Chem Path ✔ Flashcards
Name the 3 forms of Calcium in the body and proportions of each:
Free (ionized) - biologically active (50%)
Protein-bound - (40%)
Complexed with citrate/phosphate (10%)
what is normal ‘total serum Ca’ levels?
2.2-2.6 mmol/L
what is the ‘adjusted’ serum Ca?
serum Ca +0.02 *(40-serum albumin in g/L)
what happens in the body to ensure Calcium hemostasis when low Calcium is detected?
dec Ca –> PTH release by parathyroid –> ‘obtain’ Ca from 3 sources (kidney, gut, bones)
name of hormone that activates Calcium in the kidney?
renal 1-alpha-hydroxlyase activation
what does the release of PTH cause?
increased bone and renal Ca resorption, increased 1,25 OH vitamin D levels
what does increased 1,25 OH Vitamin D cause?
increased intestinal Ca absorption
what two hormones are involved in calcium homeostasis?
PTH & Vitamin D
what is the role of PTH in the body?
bone & renal Ca resorption
renal Pi wasting
1,25-OH Vitamin D synthesis
when cholecalciferol is activated in the liver, what does it become?
25-hydroxycholecalciferol (25-OH D3)
when PTH stimulates the kidney, what changes happen to 25-OHD3?
25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol
what is the physiologically active form of vitamin D?
1,25 (OH)2 D3
what is the pathway of synthesis of Vitamin D?
100% of absorbed vitamin D is hydroxlyated at the 25 position by 25-hydroxylase
then 25-hydroxy D is inactive, stored and measured
what is the pathway of activation of Vitamin D?
1-alpha hydroxylase in the kidney activates 25-hydroxy D into 1,25-OH D3
what is 1-alpha hydroxylase and where does it come from?
from the kidney, activates vitamin D
what is 25-hydroxylase and where is it made?
in the liver, hydroxylates vitamin D for storage
what is vitamin D deficiency in children vs adults?
children - rickets
adults - ostemalacia
what are some features of a child with vitamin D deficiency?
bowed legs, chostocondral swelling, widened epiphysis at the wrist, myopathy
if someone has low Ca, low Pi, raised ALP - what do you suspect?
osteomalacia
what is the blood chemistry of someone with ostemalacia?
low Ca, low Pi, raised ALP
what are Looser’s zones?
pesudo fractures from ostemalacia
what type of medication can induce osteomalacia in adults?
anticonvulsants
what is the biochemistry in osteoporosis?
NORMAL Ca but reduction in bone density
what DEXA T score is definitive of osteoporosis?
T
what DEXA T score is definitive of osteomalacia?
T score between -1 & -2.5
if someone has a T score of T
A
if someone has a T score of T=-1 on their DEXA scan, what do you suspect?
A. Osteporosis
B. Osteomalacia
C. Paget’s Disease
B. Any T score between -1 & -2.5
list some causes of osteoporosis in a systematic way:
Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional
Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings
Drugs: steroids
Others eg genetic, prolonged intercurrent illness
name 5 biological (medical) treatments for osteoporosis
1) Vitamin D/Ca
2) bisphosphonates (alendronate)
3) PTH derivative (terparatide)
4) strontium
5) HRT (estrogens)
6) SERMs (raloxifene)
name the symptoms of hypercalcemia:
polyuria/polydipsia
constipation
neuro (confusion, seizures, comas)
‘bones, stones, moans, groans’
at what level of calcium would you see hypercalcemia symptoms?
Ca > 3.0 mmol/L
what is the normal hormonal response to hypercalcemia?
PTH suppression
what are potential causes of hypercalcemia if PTH is NOT suppressed? (one common, one rare)
primary problem with PTH regulation
common - primary hyperparathyroidism
rare - familial hypocalcuric hypercalcemia (FHH)
what are potential causes of hypercalcemia if PTH is suppressed?
common - malignancy
rare- sarcoid, vitamin D excess, thyrotoxicosis, milk alkali syndrome
what is the commonest cause of hypercalcemia?
primary hyperparathyroidism
what bone chemistry do you expect to see in primary hyperparathyroidism?
increased Ca
increased/normal PTH (inappropriate!)
decreased serum phosphate
urine increased Ca
what is the CaSR and what does it do?
parathyroid - PTH release
renal - Ca resorption
what genetic condition is associated with CaSR mutations?
FHH - higher ‘set point’ for PTH release leading to some constant mild hypercalcemia
what hypercalcemia is associated with malignancy?
humoral hypercalcemia (PTHrp; small cell lung Ca)
bone mets
hematological malignancy
what non-PTH driven hypercalcemia causes are there?
sarcoidosis, thyrotoxicosis, hypoadrenalism, thiazide diuretics, excess vitamin D
what is the treatment of hypercalcemia?
fluids fluids fluids!
