 1
List some causes of neonatal hypoglycaemia with low FFAs and low ketones.
Hyperinsulinism Hypopituitarism
List some causes of neonatal hypoglycaemia with high FFAs and high ketones.
Galactosaemia Glycogen storage disease Neonatal haemochromatosis GH deficiency Glucocorticoid deficiency Septicaemia
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)
Describe the mechanism by which beta cells release insulin in response to blood glucose.
Glucose crosses the membrane of beta cells and enters glycolysis via glucokinase Glycolysis produces ATP The rise in ATP leads to the closure of ATP-sensitive K+ channels This leads to membrane depolarisation, calcium influx and insulin exocytosis
What can cause the following: low glucose, low insulin, low C-peptide, low FFAs and low ketones?
This suggests that something is pretending to be insulin This is non-islet cell hypoglycaemia caused by secretion of big IGF-2 Big IGF-2 binds to IGF-1 receptors and insulin receptors It behaves like insulin, so it causes hypoglycaemia and suppresses insulin and FFA/ketone production It is a paraneoplastic syndrome usually caused by mesenchymal tumours (e.g. mesothelioma, fibroblastoma) and epithelial tumours (carcinoma)
Describe two autoimmune causes of hypoglycaemia.
Autoimmune conditions – antibodies against insulin receptors can cause insulin resistance and hypoglycaemia (rarely) Autoimmune insulin syndrome – antibodies are directed towards insulin so sudden dissociation of the antibodies can precipitate hypoglycaemia (could be caused by drugs e.g. hydralazine, procainamide)
What is reactive hypoglycaemia?
Hypoglycamia following food intake (post-prandial) 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
Which cells produce renin?
Macula densa cells
Where are most aldosterone receptors found in the nephron?
Distal collecting tubule
What are the inner and middle layers of the filtration barrier in the kidneys?
Inner - fenestrated endothelium Middle - glomerular basement membrane (type IV collagen) Outer - podocyte foot process Negative charge of the filtration barrier is due to heparan sulphate
What is the normal range for plasma osmolality?
275-295 mmol/L
By what mechanism does acute intermittent porphyria cause hyponatraemia?
SIADH
Which type of porphyria is characterised by a photosensitive rash?
Erythropoietic protoporphyria
What is the rate-limiting step in haem synthesis?
ALA synthase
Outline the diagnostic criteria for hyperosmolar hyperglycaemic state.
Plasma glucose level >30mM
Serum osmolality >320mOsm/kg
Serum pH >7.30
Bicarbonate >15 mEq/L
State the equation that links clearance with urine and plasma concentration.
C = (U x V/P)
Name three single injection plasma clearance markers.
51Cr-EDTA 99Tc-DTPA Iohexol
Describe the key features of plasma urea.
By-product of protein metabolism Variable absorption (30-60%) by tubular cells Dependent on nutritional state, hepatic function and GI bleeding Limited clinical value
Name and briefly describe three equations that are used to estimate creatinine clearance or GFR.
Cockcroft-Gault – estimates creatinine clearance by taking into account weight, age and sex (may overestimate when GFR < 30 ml/min) MDRD – estimates GFR from creatinine clearance and takes into account age sex, serum creatinine and ethnicity (may underestimate in overweight and young people) CKD-EPI – improvement of MDRD and currently recommended
Name an alternative endogenous marker of GFR.
Cystatin C NOTE: it is constitutively produced by all nucleated cells, is generated at a constant rate and freely filtered. It is almost completely reabsorbed and catabolised by tubular cells
How is proteinuria estimated?
Spot urine protein: creatinine ratio (PCR) NOTE: this has superseded 24-hour urine collection
How can ethylene glycol poisoning cause AKI?
It gets converted to oxalic acid which precipitates with calcium to form calcium oxalate stones
What are the three stages of AKI?
Stage 1: increase in serum creatinine by 1.5-1.9 times baseline Stage 2: increase in serum creatinine by 2-2.9 times baseline Stage 3: increase in serum creatinine by 2-2.9 times baseline
Name and describe the two mechanisms that maintain renal blood flow despite changes in systemic blood pressure.
Myogenic Stretch – if the afferent arteriole gets stretched due to high pressure, it will constrict to reduce the transmission of that pressure to the glomerulus Tubuloglomerular Feedback – high chloride concentration in the early distal tubule (suggestive of high GFR) stimulates constriction of the afferent arteriole which lowers GFR and, hence, chloride concentration
List some drugs that affect renal blood flow.
ACE inhibitors – reduce efferent arteriolar constriction NSAIDs – decreased afferent arteriolar constriction Calcineurin inhibitors – decrease afferent arteriolar constriction Diuretics – affect tubular function and decrease preload
What might be seen on urine microscopy in a patient with ATN?
Epithelial cell casts
List the possible sites of disease in intrinsic AKI.
