Chem Path Flashcards
What are the three main purines?
Adenosine
Guanine
Inosine
Which joint is most commonly affected by gout and why might this be?
1st metatarsophalangeal joint – found at the periphery of the body so is likely to be cooler (lower temperatures reduce the concentration at which urate precipitates out of solution)
Describe how the kidneys handle urate.
The proximal convoluted tubule reabsorbs and secretes urate
NOTE: the reason urate is reabsorbed is probably because it is an important anti-oxidant that protects us from oxidative stress
Roughly what proportion of filtered urate will be found in the urine? What term is used to describe this?
10%
This is fractional excretion of uric acid (FEUA)
What inborn error of purine metabolism is characterised by HPRT deficiency?
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)
What are the two types of gout?
Acute (podagra)
Chronic (tophaceous)
Describe how the birefringence/crystals differ between gout and pseudogout.
Gout – monosodium urate crystals – needle-shaped and negatively birefringent
Pseudogout – calcium pyrophosphate crystals – rhomboid-shaped and positively birefringent
List three drug classes that are used in the acute management of gout.
NSAIDs
Colchicine
Glucocorticoids
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)
Which drug is contraindicated with allopurinol?
Azathioprine
What underlying condition is pseudogout often associated with?
Osteoarthritis
List some clinical features of familial hypercholesterolaemia.
Xanthelasma
Corneal arcus
Tendon xanthomata
List some causes of secondary hyperlipidaemia.
Pregnancy
Hypothyroidism
Obesity
Nephrotic syndrome
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
List some novel forms of lipid-lowering drugs
Lomitapide – MTP blocker
REGN727 – anti-PCSK9 monoclonal antibody
Mipomersen – anti-sense ApoB oligonucleotide
List three types of bariatric surgery.
Gastric banding
Roux-en-Y gastric bypass
Biliopancreatic diversion
List some beneficial effects of bariatric surgery.
Reduced diabetes risk
Reduced serum triglycerides
Increased HDLs
Reduced fatty liver
Reduced blood pressure
Which investigations are performed if a pre-hepatic cause of jaundice is suspected?
FBC
Blood film
What is the most common cause of paediatric jaundice?
Neonates have immature livers that cannot conjugate bilirubin fast enough resulting in a UNconjugated hyperbilirubinaemia
What is the inheritance pattern of Gilbert’s syndrome?
Autosomal recessive
Which drug can reduce bilirubin levels in Gilbert’s syndrome?
Phenobarbital
Outline the pathophysiology of Gilbert’s syndrome.
UDP glucuronyl transferase activity is reduced to 30% of normal
Unconjugated bilirubin is tightly albumin bound and does not enter the urine
What can worsen bilirubin levels in Gilbert’s syndrome?
Fasting
What is the significance of absent urobilinogen in the urine?
The absence of urobilinogen in the urine is suggestive of biliary obstruction
What is the most representative marker of liver function?
Prothrombin time (normal = 12-14 seconds)
What is another good marker of liver synthetic function
Albumin
Outline how hepatitis A serology changes over time.
As viral titres start to drop following initial infection, there will be a rise in IgM antibodies (during this time you will be unwell with jaundice)
After a few weeks, you will start to produce IgG antibodies (leading to cure and ongoing protection from Hep A)
NOTE: hepatitis A does NOT recur
Name the vaccine for hepatitis A.
Havrix (contains some antigens)
Outline the features of hepatitis B serology in acute infection.
Initial rise in HBeAg and HBsAg
Eventually you will develop HBeAb and HBsAb resulting in a decline in HBeAg and HBsAg
Outline the features of hepatitis B serology in someone who has been vaccinated.
They will have HBsAb but no other antibodies
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
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)
Outline the treatment of alcoholic hepatitis.
Supportive
Stop alcohol
Nutrition (vitamins especially thiamine)
Occasionally steroids (controversial but may have useful anti-inflammatory effects)
Vitamin B1 deficiency
Beri Beri
Vitamin B3 deficiency
Pellagra
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
Where does pancreatic cancer tend to metastasise to?