Treat any underlying cause
what are the clinical signs of hypocalcemia?
neuro-muscular excitability
Chvostek’s sign, Trosseau’s sign, hyperreflexia, convulsions
what causes of hypocalcemia are PTH driven?
surgical (eg post thyroidectomy)
auto-immune hypoparathyroidism
congenital absence of parathyroids (eg DiGeorge’s)
Mg deficiency
if calcium is low, what do you expect PTH to do?
increase
what cause of hypocalcemia can progress to tertiary hypoparathyroidism?
CKD
what can CKD progress to with regards to Ca homeostasis?
secondary hypoparathyroidism progression to tertiary
what are non-PTH driven causes of hypocalcemia?
vitamin D deficiency
CKD
PTH resistance ('pseudohypoparathyroidism')what is the key factor of blood chemistry in Paget’s disease? (think Ca, ALP, Albumin, PTH….)
elevated alkaline phosphatase
bone chemistry of osteoporosis: Ca, Pi, PTH, Vit D, ALP
Ca: Normal Pi: Normal PTH: Normal Vit D: Normal ALP: Normal
Diagnose the Calcium issue from this chemistry - Ca: Normal Pi: Normal PTH: Normal Vit D: Normal ALP: Normal
osteoporosis
bone chemistry of osteomalacia/rickets:
Ca: decrease or normal Pi: decrease or normal PTH: increase Vit D: decrease ALP: increase
Diagnose the calcium issue from this chemistry - Ca: decrease or normal Pi: decrease or normal PTH: increase Vit D: decrease ALP: increase
ostemalacia
bone chemistry of Paget’s disease:
Ca: normal Pi: normal PTH: normal Vit D: normal ALP: increase
diagnose the calcium issue from this chemistry - Ca: normal Pi: normal PTH: normal Vit D: normal ALP: increase
Paget’s disease
bone chemistry of parathyroid bone disease:
(inc. PTH) Ca: increase Pi: decrease PTH: increase/ normal Vitamin D: normal ALP: increase or normal
Diagnose the calcium issue from this chemistry - (inc. PTH) Ca: increase Pi: decrease PTH: increase/ normal Vitamin D: normal ALP: increase or normal
parathyroid bone disease
bone chemistry of renal bone disease
Ca: decreased or normal Pi: increased PTH: increased Vitamin D: normal (1 -alpha-hydroxylase is low) ALP: increased/normal
Diagnose the calcium issue from this chemistry -
Ca: decreased or normal
Pi: increased
PTH: increased
Vitamin D: normal (1 -alpha-hydroxylase is low)
ALP: increased/normal
renal bone disease
name that biochemical abnormality: pH 6.92, PCO2 =3
metabolic acidosis
what is the pH and PCO2 in metabolic acidosis?
pH LOW
PCO2 LOW
name that biochemical abnormality: pH 7.70, PCO2 = 3
respiratory alkalosis
what is the pH and PCO2 in respiratory alkalosis?
pH HIGH
PCO2 LOW
what is the pH and PCO2 in respiratory acidosis?
pH LOW
PCO2 HIGH
name that biochemical abnormality: pH 6.92, PCO2 = 7
respiratory acidosis
what is the pH and PCO2 in metabolic alkalosis?
pH HIGH
PCO2 HIGH
name that biochemical abnormality: pH 7.70, PCO2 = 10
metabolic alkalsosi
what does abbreviation ROME stand for in biochemistry values?
Respiratory Opposite
Metabolic Equal
what is normal PCO2 concentration on blood gas?
PCO2 = (approx.) 4 -5
what is the formula for calculating osmolality?
Osmo = 2(Na+K) + Urea + Glucose
what is formula for calculating anion gap?
AG = (Na+K) - bicarbonate - chloride
positives minus negatives
what is the normal level of lactate?
Normal Lactate < 2.0 mM
Definition of type 2 diabetes (in fasting glucose and plasma)?
Fasting glucose > 7.0 mM
GTT with plasma glucose > 11.1 mM at 2 hours
(If the 2 hour value is between 7.8 -11.1 mM then called ‘impaired glucose tolerance’)
how does type 4 renal tubular acidosis cause hyperkalemia?
reduced renin –> less angtiotensins –> less aldosterone –> less potassium secretion –> k+ inc.
how do you get type 4 renal tubular acidosis?
end stage diabetic nephropathy
how does CKD cause hyperkalemia?
reduced GFR
what is a cause of reduced GFR?
CKD
how can ACE inhibitors cause hyperkalemia?
less angiotensin II –> less aldosterone –> less potassium secretion in kidneys
how can ARBs cause hyperkalemia?
angiotensin receptor blockers block angiotensin II –> less aldosterone –> less potassium secretion
how does Addison’s disease cause hyperkalemia?
less aldosterone –> less potassium secretion
how does aldosterone antagnosists cause hyperkalemia?
block the production of aldosterone –> less potassium secretion
what are the biochemical processes to hyperkalemia? (think of 3!)
1) rhabdomyolysis (e,g. crush injuries)
2) acidosis (maintaining electro-neutrality)
3) reduced GFR/renin
what are the main causes of hyperkalemia? (think of 4!)