Vascular (e.g. vasculitis) Glomerular (e.g. glomerulonephritis) Tubular (e.g. ATN) Interstitial (e.g. AIN)
What can cause direct tubular injury?
Ischaemia (MOST COMMON) Endogenous toxins (e.g. myoglobin, immunoglobulin) Exogenous toxins (e.g. aminoglycosides, amphotericin, aciclovir)
What are the biochemical definitions of AKI?
Increase in serum creatinine > 26.5 mol/L within 48 hours Increase in serum creatinine > 1.5 times baseline within the previous 7 days Urine volume < 0.5 ml/kg/hr for 6 hours
What are the normal roles of the kidney?
Excretion of water-soluble waste Water balance Electrolyte balance Acid-base homeostasis Endocrine (EPO, RAS, vitamin D)
Outline the consequences of CKD.
Progressive failure of homeostatic function (acidosis, hyperkalaemia) Progressive failure of hormonal function (anaemia, renal bone disease) Cardiovascular disease (vascular calcification, uraemic cardiomyopathy) Uraemia and death
What are the consequences of renal acidosis?
Muscle and protein degradation Osteopaenia due to mobilisation of bone calcium Cardiac dysfunction
How is renal acidosis treated?
Oral sodium bicarbonate
What type of anaemia does chronic renal disease cause?
Normochromic, normocytic anaemia
How is anaemia of chronic renal disease treated?
Erythropoietin alfa (Eprex)
Erythropoietin beta (NeoRecormon)
Darbopoietin (Aranesp)
NOTE: if CKD is not responding to erythropoiesis stimulating agents, consider iron deficiency, malignancy, B12 deficiency etc.
List some types of renal bone disease.
Osteititis fibrosa cystica
Osteomalacia
Adynamic bone disease
Mixed osteodystrophy
Outline the pathophysiology of renal bone disease.
Damaged kidneys are unable to excrete phosphate and activate vitamin D
Phosphate retention stimulates the production of FGF23 and Klotho
This lowers the levels of activated vitamin D
To try and get rid of the excess phosphate, the body will produce more PTH
Furthermore, to try and increase levels of vitamin D, the body will produce more PTH (i.e. there are two stimuli for PTH release)
High levels of phosphate in the blood will complex with calcium leading to a reduction in the level of free calcium High levels of PTH will result in the bone becoming resistant to PTH
What is osteitis fibrosa cystica?
Caused by osteoclastic resorption of calcified bone and replacement by fibrous tissue (feature of hyperparathyroidism)
What is adynamic bone disease?
Overtreatment leading to excessive suppression of PTH result in low bone turnover and reduced osteoid
Outline the treatment of renal bone disease.
Phosphate control – dietary, phosphate binders
Vitamin D activators – 1-alpha calcidol, paricalcitol
Direct PTH suppression – cinacalcet (works by increasing the sensitivity of the calcium sensing receptor)
What is a Pott’s fracture?
Ankle fracture involving the tibia and fibula
Name and describe an eye sign of hypercalcaemia.
Band keratopathy – calcium deposition across the front of the eye
It is a feature of chronic hypercalcaemia (i.e. it will not be caused by hypercalcaemia of malignancy)
Which bacterium has a predilection to infect urinary tract stones?
Proteus mirabilis
How can urinary tract stones be prevented?
Drink more water
Treat hypercalciuria (thiazides)
Treat hypercalcaemia
NOTE: loop diuretics increase urine calcium
Outline the emergency management of hypercalcaemia.
IV access
Insert catheter 3-6 L 0.9% saline over 24 hours
The first litre should be given quickly (over 1 hour) to correct dehydration
Elderly patients should also be given furosemide (to prevent pulmonary oedema)
Which other drug may be used under desperate circumstances when managing hypercalcaemia?
Pamidronate (IV) Good at treating bone pain but takes at least 1 week to start working and gets incorporated into bone for a very long time
In which group of patients would you use dextrose rather than saline?
Liver failure – they have a tendency to retain salt
What is minimally invasive parathyroidectomy?
A technetium sesta MIBI scan shows a hyperactive parathyroid
An USS is also performed and if the results of the sesta MIBI and USS are concordant, the whole neck does not need to be opened If they are not concordant, the surgeon will need to view all four glands and take out the largest one
What is a characteristic histological feature of long-standing undiagnosed hyperparathyroidism?
Brown tumours – they are multinucleated giant cells in the bone.
The giant cells are activated osteoclasts
List some causes of hypokalaemic alkalosis.
Intestinal loss (diarrhoea, vomiting, fistula)
Renal loss (mineralocorticoid excess, diuretics, renal tubular disease, osmotic diuresis, increased sodium delivery to distal nephron)
Redistribution (insulin, alkalosis, beta agonists) Rare (renal tubular acidosis type 1 and 2, hypomagnesaemia)
How might ATN due to dehydration be treated?