Liver
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
What is the main consequence of untreated PKU?
Low IQ
How is PKU investigated?
Blood phenylalanine level
Describe the treatment of PKU.
Monitor the diet and ensure that the patient is having enough phenylalanine (but not too much)
This must be started within the first 6 weeks of life
What is congenital hypothyroidism usually caused by?
Thyroid dysgenesis or agenesis
NOTE: diagnosis is based on high TSH
Describe the pathophysiology of MCAD deficiency.
Without MCAD, you will not produce acetyl-CoA from fatty acids, which is necessary in the TCA cycle to produce ketones (which spares glucose)
Outline the treatment of MCAD deficiency.
Avoid hypoglycaemia
What are the clinical features of homocystinuria?
Lens dislocation
Mental retardation
Thromboembolism
What is the screening test for cystic fibrosis?
High serum immune reactive trypsinogen
What do all urea cycle disorders result in?
High ammonia
NOTE: this is toxic
What is the mode of inheritance of all of these urea cycle defects?
Autosomal recessive
What is the treatment of urea cycle disorders?
Remove ammonia (using sodium benzoate, sodium phenylacetate or dialysis) Reduce ammonia production (low protein diet)
List the key features of urea cycle disorders.
Vomiting without diarrhoea
Respiratory alkalosis
Hyperammonaemia
Encephalopathy
Avoidance or change in diet
What tends to cause hyperammonaemia with metabolic acidosis and a high anion gap?
Organic acidurias
Describe the presenting features of organic acidurias in neonates.
Unusual odour
Lethargy
Feeding problems
Truncal hypotonia/limb hypertonia
Myoclonic jerks
Describe the chronic intermittent form of organic acidurias.
Recurrent episodes of ketoacidotic coma
Cerebral abnormalities
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
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
What do defects in mitochondrial fatty acid beta oxidation cause?
Hypoketotic hypoglycaemia
Describe the presentation of galactosaemia.
Vomiting
Diarrhoea
Conjugated hyperbilirubinaemia
Hepatomegaly
Hypoglycaemia
Sepsis (galactose-1-phosphate inhibits the immune response)
What is a long-term complication of galactosaemia if it is not detected in the neonatal period?
Bilateral cataracts
What are the clinical features of Glycogen storage disease type I?
Hepatomegaly
Nephromegaly
Hypoglycaemia
Lactic acidosis
Neutropaenia
What is the characteristic appearance of mitochondrial myopathy on a muscle biopsy?
Ragged red fibres
List some common problems in LBW babies.
Respiratory distress syndrome
Retinopathy of prematurity
Intraventricular haemorrhage
Patent ductus arteriosus
Necrotising enterocolitis
What is necrotising enterocolitis?
Inflammation of the bowel wall progressing to necrosis and perforation
Characterised by bloody stools, abdominal distension and intramural air (pneumatosis intestinalis)
Why does glycosuria occur at a lower plasma glucose level in neonates?
Short proximal tubule means that they have a lower ability to reabsorb glucose
How are the daily fluid and electrolyte requirements different in neonates compared to adults?
Sodium, potassium and water requirements are higher
Drugs can cause electrolyte disturbances in neonates. Give examples of drugs that can do this and briefly describe the mechanism.
Bicarbonate for acidosis (contains high Na+)
Antibiotics (usually sodium salts)
Caffeine/theophylline (for apnoea) – increases renal Na+ loss
Indomethacin (for PDA) – causes oliguria
NOTE: growth can also cause electrolyte disturbance
What is hypernatraemia usually caused by in neonates?
Dehydration
What is hyponatraemia usually caused by in neonates?
Congenital adrenal hyperplasia
Outline the pathophysiology of congenital adrenal hyperplasia.
Most commonly caused by 21-hydroxylase deficiency
Leads to reduce cortisol and aldosterone production and shunting of 17-OH progesterone and 17-OH pregnenelone which goes towards androgen synthesis
Outline the clinical features of congenital adrenal hyperplasia.