1) renal impairment (CKD, reduced renal excretion)
2) drugs ( ACEi, ARBs, spironolactone)
3) Addison’s disease (low aldosterone)
4) rhabdomyolysis
5) acidosis
6) type 4 renal tubular acidosis/diabetic nephropathy
what are the 3 main causes of hypokalemia?
1) GI Loss
2) renal loss
3) cellular redistribution
what changes will you see in hyperkalemia?
ECG changes: peaked T -waves
what are the acute dangers of cocaine use?
cardiac dysrhythmias,
acute heart failure
MI
how do you manage a patient with hyperkalemia? (5 parts; include dosage)
1) 10 mL 10% calcium gluconate
2) 50 mL 50% dextrose
3) 10 units of Insulin (with dextrose)
4) nebulized salbutamol
5) treat underlying cause
what do loop diuretics do in the loop of Henle?
block sodium, potassium, chloride reabsorption in the ascending loop which leads to increase sodium delivery to the distal nephron (DCT)
what is the relationship between Na+ and K+ in the kidney?
Na+ absorbed
K+ lost
4 causes of hypokalemia:
1) GI Loss
2) Hyperaldosteronism (excess cortisol)
3) osmotic diuresis
4) insulin, beta-agonists
5) alkalosis
6) renal tubular acidosis type 1 and type 2
what biochemical abnormality does hyperaldosteronism cause?
hypokalemia
what biochemical abnormality does alkalosis cause (think Na, Bicarb, K, Cl…)
hypokalemia
what biochemical abnormality does renal tubular acidosis type 1 & type 2 cause?
hypokalemia
what biochemical abnormality does renal tubular acidosis type 4 cause?
hyperkalemia
what biochemical abnormality does insulin cause?
hypokalemia
what biochemical abnormality does acidosis cause (think Na, Bicarb, K, Cl…)
hyperkalemia
what are the clinical features (presenting symptoms) of hypokalemia?
muscle weakness
cardiac arrthymia
polyuria
polydipsia
what are the clinical features (presenting symptoms) of hyperkalemia?
often asymptomatic (may be weak, nauseous, fatigued…)
if someone presents with polyuria/polydipsia - what biochemical blood tests do you want to look for?
low potassium
high calcium
(cause resistance to effects of ADH)
what screening test would you order in a patient with hypokalemia & hypertension?
aldosterone:renin ratio (would see high aldosterone inhibiting renin; low renin)
what endocrine disorder has a high aldosterone:renin ratio: (high aldosterone, low renin)?
Conn’s syndrome
3 steps of managing a patient with hypokalemia (potassium 3.0-3.5 mmol/L) with doses?
1) oral potassium chloride (2 SandoK tabs TDS, 48 hrs)
2) recheck potassium levels
3) treat underlying cause
2 steps of managing a patient with hypokalemia (potassium <3.0 mmol/L) with doses?
1) IV potassium chloride (max rate 10mmol/hr)
2) treat underlying cause
hyperkalemia is a side-effect of which of the following drugs?
a. Fruosemide
b. Bendrofluoromethazide
c. Salbutamol
d. Ramipril
d. Ramipril (ACE inhibitor)
hypokalemia is a side-effect of which diuretic drug(s)?
thiazide
frusemide
salbutamol
hypokelaemia is a side effect of which of the following drugs?
a. Spironolactone
b. indomethacin
c. perindopril
d. Fruosemide
frusemide
what is the aldosterone - potassium relationship?
aldosterone causes potassium loss
what type of diuretic is spironolactone?
potassium-sparing
what are the causes of hypovolemic hyponatremia? (4)
diarrhea
vomiting
diuretics
salt-losing nephropathy
what are the causes of euvolemic hyponatremia? (3)
hypothyroidism
SIADH
adrenal insufficiency
what are the causes of hypervolemic hyponatremia? (3)
cardiac failure
cirrhosis
nephrotic syndrome
what is the process by which someone becomes hypovolemic hyponatremic?
reduced ECF volume & reduced sodium –> low blood volume stimulates ADH release –> retain water, sodium concentration drops
normal values of Na +?
135 - 145 mmol/L
normal values of K+?
3.5 - 5.0 mmol/L
normal values of urea?
3.0 - 7.0 mmol/L
what tests do you want to do to if someone is euvolemic and hyponatremic?
TFTs
short synacthen test (adrenal insufficiency; acth test)
plasma & urine osmolality (SIADH)
sodium low, potassium high, pigmentation, postural hypotension – name that condition!
Addison’s disease
diagnosis of SIADH:
plasma osmolality LOW
urine osmolality HIGH
no hypothyroidism or adrenal insufficiency
causes of SIADH
brain pathology lung pathology drugs (SSRI, TCA, opiates, PPIs,) tumors surgery
what investigations do you do in suspected diabetes insipidus and why:
serum glucose (exclude diabetes mellitus) serum potassium (exclude hypokalemia) serum calcium (exclude hypercalcemia) plasma & urine osmolality water deprivation test
what does ADH do?
acts on V2 receptors in renal tubular cells in collecting duct, insertion of aquaporin-2
acts on V1 receptors at higher concentration - vasoconstriction (vasopressin)
when does the body release ADH?