3 weeks of dialysis
Which three stimuli of pituitary hormone secretion are used in the CPFT?
Hypoglycaemia – increases CRF/ACTH and increases
GHRH/GH TRH – increases TSH and prolactin
LHRH (GnRH) – increases LH and FSH
NOTE: CPFT = combined rapid anterior pituitary evaluation panel
What blood glucose concentration is normally required to stimulate the pituitary gland?
< 2.2 mM
NOTE: < 1.5 mM will produce neuroglycopaenic symptoms
How should a patient be rescued if they experience severe hypoglycaemia during a CPFT?
50 mL 20% dextrose
How much insulin should be given in a CPFT?
0.15 U/kg
Outline the dosing of various drugs in the CPFT.
5 mL syringe
Insulin (0.15 U/kg)
TRH 200 µg
LHRH 100 µg
NOTE: the patient may experience a warm flush and vomit when the drug is administered
How frequently should hormone levels in the blood be measured?
Every 30 mins for 60 mins – LH, FSH, TSH, prolactin
Every 30 mins for 120 mins – glucose, GH, cortisol
What level of cortisol and GH is considered a normal response to a CPFT?
Cortisol > 550 nM
GH > 10 IU/L
List the order of hormone replacement in someone with panhypopituitarism.
HYDROCORTISONE
Thyroxine
Oestrogen
GH
NOTE: fludrocortisone is not necessary because the adrenals can still produce aldosterone
How should you investigate a child with poor growth who is suspected of having a GH deficiency?
Take a random plasma GH measurement (GH is pulsatile but if you happen to measure it during a pulse and they have detectable GH then it shows that they are producing GH)
Exercise test Insulin tolerance test (effective but dangerous so should NOT be done straight away)
List some other causes of high CK.
Muscle damage
Myopathy (e.g. Duchenne muscular dystrophy)
MI Severe exercise
Physiological (Afro-Caribbeans)
Where is CK-MB found within cells?
Within the mitochondria and nucleus
Describe how troponin levels change with time following an MI.
Rise at 4-6 hours post-MI
Peaks at 12-24 hours
Remains elevated for 3-10 days
So, troponins should be measured at 6 hours and 12 hours after the onset of chest pain in a suspected MI
Outline the diagnostic criteria for MI.
Typical rise and gradual fall in troponin or more rapid rise and fall in CK-MB with at least one of the following:
- Ischaemic symptoms
- Pathological Q waves
- ECG changes suggestive of ischaemia
- Coronary artery intervention
Pathological findings of acute MI
Define 1 international unit of enzyme activity.
Quantity of enzyme required to catalyse a reaction of 1 µmol of substrate per minute
NOTE: activity is affected by assay conditions such as pH and temperature (so reference ranges may differ between laboratories)
State the manifestations of the following vitamin deficiencies. a. Vitamin A (Retinol)
b. Vitamin D (Cholecalciferol)
c. Vitamin E (Tocopherol)
d. Vitamin K (Phytomenadione)
e. Vitamin B1 (Thiamine)
f. Vitamin B2 (Riboflavin)
g. Vitamin B6 (Pyridoxine)
h. Vitamin B12 (Cobalamin)
i. Vitamin C
j. Folate
k. Niacin (Vitamin B3)
a. Vitamin A (Retinol) Colour blindness
b. Vitamin D (Cholecalciferol) Osteomalacia/rickets
c. Vitamin E (Tocopherol) Anaemia, neuropathy
d. Vitamin K (Phytomenadione) Defective clotting
e. Vitamin B1 (Thiamine) Beri-beri Neuropathy Wernicke syndrome
f. Vitamin B2 (Riboflavin) Glossitis
g. Vitamin B6 (Pyridoxine) Dermatitis, anaemia
h. Vitamin B12 (Cobalamin) Pernicious anaemia
i. Vitamin C Scurvy
j. Folate Megaloblastic anaemia, NTD
k. Niacin (Vitamin B3) Pellagra
State the manifestations of an excess of the following vitamins. a. Vitamin A
b. Vitamin D
c. Vitamin B6
d. Vitamin C
a. Vitamin A Exfoliation, hepatitis
b. Vitamin D Hypercalcaemia
c. Vitamin B6 Neuropathy
d. Vitamin C Renal stones
State the manifestations of the following deficiencies in trace elements. a. Iron b. Iodine c. Zinc d. Copper e. Fluoride
a. Iron Anaemia
b. Iodine Goitre, hypothyroidism
c. Zinc Dermatitis
d. Copper Anaemia e. Fluoride Dental caries NOTE: excess causes fluorosis
Describe the adiponectin levels in obese people.