Hyponatraemia/hyperkalaemia
Hypoglycaemia
Ambiguous genitalia in female neonates
Growth acceleration
What is the issue with free bilirubin?
It can cross the blood-brain barrier leading to kernicterus
List some causes of neonatal jaundice.
G6PD Deficiency
Haemolytic anaemia (ABO, rhesus)
Crigler-Najjar syndrome
List some causes of prolonged jaundice (neonatal)
Prenatal infection/sepsis
Hypothyroidism
Breast milk jaundice
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)
How is osteopaenia of prematurity treated?
Phosphate/calcium supplements
1-alpha calcidol
List some presenting features of rickets.
Frontal bossing
Bowed legs
Muscular hypotonia
Tetany/hypocalcaemic seizure
Hypocalcaemic cardiomyopathy
What is porphyria?
Disorders caused by deficiencies in enzymes of the haem synthesis pathway
This leads to the accumulation of toxic haem precursors
What is the most common type of porphyria?
Porphyria cutanea tarda
What is the most common type of porphyria in children?
Erythropoietic protoporphyria
What does ALA synthase deficiency cause?
X-linked sideroblastic anaemia
Outline the clinical features of acute intermittent porphyria.
Rise in PBG and ALA
Autosomal dominant
Neurovisceral attacks
· Abdominal pain
· Tachycardia and hypertension
· Constipation, urinary incontinence
· Hyponatraemia and seizures
· Sensory loss/muscle weakness
· Arrhythmias/cardiac arrest
IMPORTANT: there are NO skin symptoms (because no porphyrinogens are produced)
NOTE: 90% will be asymptomatic
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
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)
Which drug can trigger porphyria cutanea tarda?
Hexachlorobenzene
What haematological condition are erythropoietic protoporphyria and congenital erythropoietic porphyria associated with?
Myelodysplastic syndromes
During acute porphyria, what is the most useful sample to send?
Urine
Which enzyme converts iodide to iodine?
Thyroid peroxidase
How is thyroxine produced?
Iodination of tyrosine residues in thyroglobulin generates MIT and DIT which leads to the formation of T3 and T4
What does thyroxine bind to in the blood?
Thyroxine binding globulin (TBG)
Thyroxine-binding prealbumin (TBPA)
Albumin
List some causes of hypothyroidism.
Hashimoto’s thyroiditis (autoimmune)
Atrophic thyroid gland
Post-Graves’ disease (after treatment)
Post-thyroiditis
Drugs (e.g. amiodarone, lithium)
Iodine deficiency
Pituitary disease
Peripheral thyroid hormone resistance
Outline the investigation findings that may be seen in hypothyroidism.
High TSH
Low T4
Thyroid peroxidase antibodies
Look out for other autoimmune conditions
Why is it important to do an ECG in patients with suspected hypothyroidism?
If someone with hypothyroidism has underlying cardiovascular disease, giving them thyroxine may induce ischaemia
NOTE: so you would start on a low dose of thyroxine and ten escalate
What are some risks of overtreatment with thyroxine?
Osteopaenia
Atrial fibrillation
What is subclinical hypothyroidism?
Normal T4 with high TSH, 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
How is neonatal hypothyroidism diagnosed?
Guthrie test
What are the TFT findings in sick euthyroid?
Low T4 and T3
Normal/high TSH
NOTE: these patients do not have symptoms of hypothyroidism
What are the three main causes of hyperthyroidism?
Graves’ disease
Toxic multinodular goitre
Single toxic adenoma
Others: subacute thyroiditis, post-partum thyroiditis
List some features of Graves’ disease.
Diffuse goitre
Thyroid-associated ophthalmopathy
Pretibial myxoedema
Thyroid acropachy
NOTE: radioiodine can make Graves’ eye disease worse
What is the mechanism of action of thionamides?
Prevents the conversion of iodide to iodine by thyroid peroxidase
Outline the management of hyperthyroidism.
Beta-blocker
ECG
Bone mineral density
Radioiodine
Thionamides
What is a rare but important side-effect of thionamides?