- when serum osmolality increases (e.g. don’t drink), release ADH & reabsorb water to bring osmolality down
- low blood volume/low BP (as sensed by baroreceptors)
how does cardiac failure cause hyponatremia (hypervolemic)
reduced CO –> reduced BP –> sensed by baroreceptors –> increased ADH –> increased water retention –> decreased [Na]
how does cirrhosis cause hyponatremia (hypervolemic)
increased NO –> vasodilation –> reduced BP –> sensed by baroreceptors –> increased ADH –> increased water retention –> decreased [Na]
how does hypothyroidism cause hyponatremia (euvolemic)
reduced cardiac contractility –> reduced BP –> sensed by baroreceptors –> increased ADH –> increased water retention –> less [Na]
how does adrenal insufficiency cause hyponatremia? (euvolemic)
low cortisol –> low BP –> more ADH –> more water –> less [Na]
do you give normal saline to someone with SIADH?
NO!
You are adding more water to someone retaining water, causing hyponatremia to drop further. You will make them sicker.
how do you treat hyponatremia from SIADH?
fluid restriction, treat underlying cause
how do you treat someone with hyponatremia that is hypovolemic?
normal saline 0.9%
how do you treat someone with severe hyponatremia?
reduced GCS, at risk of seizures. Need urgent hypertonic saline (2 or 3%). You want to increase it slowly (no more than 8-10 mmol/L in 24 hours).
how do you treat someone with euvolemic hyponatremia?
fluid restriction, treat the cause
what is the most important risk in correcting hyponatremia?
must NOT be corrected by >8-10 mmol/L in 24 hours due to risk of osmotic demyelination (Central Pontine Myelionlysis)
what happens in central pontine myelionlysis (osmotic demyelination)?
quadriplegia, dysarthria, dysphagia, seizures, coma, death – all 2-6 days after treatment
endothelial shrinkage –> disrupted BBB –> cytotoxic complements can penetrate BBB
if water restriction is insufficient, what drugs can be used to treat SIADH?
demeclocycline (causes ADH resistance, monitor U&Es)
tolvaptan (V2 receptor antagonist)
what are the causes of hypernatremia?
loss of water: GI Loss (diarrhea/vomiting) if not replacing with water, or because not enough ADH (e.g. diabetes insipidus)
how do you treat hypernatremia? (4 steps)
1) fluid replacement (NOT with normal saline)
- -> 5% dextrose
2) correct any ECF volume depletion (with 0.9% saline)
3) serial 4 hrly Na level checks
4) treat underlying cause
suppose a patient has significant GI losses and
a) are drinking water
b) are not drinking water
will they have hyponatremia or hypernatremia?
a) hypo
b) hyper (not replacing GI losses)
someone comes into A&E unconscious, known diabetic. Cannot swallow. What are the steps of treatment? (3 steps)
1) IV Access
2) 50ml of 50% glucose or 100 mls of 20% glucose
3) if difficult to do any of the above, consider IM/SC 1mg glucagon
what are the 4 steps the body naturally does when glucose is running low and in what order?
1) reduce peripheral uptake of glucose
2) increase glycogenolysis
3) increase gluconeogenesis
4) increase lipolysis
name the oral hypoglycemic drugs that can be given for diabetes TMD2 (3 classes)
sulfonylureas
GLP-1 agents
meglitinides
name the syndrome that can occur when DM Type 2 is concurrent with Addisons and what is it?
polygladular autoimmune syndrome
hypos common
what is c-peptide?
product of insulin cleavage (takes longer to clear in the blood system)
name some causes of hypoglycemia with low insulin, low C-peptide levels?
fating/starvation critical illness strenous exercise hypopituitarism liver failure anorexia nervosa (any appropriate response to hypoglycemia)
which metabolic disorders can cause neonatal hypoglycemia? what will insulin & C-peptide levels be?
suppressed insulin, suppressed C-peptide, low ketones –>
FAOD
GSD type 1
MCADD
Carnitine disorders
name that cause: neonatal hypoglycemia, raised fatty acids, normal/low ketones
Fatty acid defects metabolic issues (eg MCADD)
name that cause: neonatal hypoglycemia, normal/low fatty acids, normal/low ketones
hyperinsulinism
hypopituitarism
name that cause: neonatal hypoglycemia, with raised FFA, raised ketones.
glycogen storage issues
drug toxicitiy (if lactate high)
glucocorticoid deficiency
septicemia
what are the 3 causes of pancreatic islet cell hyperplasia?
infant of a diabetic mother
Beckwith Weidemann Syndrome
Nesidioblastosis
spot diagnosis: low glucose, high insulin, high C-peptide, having fits
endogenous insulin production if high c-peptide. Thus, insulinoma or sulphonylurea abuse.
spot diagnosis: decreased glucose, increased insulin, decreased c-peptide
factitious (extra external )insulin
spot diagnosis: decreased glucose (persistent despite glucose infusion), decreased insulin, decreased c-peptide, decreased FFA, ketones negative
non-islet cell tumor hypoglycemia (paraneoplastic syndrome from secretion of IGF2)
6 aspects of normal liver function:
intermediary metabolism protein synthesis xenobiotic metabolism horomone metabolism bile synthesis reticulo-endothelial system
what 3 types of chemical modification occurs in the liver?