Reduced – this leads to insulin resistance
NOTE: insulin causes a slight increase in satiety and thermogenesis
Define and give an example of:
a. Indispensable protein
b. Conditionally indispensable protein
c. Dispensable protein
a. Indispensable protein Cannot be made in the body and must be obtained from the diet E.g. leucine
b. Conditionally indispensable protein Can be synthesised at certain stages in your life (e.g. very young, pregnancy) E.g. cysteine
c. Dispensable protein Can be produced by the body There are 6: alanine, aspartic acid, asparagine, glutamic acid, serine and selenocysteine
Name two techniques that can be used to assess protein levels.
Nitrogen excretion and balance
Tracer techniques
What are the five features that constitute metabolic syndrome?
Fasting glucose > 6 mmol/L
HDL < 1 (men) or < 1.3 (women)
Waist circumference > 102 (men) > 88 (women)
Hypertension > 135/80
Microalbumin/insulin resistance
List some metabolic consequences of liver failure.
Reduction in blood sugar due to a lack of glycogen
Lactic acidosis (reduced ability to metabolise lactic acid)
Increased ammonia (no longer able to process amino acids)
What is the function of ALT and AST?
Catalyse the transfer of alanine and aspartate to the alpha-keto group of alpha-ketoglutarate, thereby producing pyruvate and oxaloacetate
How much albumin is produced by the liver per day?
8-14 g/day
Half-life = 20 days
List some causes of low albumin.
Low production (e.g. chronic liver disease, malnutrition)
Increased loss (e.g. gut, kidney)
Sepsis (3rd spacing – endothelium becomes leaky and albumin leaks into the tissues)
What causes a high alpha-fetoprotein?
Hepatocellular carcinoma
Pregnancy
Testicular cancer
Under what circumstance may bilirubin be detected in the urine?
There should be NO bilirubin in the urine.
Only conjugated bilirubin can be seen in the urine as it is soluble.
This would only occur when the bile duct is blocked leading to backflow of conjugated bilirubin into the circulation.
List some other investigations that may be used as part of a liver panel.
Coeliac serology
Hepatitis serology
Alpha-1 antitrypsin
Caeruloplasmin
Immunoglobulins
Ferritin
Name a dye test used to assess liver function.
Indocyanine green/bromsulphalein – measures excretory capacity of the liver and hepatic blood flow
Name a breath test used to assess liver function.
Aminopyrine/galactose (carbon 14) – measures residual functioning of liver cell mass
What is an important cause of jaundice with LFT changes consistent with biliary obstruction?
Drug-induced cholestasis
NOTE: biliary USS will be normal. It usually resolves over 3 weeks
Most Common Cause: CO-AMOXICLAV
How often should patients with cirrhosis be followed up to check for hepatocellular carcinoma?
Every 6 months
Describe how AST changes after an MI.
AST is found in myocytes It rises about 3 days after an MI and remains raised for 14 days
How can acute kidney injury be prevented in patients with a very high CK due to muscle breakdown?
IV sodium bicarbonate
Under what circumstance will urea rise more than creatinine?
Acute renal failure caused by dehydration
NOTE: chronic renal failure caused by a fall in GFR will lead to a more prominent rise in creatinine
State the indications for dialysis.
Hyperkalaemia
Acidosis
Pulmonary oedema
Uraemia (pericarditis, encephalopathy)
What is used as a marker of blood glucose control over the last 3 weeks?
Fructosamine
Which markers are increased in Paget’s disease of the bone?
ALP and osteocalcin
NOTE: activity of osteoclasts and osteoblasts is increased
Which radioactive marker can be used to identify neuroendocrine cells?
Gallium 68 is stuck to a somatostatin analogue which then binds to any cell with somatostatin receptors (i.e. any neuroendocrine cell)
This is called a Gallium Dotatate scan
These scans will pick up ANY neuroendocrine tumours (e.g. insulinoma, phaeochromocytoma)
NOTE: the spleen has a lot of somatostatin receptors
What are MIBG scans used to identify?
Phaeochromocytoma – MIBG is a precursor for adrenaline
Which scan is useful for investigating the parathyroid glands?
Sesta MIBI
NOTE: MIBI is taken up by the parathyroid and myocardium E.g. in myocardial infarction, there will be an area that does not take up MIBI
Which transaminase rises the most in cirrhosis?
AST
Which diseases tend to cause low bone density and fractures in the spine?
Cushing’s syndrome
Hyperthyroidism
Post-menopausal
NOTE: primary hyperparathyroidism causes fractures in the wrist
What effect does Addison’s disease have on calcium levels?
Causes a slight increase
What’s the difference between osmolality and osmolarity?
Osmolality = mmol/kg
Osmolarity = mmol/L
What is pseudohyponatraemia?
A machine error that gives a reading of hyponatraemia due to high levels of lipids or paraptortein in the plasma In this case the osmolality would be normal but sodium would be low
What would cause high osmolality but low sodium?