Agranulocytosis
Which drug can be given to hyperthyroid patients prior to surgery to block uptake of iodide?
Potassium perchlorate
What are the two most common forms of thyroid cancer?
Papillary thyroid cancer
Follicular thyroid cancer
How is thyroid cancer treated?
Total thyroidectomy
NOTE: radioiodine treatment may also be given
NOTE: high dose thyroxine may be given to suppress TSH levels to prevent TSH from stimulating any remaining cells
Which cells do medullary thyroid cancer arise from?
Calcitonin-producing C cells
NOTE: it is part of MEN2
Name two tumour markers used for medullary thyroid cancer?
Calcitonin
CEA
What are the consequences of high and low plasma calcium for nerve conduction?
High calcium – failure of depolarisation
Low calcium – trigger happy neurological system leading to epilepsy
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 effects of PTH?
Liberation of calcium from the bone (increased bone breakdown) and kidneys (increased calcium resorption)
Stimulates 1a-hydroxylase activity resulting in increased activated vitamin D
Stimulates renal phosphate excretion
What is the rate-limiting step in vitamin D activation?
1a-hydroxylase
How can sarcoidosis lead to hypercalcaemia?
Lung cells of sarcoid tissue express 1a-hydroxylase
What are the main roles of vitamin D?
Increased intestinal calcium absorption
Increased intestinal phosphate absorption
Critical for bone formation
What is ALP?
By-product of osteoblast activity
What disease states does vitamin D deficiency cause?
Osteomalacia
Rickets
List some risk factors for vitamin D deficiency.
Lack of sunlight
Dark skin
Dietary
Malabsorption
Outline some clinical features of osteomalacia.
Bone and muscle pain
Increased fracture risk
Looser’s zones
Outline the biochemical changes in osteomalacia.
Low calcium
Low phosphate
High ALP
List some clinical features of rickets.
Bowed legs
Costochondral swelling
Widened epiphyses of the wrists
Myopathy
Outline the pathophysiology of osteomalacia.
Vitamin D deficiency leads to secondary hyperparathyroidism which stimulates the liberation of calcium from the bone (leading to demineralisation of the bone)
Which group of drugs is associated with vitamin D deficiency?
Anticonvulsants – promote the breakdown of vitamin D
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
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)
List some symptoms of hypercalcaemia.
Polyuria/polydipsia
Constipation
Confusion, seizures, coma
What are the main causes of primary hyperparathyroidism?
Parathyroid adenoma
Parathyroid hyperplasia (associated with MEN1)
Parathyroid carcinoma
What are the three types of hypercalcaemia of 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
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)
Outline the management of hypercalcaemia.
Fluids, fluids and more fluids
Bisphosphonates (stops cancer from eating bone)
Treat the underlying cause
Where can a sample be taken from for drug concentration measurement?
Femoral vein blood
When is vitreous humour used as a sample?
Used to measure glucose (may be elevated in DKA)
Describe the consequences of amphetamine overdose.
Causes hyperthermia to rhabdomyolysis to renal failure
Also has a direct toxic effect on the heart
What is the underlying pathogenesis of hyponatraemia?
Increased extracellular water
What are the two main stimuli for ADH release?
Increased serum osmolality (via hypothalamic osmoreceptors)
Blood volume/pressure (via baroreceptors)
What is the most reliable clinical sign of hypovolaemia?
Low urine sodium (suggests that you are trying to retain fluid)
NOTE: this may be high in patients on diuretics
List some causes of hyponatraemia:
a. Hypovolaemic
Diarrhoea
Vomiting
Diuretics
Salt-losing nephropathy
b. Euvolaemic
Adrenal insufficiency
Hypothyroidism
SIADH
c. Hypervolaemic
Cirrhosis
Cardiac failure
Nephrotic syndrome
List some causes of SIADH.
CNS pathology
Lung pathology
Drugs (SSRIs, TCAs, opiates, PPIs, carbamazepine)
Tumours
Surgery
List the main investigative feature of SIADH.