P450 enzyme system
acetylation/de-acetylation
redox
what 3 types of hormones are metabolised in the liver and how?
vitamin D - hydroxylation
steroid hormones - conjugated/excreted
peptide hormones - catabolised
what is the purpose of Kupffer cells in the liver?
clearance of infection/LPS
antigen presentation
immune modulation (cytokines)
what are the immune modulating cells of the liver?
Kupffer cells
what are the two parts of the liver that make up reticuloendothelial function?
Kupffer cells
EPO
what 6 tests fall under LFTs?
ALT AST ALP GGT PT AFP
what 4 LFT tests show serum markers of liver cell damage?
ALT, AST, ALP, GGT
what two LFT tests show marker of function?
albumin
PT
when are ALT and AST raised?
when hepatocytes die -
AST specifically in alcoholic liver disease, cirrhosis
when is GGT raised?
in chronic alcohol use; bile duct disease; hepatic metastasis
when is ALP raised?
markedly elevated if obstructive jaundice or bile duct damage, less elevated in viral hepatitis or alcoholic liver disease
when is albumin low?
low production, loss (gut, kidney), sepsis or ‘3rd spacing’
is unconjugated or conjugated bilirubin raised in pre-hepatic causes of jaundice?
pre-hepatic cause = hemolysis so, unconjugated raised
is unconjugated or conjugated bilirubin raised in hepatic causes of jaundice?
hepatic causes: genetic, hepatitis, drugs
both unconjugated & conjugated are raised
is unconjugated or conjugated bilirubin raised in post-hepatic causes of jaundice?
post- hepatic causes are bile duct obstruction, drugs
conjugated bilirubin is raised in post-hepatic
what dye tests are used to measure hepatic blood flow and excretory capacity of the liver?
indocyanine green
bromsulphalein
what breath tests are used to measure reisdual functioning liver cell mass?
aminopyrine
galactose (carbon 14)
what is the purpose of doing ALT/AST/GGT/ALP?
help to locate site/cause of inflammation or cell damage in liver
what is the purpose of albumin/PT tests?
represent the ‘synthetic’ function of liver, prognostically important in acute and chronic liver disease
List the six anterior pituitary hormones & what stimulates their release:
GH - controlled by GHRH prolactin - controlled by TRH TSH - controlled by TRH LH/FSH - controlled by LHRH ACTH - controlled by CRH
what will patients present with in pituitary failure?
galactorrhea/amenorrhea (in females)
subtle/nothing often seen in males
when is a pituitary tumor termed to be macroadenoma?
> 1cm
what complication of a large pituitary tumor should you watch out for?
bitemporal hemianopia
spot diagnosis: 30 year old with galactorrhea, never had sexual intercourse, prolactin 30,000
large tumor, prolactinoma
Pituitary Function testing:
LHRH + TRH + stress (hypoglycemia) administered –> then measure ACTH/GH, cortisol
should increase cortisol –> ACTH and GHRH –> GH
what is a ‘Triple Test’ with regards to pituitary?
hypoglycemia (must be <2.2mM glucose)
TRH
LHRH
should stimulate TSH, prolactin, ACTH, GH if no pituitary failures
If someone is in complete anterior pituitary failure - what order does replacements need to be? (5 steps)
1) hydrocortisone
2) thyroxine
3) estrogen
4) GH replacement
5) treat prolactinoma with dopamine agonist (bromocriptine or cabergoline)
what effects do non-functioning pituitary adenomas have?
press on stalk causing pituitary failure cause hyperprolactinemia
adrenal failure:
fludrocortisone, not hydrocortisone
what test can we use to confirm acromegaly?
glucose tolerance test (should suppress GH to zero) or IGF1
what is the best treatment for acromegaly?
octreoide or pituitary surgery
what does the zona fasciculata of the adrenal make?
cortisol
what does the zona glomerulosa make in the adrenal gland?
aldosterone
spot diagnosis: very high TSH with low free T4
primary hypothyroidism
spot diagnosis: high TSH, high free T4
TSH producing pituitary adenoma
what deficiency is suggested by hyponatremia, hyperkalemia?
deficiency of mineralocorticoid (aldosterone)
spot diagnosis: low sodium, high potassium, low glucose
adrenal failure –> Addison’s disease
what is Schmidt’s Syndrome?
Addison’s disease + Primary Hypothyroidism
how do you test for Addison’s disease?
short synacthen test (ACTH); measure cortisol and ACTH before and after injection. Check at 30 minutes, 60 minutes. If don’t rise in cortisol, then positive
possible adrenal masses:
phaeochromocytoma (adrenaline secreting)
Conn’s syndrome (aldosterone secreting)
Cushing’s syndrome (cortisol secreting)
phaeochromocytoma treatments:
urgent - alpha blockers (phenoxybenzamine)
then add beta-blockers,
then long-term - surgery
spot diagnosis: hypertension, low potassium, raised aldosterone, suppressed renin
Conn’s syndrome
in a hypertensive with low potassium, what do you need to think of?
aldosterone (raised) and renin (suppressed) via Conn’s syndrome
spot diagnosis: hypertensive woman with bruising, sodium borderline high, potassium low, renin low, aldosterone low
Cushing’s syndrome
what tests do you do for cushing’s?