Glucose/mannitol infusion
NOTE: with hyponatraemia, osmolality should be low
Describe the four types of renal tubular acidosis.
Type 1: most severe, reduced H+ excretion and hypokalaemia (failed H+/K+ pump)
Type 2: milder, reduced bicarbonate reabsorption, leads to acidosis and hypokalaemia
Type 3: rarely relevant
Type 4: aldosterone deficiency or resistance
List some causes of a raised anion gap metabolic acidosis.
Ketoacidosis (DKA, alcohol, starvation)
Uraemia
Lactic acidosis
Toxins (ethylene glycol, methanol, paraldehyde, salicylate)
NOTE: normal range is 14-18 mmol/L
What is an osmolar gap and what is its significance?
Osmolar Gap = Osmolality (measured) - Osolarity (calculated)
Normal: < 10 High = presence of abnormal solute (e.g. ethylene glycol, ethanol, methanol, mannitol)
List some triggers for acute intermittent porphyria.
ALA synthase inducers (e.g. steroids, ethanol, barbiturates)
Stress (infection, surgery)
Reduced caloric intake and endocrine factors
List some contraindications for the CPFT.
Ischaemic heart disease
Epilepsy
Untreated hypothyroidism
Side-Effects: flushing and nausea, palpitations, loss of consciousness, convulsions
What is dipsogenic diabetes insipidus?
Failure/damage to the hypothalamus and thirst drive
Hyperntraemia without increased thirst
Which types of renal stone are radio-lucent?
Uric acid
Cysteine
Which mutation causes familial hyper-alpha lipoproteinaemia?
CETP deficiency
Leads to increase in HDL and is associated with longevity
Which mutation causes phytosterolaemia?
ABC G5 and G8
Leads to increased plasma concentrations of plant sterols (leads to premature atherosclerosis)
Which investigations are used for:
A - thiamine deficiency
B - B2 deficiency
C- B6 deficiency
Thiamine deficiency - RBC transketolase
B2 deficiency - RBC glutathione reductase
B6 deficiency - RBC AST activation
What are the main features of organic acidaemias?
Inability to break down branched-chain amino acids
High urea and ketones
Metabolic acidosis
Treat with low protein diet, acylcarnitine and haemofiltration
Often have funny smelling urine because of organic acids
What are the main features of fatty acid oxidation disorders (e.g. MCAD deficiency)?
Hypoglycaemia
Cardiomyopathy
Rhabdomyolysis
Low ketones
List some key features of peroxisomal disorders.
Can’t catabolise very long chain fatty acids or make bile acids
Poor feeding
Seizures
Retinopathy
Hepatomegaly
Mixed hyperbilirubinaemia
Give an example of a lysosomal disorder and describe some key features.
Tay Sachs disease
Very slow progression
Neuroregression
Hepatosplenomegaly
Cardiomyopathy
NOTE: test urine mucooligopolysaccharides and WBC enzyme levels
What are the biochemical criteria for diagnosing DKA?
pH < 7.3
Plasma glucose > 11 mM
Blood ketones > 3 mM (2+ urine)
Describe the pathway of purine catabolism (include the enzymes and substrate names).
Purines Hypoxanthine Xanthine Urate Allantoin
Conversion from hypoxanthine to urate is performed by xanthine oxidase
Conversion of urate to allantoin is performed by uricase
Which reactions does HPRT catalyse?
Hypoxanthine –> IMP
Guanine –> GMP
Describe the mechanism of colchicine.
Inhibits the manufacture of tubulin
Short-term administration of colchicine inhibits microtubule formation enough to reduce the motility of neutrophils (thereby reducing their ability to migrate to the site of inflammation)
What reaction is catalysed by HMG CoA reductase?
Mevalonic acid + acetyl CoA –> cholesterol
What are the effects of CETP on the movement of substances between lipoproteins?
Moves cholesterol from HDL VLDL
Moves triglycerides from VLDL HDL
Describe how phototherapy for jaundice works.
Phototherapy converts unconjugated bilirubin into lumirubin and photobilirubin which are soluble and do not require conjugation for excretion
What is the main role of the urea cycle?
Taking ammonia and producing urea
NOTE: there are 7 enzymes in the 13. List three branched chain amino acids.
Describe the presenting features of organic acidurias in neonates.
Unusual odour
Lethargy
Feeding problems
Truncal hypotonia/limb hypertonia
Myoclonic jerks
What is Reye syndrome?
Rapidly progressive encephalopathy that can be triggered by aspirin use in children (also triggered by antiemetics and valproate)
Describe the features of Reye syndrome.
Vomiting
Lethargy
Increased confusion
Seizures
Decerebration
Respiratory arrest
List some investigations for galactosaemia.