Low plasma osmolality
High urine osmolality
Which tests would you do for euvolaemic hyponatraemia?
TFTs
Short synacthen test
Plasma and urine osmolality
What is the main danger of rapidly correcting hyponatraemia?
Can cause central pontine myelinolysis (osmotic demyelination)
This can lead to quadriplegia, dysarthria, dysphagia, seizures, coma and death
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
List some investigations that are used in suspected diabetes insipidus.
Plasma glucose (rule out DM)
Plasma K+ (rule out hypokalaemia)
Plasma Ca2+ (rule out hypercalcaemia)
Plasma and urine osmolality
Water deprivation test
How is hypernatraemia treated?
Fluid replacement – use dextrose because this will replace the fluid without adding to the salt
NOTE: if someone is hypovolaemic with hypernatraemia, they may initially be given 0.9% saline to treat the hypovolaemia before switching to dextrose to treat the hypernatraemia
How often should serial Na+ measurements be taken in someone being treated for hypernatraemia?
4-6 hours
What are the two main hormones involved in the regulation of potassium?
Angiotensin II
Aldosterone
What does aldosterone do?
Aldosterone stimulates sodium reabsorption and potassium excretion in the principal cells of the cortical collecting tubule
NOTE: water will also be drawn in with the sodium so aldosterone should not greatly affect sodium concentration
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)
Explain how acidosis leads to hyperkalaemia.
When plasma H+ concentration is high, the cells try to take in more H+ from the plasma
To maintain electrochemical neutrality, K+ must leave the cell when H+ enters
This leads to hyperkalaemia
Outline the management of hyperkalaemia.
10 mL 10% calcium gluconate
50 mL 50% dextrose + 10 U insulin
Nebulised salbutamol
Treat the cause
What are the clinical features of hypokalaemia?
Muscle weakness
Arrhythmia
Polyuria and polydipsia (due to DI)
What screening test should be done in a patient with hypokalaemia and hypertension?
Aldosterone: renin ratio (primary hyperaldosteronism will show high aldosterone and low renin)
Outline the management of hypokalaemia:
a. 3-3.5 mmol/L
Oral potassium chloride (2 x SandoK TDS for 48 hours)
Re-check serum K+ concentration
b. < 3 mmol/L
IV potassium chloride infusion
Maximum rate: 10 mmol/hr
NOTE: rates > 20 mmol/hr irritate the superficial veins
TREAT THE CAUSE
State the equation for osmolality
Osmolality = 2(Na + K) + urea + glucose
List some causes of high anion gap.
Ketosis
Lactic acidosis
Methanol
Ethylene glycol poisoning
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)
What is the danger of giving lots of fluids to someone with hyperglycaemic hyperosmolar state?
It can cause cerebral oedema, so 0.9% saline should be used to achieve a slower reduction in plasma sodium
What is a major consequence of metformin overdose?
Lactic acidosis
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
What is the difference between pink puffers and blue bloaters in COPD?
Pink puffers – very breathless, because they are still sensitive to CO2 which rises due to poor lung function in COPD
Blue bloaters – the brain stops responding to rising CO2 so you are not breathless and the CO2 will continue to rise
What are the five layers of the adrenal gland?
Capsule
Glomerulosa
Fasciculata
Reticularis
Medulla
What can cause adrenal glands to appear wasted?
Addison’s disease
Long-term steroid use
What can cause adrenal glands to become hyperplastic?
Cushing’s disease
Ectopic ACTH
What is the term used to describe the co-existence of primary hypothyroidism and Addison’s disease?
Schmidt syndrome
What is the differential diagnosis for hypertension with an adrenal mass?
Phaeochromocytoma
Conn’s syndrome
Cushing’s syndrome
What is a useful investigation for diagnosing phaeochromocytoma?
Urine catecholamines
What are the disastrous consequences of phaeochromocytoma?
Severe hypertension
Arrhythmia
Death
Outline the treatment of phaeochromocytoma.