9 am cortisol (meant to be high)
12 am (midnight) cortisol (meant to be low)
dynamic test: dexamethasone suppression test
what are potential causes of cushing’s syndrome? (4)
1) oral steroids treatment for something else
2) cushingoid tumor (ectopic ACTH, 5%)
3) pituitary dependent Cushing’s disease (in 85% not on steroid)
4) adrenal adenoma (10%)
what is the normal result (non pathological) of dexamethasone suppression test?
should fall to undetectable levels
spot diagnosis: low dose dexamethasone does not suppress but high dose dexamethasone does suppress
pituitary dependent Cushing’s disease (do pituitary MRI for microadenomas)
spot diagnosis: low dose dexamethasone does not suppress, high dose dexamethasone does not suppress
ectopic ACTH, or lung cancer (do CXR to look for an ectopic source)
which of the following commonly presents with depression?
a) hyperkalemia
b) hypokalemia
c) hypercalcemia
d) hypocalcemia
e) uraemia
c) hypercalcemia
what does hypocalcemia?
irritability, fits, tetany
spot diagnosis: abdominal pains and frank blood
renal stones
what are the two reasons why enzyme levels may increase?
cell necrosis/damage & leaky membranes
where is alk phos (ALP) found?
in high concentrations in liver, bone, intestine, placenta
causes of raised ALP (two bone, two liver)
bone: pagets, osteomalacia
liver: cholestasis, cirrhosis
what are the 3 forms of CK (creatine kinase) and where are they found?
CK-MM: skeletal muscles
CK-MB: cardiac muscles (1&2)
CK-BB: brain (minimal even in severe brain damage)
causes of raised CK (creatine kinase)?
Muscle damage due to any cause Myopthy e.g. Duchenne muscular dystrophy (>10xULN) Myocardial Infarction (>10xULN) Severe exercise (5xULN) Physiological – Afro-Caribbean (<5xULN) Polypharmacy High-dose statin
what are the 3 cardiac markers of MI?
CK-MB
Cardiac Troponin
Myoglobin
what is the relation between PTH and calcium?
inverse - if calcium goes up, PTH is no longer produced
spot diagnosis: high calcium, ‘normal’ PTH, many fractures
primary hypoparathyroidism
inappropriately normal PTH
spot diagnosis: high calcium, low PTH, many fractures
cancer (mets)
what are 40-60% of renal stones composed of?
calcium oxalate or phosphate (will be radioopaque)
what are staghorn renal stones made of?
struvite (magnesium ammonium phosphate)
emergency treatment for hypercalcemia?
fluids (0.9% saline) -4L in 24 hours via IV access
induce diuresis with furosemide
if patient has known cancer –> IV pamidronate 30-60mg
non-urgent treatment for hypercalcemia?
keep hydrated, avoid thiazides. Use surgery (parathyroidectomy)
spot diagnosis: BHL on CXR, suppressed PTH, hypercalcemia
sarcoidosis
treatment - high dose steroids
how does sarcoidosis cause high calcium?
unregulated macrophages in the lungs producing 1-alpha hydroxylase and activating vitamin D. This causes more absorption of the calcium.
name 4 causes of pre-renal AKI
Hypotension
Oedematous states
Selective renal ischaemia
Drugs affecting glomerular blood flow
how do we classify` AKI?
pre-renal
renal
post-renal
T or F: Pre-Renal AKI is not associated with structural renal damage and responds immediately to restoration of circulating volume
T
what is the hallmark of post-renal AKI?
obstruction to flow in the kidneys
list 3 possible causes of post-renal AKI:
Ureteric obstruction (bilateral) Prostatic / Urethral obstruction Blocked urinary catheter
T or F: Immediate relief of obstruction (post- renal AKI) restores GFR fully, with no structural damage
T
what is the hallmark of intrinsically renal AKI?
abnormality of any part of nephron
list 4 possible causes of renal AKI:
Vascular Disease eg vasculitis
Glomerular Disease eg glomerulonephritis
Tubular Disease eg ATN
Interstitial Disease eg analgesic nephropathy
list 3 causes of direct tubular injury in kidneys:
drugs /contrast - exogenous toxins
myoglobin, Igs - endogenous toxins
ischemic
what two chemical measures do we have for the severity of an AKI?
creatinine & urine output
what is a normal level of GFR?
> 90
what are 6 causes of CKD?
