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