Urine reducing substances (high levels of galactose) Red cell Gal-1-PUT
Describe the typical changes in the following parameters you would expect to see in acute intermittent porphyria:
Urine ALA and PBG
Urine Porphyrins
Faecal Porphyrins
RBC Porphyrins
Urine ALA and PBG: HIGH
Urine Porphyrins: HIGH Uro
Faecal Porphyrins: NORMAL
RBC Porphyrins: NORMAL
Describe the typical changes in the following parameters you would expect to see in variegate porphyria:
Urine ALA and PBG
Urine Porphyrins
Faecal Porphyrins
RBC Porphyrins
Urine ALA and PBG: HIGH
Urine Porphyrins: HIGH Copro
Faecal Porphyrins: HIGH Copro + Proto
RBC Porphyrins: NORMAL
Describe the typical changes in the following parameters you would expect to see in hereditary coproporphyria:
Urine ALA and PBG
Urine Porphyrins
Faecal Porphyrins
RBC Porphyrins
Urine ALA and PBG: HIGH
Urine Porphyrins: HIGH Copro
Faecal Porphyrins: HIGH Copro
RBC Porphyrins: Normal
Describe the typical changes in the following parameters you would expect to see in porphyria cutanea tarda:
Urine ALA and PBG
Urine Porphyrins
Faecal Porphyrins
RBC Porphyrins
Urine ALA and PBG: NORMAL
Urine Porphyrins: HIGH Uro
Faecal Porphyrins: HIGH Isocopro
RBC Porphyrins: NORMAL
Describe the typical changes in the following parameters you would expect to see in protoporphyria:
Urine ALA and PBG
Urine Porphyrins
Faecal Porphyrins
RBC Porphyrins
Urine ALA and PBG: NORMAL
Urine Porphyrins: NORMAL
Faecal Porphyrins: HIGH Proto
RBC Porphyrins: HIGH Proto
Describe the changes in the following parameters you would expect to see in congenital erythropoietic porphyria:
Urine ALA and PBG
Urine Porphyrins
Faecal Porphyrins
RBC Porphyrins
Urine ALA and PBG: NORMAL
Urine Porphyrins: HIGH Uro + Copro
Faecal Porphyrins: HIGH Copro
RBC Porphyrins: HIGH Copro
List some common problems in LBW babies.
Respiratory distress syndrome
Retinopathy of prematurity
Intraventricular haemorrhage
Patent ductus arteriosus
Necrotising enterocolitis
How are calcium and phosphate levels different in babies?
After birth, calcium levels will fall
Phosphate is higher in babies (they are good at reabsorbing it)
Which reaction is catalysed by ALA synthase?
Succinyl CoA + Glycine –> 5-ALA
5-ALA = 5-aminolevulinic acid
Which drug can trigger porphyria cutanea tarda?
Hexachlorobenzene
List some drugs that may be used in the treatment of osteoporosis.
Vitamin D
Bisphosphonates
Teriparatide (PTH derivative)
Strontium (anabolic and anti-resorptive)
HRT
SERMs (e.g. raloxifene)
Describe the clinical features of ecstasy overdose.
Fever
Confusion
Sweaty
Dilated pupils
Hyperthermia
High urea and creatinine
High myoglobin
Hyponatraemia (through SIADH)
What are the main features of cyanide poisoning?
Brick red skin
Odour of almonds
Describe some features of TCA overdose.
Drowsy
Sinus tachycardia
Wide dilated pupils
Marked reflexes
Wide QRS
Describe some clinical features of organophosphate overdose.
Headache
Hypersalivation
Nausea and vomiting
Breathing difficulty
Sweaty
Flaccid paralysis of limbs
Low plasma cholinesterase
Which drug is responsible for the most addict related death?
Morphine
Why do some patients become hyponatraemic after surgery?
Due to iatrogenic infusion of hypotonic fluids
NOTE: it can also be caused by SIADH
What is Nelson syndrome?
Rare disorder in patients who have had both adrenal glands removed
The patient develops macroadenomas that secrete ACTH
What is elevated in the urine of patients with CAH?
Pregnenetriol
Which primary cancer typically gives rise to cannonball metastases?
Renal cell carcinoma
Chorioncarcinoma
Less common: prostate, endometrial, synovial
The deficiency of which enzyme causes McArdle’s glycogen storage disease?
Mycophorphorylase
NOTE: this causes muscle stiffness following exercise
A deficiency in which enzyme causes Fabry disease?
Galactosidase A
Causes full body or localised pain in the extremities, renal failure, cardiomyopathy, angiokeratoma (also causes seizures, deafness and/or blindness)
Name some drugs that are contraindicated in porphyria.
Diclofenac
Co-trimoxazole
NOTE: alcohol can result in chronic porphyria
What effect does aspirin have on gout?
Decreases renal excretion of uric acid
Results in increased risk of gout flare ups
What is pseudohypoparathyroidism? What are the main clinical features?