- Diabetes
- Atherosclerotic renal disease
- Hypertension
- Chronic Glomerulonephritis
- Infective or obstructive uropathy
- Polycystic kidney disease
T or F: Whereas AKI is irreversible, CKD is reversible
F (opposite)
list 5 consequences of CKD:
1]Progressive failure of homeostatic function
- Metabolic Acidosis (treat w/oral Na bicarb)
-Hyperkalaemia (ECG Changes - wide QRS with peaked T wave)
2]Progressive failure of hormonal function
-Anaemia (Normochromic, normocytic )
-Renal Bone Disease (hyperparathyroidism)
3]Cardiovascular disease
-Vascular calcification
-Uraemic cardiomyopathy (LV hypertrophy, dilatation, dysfunction)
what test confirms Diabetes Mellitus Type 2?
Fasting plasma glucose > 7.0mM
2 hour GTT plasma glucose > 11.1 mM
Hba1c > 6.5% (currently in WHO discussions)
3 causes of metabolic alkalosis:
sodium bicarbonate ingestion
loss of H + (vomiting)
hypokalemia
what is the relationship between hypokalemia and alkalosis?
hypokalemia & alkalosis cause each other. the process of not having enough K+ into cells means that H+ goes into cells - thus raising the pH and causing an alkalosis. the presence of H+ brings K+ into cells, thus causing a hypokalemia
what is the relationship between sodium and potassium in the collecting duct? (think hypokalemia… hyponatremia…)
Two separate processes.
Sodium is controlled in the distal collecting duct of the kidney by aldosterone. When aldosterone is increased, SODIUM absorption is increased as is H2O (via ADH). ADH levels and water then determine sodium concentration.
i.e. by the same pathway, SIADH would lead to more water absorption and decreased sodium concentration
Meanwhile, potassium is controlled by the osmotic and electrochemical gradients of the DCT. Thus when aldosterone brings sodium out, the lumen is more negative and potassium moves from ICF to ECF in the lumen to make it more positive. Potassium fixes the gradient. Osmotic diuresis also has an effect on the potassium - as glucose will take out H20 and Potassium with it. .
what is the most common cause of primary hypercholesterolaemia?
familial hypercholesterolaemia, due to loss of function mutations of the LDL receptor and apoB-100 genes or gain of function mutations of the PCSK9 gene
how does one have primary HYPOcholesterolaemia?
Primary hypolipoproteinaemia (hypolipidaemia) is always of genetic origin and includes abetalipoproteinaemia, due to recessively inherited mutations of microsomal triglyceride transport protein (MTP); familial (homo or heterozygous inheritance of apoB gene mutations), or Tangier disease
where is cholesterol (i.e. lipid) transport in the plasma volume?
- LDL carries 70% of cholesterol
- HLDL/VLDL carry about half of the remainder each
in comparison, where is the most of the triglyceride transport in plasma volume?
- VLDL alone carries about 55% of the body’s triglycerides
- LDL carries about 30%
what is the ‘life cycle’ of the triglyceride and cholesterol in the blood?
-bile salts and cholesterol picked up from bloodstream by chylomicrons –> move remnant FFA to liver –> the liver converts VLDL into LPL, IDA, FFA, adipose tissue. The adipose tissue can be brought back to the liver with FFA/Albumin combined
when do tendon xanthomas present?
hypercholesteremia
how does H+ come out into the kidneys?
- DCT
- when Na + comes out, exchange for H+
- bicarbonate regenerated and comes out into the body
- Bicarbonate reabsorption also in the proximal tubule
how is CO2 regulated in the body?
- CO2 is produced in protein, carb, and fat metabolism and excreted from the lungs
- CO2 excretion controlled by chemoreceptors in the hypothalamic respiratory centre
- CO2 transported in the blood with water: CO2 + H20 –> H + HCO3
- the bicarbonate is used for balance, the H+ combines with hemoglobin
what happens in the body in metabolic acidosis?
- increased H+ (decreased pH) with decreased bicarbonate
- either because we’ve made too much H+, are not excreting enough H+ or lost too much bicarbonate
- -> DKA (too much), Rental Tubular Acidosis (can’t excrete enough), intestinal loss (losing bicarb)
- this stimulates the respiratory center to compensate (as seen by fall in PCO2 - rise in RR)
what is acronym ROME referring to in acid-base balance?
Respiratory Opposite
Metabolic Equal
looking at PCO2 & pH and the direction out of normal values that it lies (eg metabolic acidosis - pH dec, and PCO2 dec)
what happens in the body in respiratory acidosis?
Increased CO2 –> increased H+ –> decreased pH, increased HCO3
Causes: poor lung perfusion, poor air intake, impaired gas exchange (ie. too much CO2 kept in); eg- pneumonia, copd
Metabolic compensation: increased renal excretion of H+ combined with generation of bicarbonate (leading to inc. bicarb and CO2 levels remaining) –> pushes from ‘acute’ to ‘chronic’ resp acidosis
what happens in the body in metabolic alkalosis?
*decreased H+ –> increased pH; increased bicarb.