Urgent alpha blockade (with phenoxybenzamine or phentolamine or doxazocin)
Some fluids may be given before alpha blockade as it can cause a dramatic drop in blood pressure
A beta-blocker should be given after the alpha-blocker to prevent reflex tachycardia
Patients should receive high-dose alpha and beta-blockade before surgery as the action of surgery can cause the release of catecholamines from the adrenals
Name three genetic syndromes associated with phaeochromocytomas.
MEN2
Von Hippel Lindau syndrome
Neurofibromatosis type I
Describe the levels of aldosterone and renin in Conn’s syndrome.
High aldosterone
Low renin
What is pseudo-Cushing’s syndrome?
Obesity can change your metabolism of cortisol to produce a clinical syndrome that looks like Cushing’s syndrome
What proportion of endogenous Cushing’s syndrome is caused by Cushing’s disease?
85%
What is the optimal medical therapy for people with coronary heart disease?
Intensive lifestyle modification
Aspirin
High-dose statin (atorvastatin 40-80 mg OD)
Optimal blood glucose control
Thiazides
Assessment for probably T2DM
Describe how SGLT2 inhibitors (Empagliflozin) 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
What are the effects of SGLT2 inhibitors on incidence of cardiovascular events and mortality?
Reduces the incidence of cardiovascular events
Reduces mortality
Reduced the incidence of renal failure
How long is it likely to take for IM glucagon to cause an increase in blood glucose?
15-20 mins
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
List some non-diabetic medications that can cause hypoglycaemia.
Beta-blockers
Salicylates
Alcohol
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 autoimmune syndrome)
List some physiologically explicable causes of neonatal hypoglycaemia.
Prematurity
IUGR
Inadequate glycogen/fat stores
NOTE: this should improve with feeding
List some tests that may be useful in the investigation of neonatal hypoglycaemia.
Insulin/C-peptide
FFA
Ketone bodies
Lactate
Hepatomegaly
Name an alternative endogenous marker of GFR.
Cystatin C
Aside from blood, what else can cause a urine dipstick to be positive for blood?
Myoglobinuria (from rhabdomyolysis)
What is specific gravity?
A measure of urine concentration
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
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 is a consequence of prolonged pre-renal insult?
Acute tubular necrosis (ATN)
What might be seen on urine microscopy in a patient with ATN?
Epithelial cell casts
What can cause direct tubular injury?
Ischaemia (MOST COMMON)
Endogenous toxins (e.g. myoglobin, immunoglobulin)
Exogenous toxins (e.g. aminoglycosides, amphotericin, aciclovir)
Which diseases can cause AKI due to infiltration/abnormal protein deposition?
Amyloidosis (associated with nephrotic syndrome)
Lymphoma
Myeloma
What are the four processes of acute wound healing?
Haemostasis
Inflammation
Proliferation
Remodelling
List some causes of CKD.
Diabetes mellitus
Hypertension
Chronic glomerulonephritis
Atherosclerotic renal disease
Infective or obstructive uropathy
Polycystic kidney disease
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
Which medications can cause hyperkalaemia?
ACE inhibitors
Spironolactone
Potassium-sparing diuretics
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
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)
Describe the effect of hypokalaemia on the myocardium.
Increases myocardial irritability
Describe the cardiac consequences of plasma potassium being too high or too low.
Too Low – ventricular fibrillation
Too High – asystole (ultimate stable rhythm)
What is the difference between a Colles’ fracture and a Smith’s fracture?
Colles’ – fracture caused by falling on an outstretched hand. The radial head will be displaced backwards (away from the palm)
Smith’s – fracture caused by falling on a flexed wrist. The radial head will be displaced forwards (towards the palm)
What is a Pott’s fracture?
Ankle fracture involving the tibia and fibula
What would you expect to see on the urine dipstick of someone with subacute bacterial endocarditis?
Microscopic haematuria
What is a key difference between calcium stones and urate stones?
Calcium stones are radio-opaque
Urate stones are radiolucent
List some complications of hypercalcaemia.
Renal stones
Pancreatitis
Peptic ulcer disease
Skeletal changes (osteitis fibrosa cystica)
List some risk factors for hypercalcaemia.