Caused by resistance to PTH
Results in low calcium, high phosphate, high PTH
Features include hypocalcaemia, round face and short metacarpals/metatarsals
Which cancers typically cause lytic bone lesions
Breast
Lung
Lymphoma
Thyroid
Kidney
Prostate
Multiple myeloma
In which metabolic condition does the plasma have a milky appearance with the presence of chylomicrons?
Lipoprotein lipase deficiency
Which inborn errors of metabolism cause dysmorphic features?
Peroxisomal disorders (and jaundice)
Congenital disorders of glycosylation
Outline the management of hyperkalaemia.
10 mL 10% calcium gluconate
50 mL 50% dextrose + 10 U insulin
Nebulised salbutamol
Treat the cause
How are the results of an oral glucose tolerance test (75 g glucose) interpreted?
Impaired glucose tolerance = 7.8 – 11.1 mM at 2 hours
Diabetes = > 11.1 mM at 2 hours
Describe the short synacthen test.
Measure cortisol and ACTH at the start of the test
Administer 250 µg synthetic ACTH by IM injection
Check cortisol at 30 and 60 mins
Healthy people should produce > 550 nM of cortisol within 30 mins
What should be considered if a hypoglycaemic patient is deteriorating or does not appear to be responding to the first step in their management?
IM/SC 1 mg glucagon
What is a urine reducing substances test?
A screening test for inborn errors of carbohydrate metabolism
What is the normal range for random blood glucose?
Normal < 11.1 mmol/L
Diabetes > 11.1 mmol/L
NOTE: fasting normal would be < 5.5 mmol/L
Fasting blood glucose, random blood glucose and OGTT are used to diagnose diabetes. How many positive results are required to diagnose diabetes?
1 positive result + symptoms of diabetes
OR
2 positive results in two different tests
How is HbA1c interpreted when used as a diagnostic test for diabetes?
Diabetes: > 48 mmol/mol (6.5%)
Pre-diabetes: 42-47 mmol/mol
Normal: < 42 mmol/mol
List some causes of hyponatraemia that are associated with:
High Osmolality
Normal Osmolality
High Osmolality: glucose (HHS), mannitol
Normal: Drip arm, high lipids or protein (e.g. myeloma)
What urine sodium concentration would you expect in hyponatraemia with functional kidneys?
< 20 mM (because the kidneys should be trying to retain as much salt as possible)
What is the best first-line investigation in a patient with hyponatraemia?
Plasma and urine osmolality
What is the normal range for urine specific gravity?
1.005-1.030
< 1.005 = diabetes insipidus, primary polydipsia
> 1.030 = SIADH, dehydration
Which other ion should be checked in a patient with persistent hypokalaemia?
Magnesium
Name two potassium sparing diuretics.
Spironolactone
Amiloride
How is acromegaly diagnosed?
Oral glucose tolerance test
NOTE: IGF-1 is sensitive but not specific
What is the usual first-line investigation for Cushing’s syndrome and Addison’s disease?
9 am cortisol
Which blood marker is monitored to check for recurrence in patients with resected papillary thyroid cancer?
Thyroglobulin
List some causes of erroneously high calcium.
Drip arm (calcium gluconate infusion)
Cuffed sample (raised albumin, normal urea)
Dehydration (raised albumin and urea)
Through which membrane channel does glucose enter beta cells?
GLUT2
It is also found in the liver
NOTE: GLUT4 channels are dependent on insulin
How is HHS treated?
IV 0.9% saline slowly over 48 hours
Replace K+ when urine starts to flow
Consider insulin if blood glucose not falling
Manage VTE risk (consider LMWH)
What is a useful marker to measure to check for reinfarction in a patient who is currently in hospital recovering from a myocardial infarction?
CK-MB
Rises after about 6-12 hours
Peaks at 24 hours
Returns to normal within 48-72 hours
What are the main sites of porto-systemic anastomosis in chronic liver disease?
Oesophageal varices
Rectal varices
Umbilical vein recanalising
Spleno-renal shunt
What effect does phytic acid have on vitamin D levels?
Chelates vitamin D in the gut and reduces absorption
What is the most common site of adrenal metastases?
Lung
Which metabolite is likely to be detected in the urine of a patient with neuroblastoma?
Homovanilic acid (HVA)
It is a metabolite of adrenaline and noradrenaline and is associated with a better prognosis
What are the main features of von Hippel Lindau syndrome?
Phaeochromocytomas
Renal cell carcinoma
Renal cysts
Retinal/CNS haemangioblastomas
What are the main features of neurofibromatosis type 1?
Peripheral and spinal neurofibromas
Multiple café au lait spots
Freckling (axillary/inguinal)
Optic nerve glioma
Lisch nodules (on iris)
Skeletal deformities
Phaeochromocytomas
Renal artery stenosis
Name some key studies on heart disease and briefly describe their main findings.