Family history
Dehydration
Hyperparathyroidism
Which bacterium has a predilection to infect urinary tract stones?
Proteus mirabilis
What are some management options for urinary tract stones?
Lithotripsy
Cystoscopy
Lithotomy
What feature may you see on an X-ray of the hands in a patient with primary hyperparathyroidism?
Cystic changes in the radial aspect
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
What is the mainstay of treatment of sarcoidosis?
Steroids
What is the histological hallmark of sarcoidosis?
Non-caseating granulomas
List some causes of metabolic alkalosis.
H+ loss (e.g. vomiting)
Hypokalaemia
Ingestion of bicarbonate
Outline the relationship between hypokalaemia and alkalosis.
Low K+ leads to a shift of H+ into cells
This causes alkalosis
Similarly, low H+ will result in a shift of K+ into cells
How can ectopic ACTH be distinguished from other causes of Cushing’s syndrome?
Ectopic ACTH cannot be suppressed by high-dose dexamethasone suppression test
Which cause of Cushing’s syndrome is most commonly associated with hypokalaemia?
Ectopic ACTH
What is the only definitive way of distinguishing acute renal failure from chronic renal failure?
Renal biopsy
What does slow-onset upper motor neurone lesions in a cancer patient suggest?
Brain metastases
Why doesn’t hypopituitarism cause low blood pressure?
The adrenals are still able to produce aldosterone
Which hypothalamic hormones affect prolactin release?
Dopamine – negative
TRH – positive
NOTE: hypothyroidism causes hyperprolactinaemia
How might pituitary failure present in women?
Amenorrhoea and galactorrhoea
What physical manifestation might a macroadenoma of the pituitary gland (> 1 cm) cause?
Bitemporal hemianopia
What blood glucose concentration is normally required to stimulate the pituitary gland?
< 2.2 mM
How frequently should hormone levels in the blood be measured in combined pituitary function test?
Every 30 mins for 60 mins – LH, FSH, TSH, prolactin
Every 30 mins for 120 mins – glucose, GH, cortisol
List the order of hormone replacement in someone with panhypopituitarism.
HYDROCORTISONE
Thyroxine
Oestrogen
GH
How should a patient with a prolactinoma be treated?
Dopamine agonists (e.g. cabergoline)
This reduces the size of the tumour and can avoid surgery
Name two tests that may be used to investigate suspected acromegaly.
Oral glucose tolerance test
IGF-1 levels
NOTE: the normal ranges for IGF-1 are not fully resolved and they vary with age
In which tissues is ALP present in high concentration?
Liver
Bone
Intestines
Placenta
What is an increase in bone ALP caused by?
Increased osteoblast activity
List some physiological causes of high ALP.
Pregnancy – 3rd trimester (from placenta)
Childhood – growth spurt
List some causes of very high ALP (> 5 x upper limit of normal).
Bone – Paget’s disease, osteomalacia
Liver – cholestasis, cirrhosis
List some causes of moderately raised ALP (< 5 x upper limit of normal).
Bone – tumours, fractures, osteomyelitis
Liver – infiltrative disease, hepatitis
What are the three forms of creatine kinase?
CK-MM = skeletal muscle
CK-BB = brain
CK-MB = cardiac muscle
List some risk factors for statin-related myopathy
Polypharmacy (particularly fibrates and ciclosporin and other drugs metabolised by CYP3A4)
High dose
Genetic predisposition
Previous history of myopathy
Vitamin D deficiency
List some other causes of high CK.
Muscle damage
Myopathy (e.g. Duchenne muscular dystrophy)
MI
Severe exercise
Physiological (Afro-Caribbeans)
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
Vitamin A deficiency
Colour blindness
Vitamin D deficiency
Osteomalacia/ rickets
Vitamin E deficiency
Anaemia, neuropathy
Vitamin K deficiency
Defective clotting
Vitamin B1 deficency
Beri Beri
Neuropathy
Wernicke’s
Vitamin B2 deficiency
Glossitis
Vitamin B6 deficiency
Dermatitis, anaemia
Folate deficiency
Megaloblastic anemia
Vitamin A excess
Exfoliation, hepatitis
Vitamin D excess
hypercalcaemia
Vitamin B6 excess
neuropathy
Vitamin C excess
Renal stones
What are the main features of pellagra?