DCCT: T1DM - good control improves outcomes
UKPDS: legacy effect in T2DM
ACCORD: sudden aggressive blood glucose control in lond-standing diabtes is associated with increased mortality
ADVANCE: HbA1c of 6.5% leads to reduced mortality
Describe the following types of fracture:
Colles’
Smith’s
Pott’s
Colles - radius fracture that is displaced backwards (fall on outstretched hand)
Smith - radius fracture that is displaced fowards (fall on flexed hand)
Pott - ankle fracture involving the tibia and fibula
What X-ray change might you see in patients with primary hyperparathyroidism?
Cystic changes in the radial aspect of the wrist
What investigation are you likely to request first in a patient with sarcoidosis?
CXR
Followed by FBC, U&E, ECG and echocardiogram
Name two types of technetium scan.
Technetium Bisphosphonate - to look for bone metastases and areas of increased bone activity
Technetium (99m) Pertechnetate - looks at iodine uptake by the thyroid gland
List and briefly describe the articles of the Human Rights Act that apply to healthcare.
Article 2: absolute right to life (however, no absolute obligation to provide life-saving treatment)
Article 3: absolute prohibition of torture (may be breached by non-consensual treatment and excessive restraint)
Article 5: right to liberty (not absolute - e.g. detention for mental illness)
Article 8: right to a private life (not absolute - protects right to confidentiality and right to refuse treatment)
Describe the clinical manifestations of vitamin E deficiency.
Haemolytic anaemia
Spino-cerebellar neuropathy (ataxia, areflexia)
Risk of atherosclerosis
Describe the clinical manifestations of vitamin B6 deficiency.
Sideroblastic anaemia
Seborrhoeic dermatitis
Describe the clinical manifestations of Vitmin B2 deficiency.
Mucosal damage leading to angular stomatitis, glossitis and corneal ulceration
Describe the clinical manifestations of homocystinuria.
Amino acid disorder
Very fair skin
Brittle hair
Developmental delay and progressive learning difficulties
Convulsions, skeletal abnormalities and VTE
Describe the manifestations of digoxin overdose.
Nause, abdominal pain, confusion and blurred vision
Prolonged PR interval and bradycardia
What distinctive clinical feature is highly suggestive of lysosomal storage disorder?
Cherry-red spot on the macula
Why does vitamin C deficiency lead to mucosal bleeding?
Vitamin C is needed to produce stable collagen
Describe the manifestation of phenytoin toxicity.
Hypotension
Heart block
Ventricular arrhythmia
Ataxia
What is the mechanism of action of acarbose?
Alpha-glucosidase
Describe the presentation of theophylline overdose.
Arrhythmia
Anxiety
Tremor
Convulsions
What are the technical terms for:
Vitamin A
Vitamin E
Vitamin K
Vitamin B12
Vitamin A - retinol
Vitamin E - tocopherol
Vitamin K - phytomenadione
Vitamin B12 - cobalamin
What is a key distinguishing feature between urea cycle disorders and organic aciduria?
Urea cycle disease: Respiratory Alkalosis
Organic acidaemia: Metabolic Acidosis (HIGH anion gap)
BOTH cause HIGH AMMONIA
What is the first line investigation for suspected acute porphyria?
Urine PBG
What is the first-line investigation for suspected porphyria with skin lesions?
Urine and faecal porphyrins
What is the first-line investigation for suspected porphyria presenting with a photosensitive rash?
RBC protoporphyrins
Which oral agents can be added in the 2nd step of the medical management of type 2 diabetes mellitus after the use of metformin?
Sulphonylurea (e.g. gliclazide)
SGLT2 inhibitor (e.g. empagliflozin)
DPP4 inhibitor (e.g. saxagliptin)
NON-oral alternatives: GLP-1 analogue (e.g. liraglutide) or basal insulin
3rd line: alpha-glucosidase inhibitor (e.g. acarbose), thiazolidinediones (e.g. pioglitazone)
Which test is requested if a congenital disorder of glycosylation was suspected?
Transferrin glycoforms
What are the main clinical features of peroxisomal disorders?
Issue with the metabolism of very long chainfatty acids
Neonate: severe muscular hypotonia, seizures, hepatic dysfunction, mixed hyperbilirubinaemia, DYSMORPHIC
Infant: retinopathy and early blindness, sensorineural deafness, mental retardation, bony changes
Which test should be requested if peroxisomal disorders are suspected?
Very long chain fatty acid profile
What are the main features of lysosomal storage disorders?
Dysmorphia
Developmental regression
Organomegaly
Which investigation should be requested if a lysosomal storage disorder is suspected?
Urine mucopolysaccharides and/or oligosaccharides
Leucocyte enzyme activities
NOTE: treated with bone marrow transplant and exogenous enzyme