Dementia
Diarrhoea
Dermatitis
What are the effects of leptin, ghrelin and PYY?
Leptin – anti-hunger hormone
Ghrelin – hunger hormone
PYY – satiety hormone produced by the intestines
What are the roles of Kupffer cells?
Clearance of infection and lipopolysaccharide (LPS)
Antigen presentation
Immune modulation (e.g. cytokine production)
Where is ALT and AST found?
Within the cytoplasm of hepatocytes
Other than the liver, where else is ALT and AST found?
Muscle, kidney, bone, pancreas
Describe the rise in ALT and AST seen in alcoholic liver disease.
AST: ALT > 2:1 in alcoholic liver disease
Describe typical ALT and AST levels in cirrhosis.
May be raised
May be normal in long-standing chronic liver disease
List some causes of raised GGT.
Alcohol abuse
Bile duct disease (e.g. gallstones)
Hepatic metastases
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
List some causes of increased urobilinogen in the urine.
Haemolysis
Hepatitis
Sepsis
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
What is the most common cause of drug-induced cholestasis?
Co-amoxiclav
State three causes of ALT > 1000.
Toxins (paracetamol)
Viruses
Ischaemia (e.g. post-resuscitation)
How often should patients with cirrhosis be followed up to check for hepatocellular carcinoma?
Every 6 months
Describe how the AST and ALT levels differ in alcohol liver disease and viral hepatitis.
AST: ALT < 1 = viral hepatitis
AST: ALT > 2 = alcoholic liver disease
What happens to vitamin D levels in primary hyperparathyroidism?
Decreases – because PTH activates 1-alpha hydroxylase leading to more conversion of vitamin D to the activated form
NOTE: assays for vitamin D levels will actually measure 25-OH vitamin D levels
State the indications for dialysis.
Hyperkalaemia
Acidosis
Pulmonary oedema
Uraemia (pericarditis, encephalopathy)
Which markers are increased in Paget’s disease of the bone?
ALP and osteocalcin
NOTE: activity of osteoclasts and osteoblasts is increased
What is a characteristic morphological feature of Paget’s disease
Bowed tibia
How is Paget’s disease of the bone treated?
Bisphosphonates (only if painful)
What is the difference between the Z-score and T-score with regards to DEXA scans?
Z-score: number of standard deviations from the bone mineral density of an age and gender-matched individual
T-score: number of standard deviations from the bone mineral density of a healthy young person
Which diseases tend to cause low bone density and fractures in the spine?
Cushing’s syndrome
Hyperthyroidism
Post-menopausal
Which part of the body tends to get fractured due to low bone mineral density caused by primary hyperparathyroidism?
Wrist (radius)
Age 0 most likely meningitis organism
Escherichia coli
Group B Streptococcus
Listeria monocytogenes
Age 6 most likely meningitis organism
Haemophilus influenzae
Neisseria meningitidis
Streptococcus pneumoniae
Age 18-25 most likely meningitis organism
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
Age 60+ most likely meningitis organism
Streptococcus pneumoniae
Listeria monocytogenes
Mycoplasma pneumoniae is difficult to culture. What is a different laboratory feature that can help identify this organism?
Cold agglutinins
List some signs of infective endocarditis.
Roth spots
Splinter haemorrhages
Janeway lesions
Osler’s nodes
Clubbing
Microscopic haematuria
Splenomegaly
Describe the appearance of pseudogout crystals under polarised light microscopy.
Positively birefringent rhomboid-shaped crystals
What type of deafness could Paget’s disease cause?
BOTH
Conductive – Paget’s disease of the ossicles will cause conductive deafness
Sensorineural – Paget’s disease of the skull can compress the 7th cranial nerve causing sensorineural deafness