Causes - either ingesting too much biarcbonate; losing too much H+ (GI loss) or decreased K+ (as K+ ECF means H+ ICF for electrochemical gradient)
Compensated –> respiratory center inhibited so rise in pCO2
which acid-base imbalance is hypokalemia associated with?
metabolic alkalosis:
A low K+ concentration outside the cell will lead to the raising of the pH of the fluid outside the cell because of H+ ions from outside the cell being exchanged for K+ ions from inside the cell. (lower H+ = higher pH)
what happens in the body in respiratory alkalosis?
-happens when the body is getting rid of CO2 too quickly, so that shifts the balance of the H+ + HCO3 - H2C03 CO2 + H2O so that H+ and HCO3- must also decrease
Causes: hyperventilation (eg panic attack)
Metabolic compensation:
If prolonged resp. alkalosis this leads to decreased renal excretion of H+ and less bicarbonate generation (pCO2 low, bicarb low)
define positive and negative predictive value, i.e. PPV and NPV:
PPV - True positive / Total positive
NPV - true negative/ total negative
name some tests on Guthrie card for newborns -
PKU from 1969 Congenital hypothyroidism added 1970 Sickle cell disease added 2006 Cystic fibrosis Homocystinuria Maple Syrup Urine Disease MCADD \+ urea cycle, AA, fatty acid oxidation, organic aciduria disorders
what sort of presentation would make you wonder if somebody has a uric cycle disorder?
RED FLAGS
- vomiting w/o diarrhea
- respiratory alkalosis
- hyperammonemia
- neuro: encephalopathy, coma, confused
- avoidance/change in diet causing these effects
how would you treat someone presenting with a uric acid cycle disorder?
- means that they are unable to deal with ammonia in the body, which is toxic when it builds up
- treat by reducing ammonia produced and removing the ammonia present
what is the inheritance & pathophysio of uric acid cycle disorders?
- usually Auto Recessive (except OTC def which is x-linked)
- 7 possible defects
- all lead to hyperammonemia
when would you suspect someone of having an organic aciduria?
Adult/Child:
- Hyperammonaemia with metabolic acidosis and high anion gap
- cheesy/sweaty smell
- recurrent episodes of ketoacidotic coma, Reye syndrome
Neonate:
- abnormal smell (cheesy/sweaty)
- lethargy
- feeding problems
- hypocalcemia
- neutropenia/pancytopenia
- truncal hypotonia / limb hypertonia, myoclonic jerks
what is Reye syndrome?
Presents with vomiting, lethargy, increasing confusion, seizures, decerebration, respiratory arrest
Triggered by: e.g. salicylates, antiemetics, valproate
how would we test for Reye syndrome?
Plasma/blood ammonia Plasma / urine amino acid Urine organic acids Plasma/blood glucose and lactate Blood spot carnitine profile - will stay abnormal in remission
when do we suspect that somebody may be presenting with a fatty acid oxidation abnormality (eg MCADD)?
Hypoketotic hypoglycaemia
Hepatomegaly
Cardiomyopathy
(Bloods will show abnormal blood ketones, acylcarnitine profile, and urine organic acids)
what is the most common carbohydrate metabolism disorder?
galactose-1-phoshate uridyl transferase (Gal-1-PUT) is the most severe and the most common. It will cause liver & kidney disease
how do carbohydrate metabolism disorders present?
-D&V
-conjugated hyperbilirubinemia
-hepatomegaly
-hypoglycemia
-sepsis
Almost always in neonate (w/o treatment won’t become adult). bilaterial cateracts as kids from carb abnormal metabolism SE
Besides digesting and metabolizing carbohydrates, we also need to store them appropriately - how would someone with a glycogen storage disorder present?
Hypoglycaemia Lactic acidosis Neutropenia Hepatomegaly Nephromegaly
what is MELAS and how does it present?
MELAS (‘mitochondrial encephalopathy, lactic acids and stroke-like episodes’)
- mitochondrial disorder
- usually presents in ages 5-15
- lactic acid in blood
- stroke-like episodes
- mito. encephalopathy
what is Kearns-Sayre disorder and how does it present?
-mitochondrial disorder
-usually presents over the age of 15
Presents with: Chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia
what tests do you want to run when you suspect a mitochondrial disorder?
- Elevated lactate (alanine) – after periods of fasting, before and after meals
- CSF protein (raised in Kearns-Sayre syndrome)
- CK
- Muscle biopsy
When we store glycogen and then utilize it later, we need to glycosylate. How might someone with a glycosylation disorder present?
-Multisystem disorders
-associated with cardiomyopathy, osteopenia, hepatomegaly
E.g. CDG type 1a - abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction.
Check: blood serum transferrin glycoforms
If a perioxosomal disorder is not detected at birth, how might neonate present?
peroxisome - Metabolism of very long chain fatty acids and biosynthesis of complex phospholipids
- severe muscular hypotonia
- seizures
- hepatic dysfunction (including hyperbilirubinaemia
- retinopathy often with sensorineural deafness
- mental deficiency
X-ray: Bony changes involve a large fontanel which late, osteopenia of long bones, and often calcified stippling
Profile: very long chain fatty acids in neonate/child’s blood
Lysosomal storage diseases present in a very severe fashion at a very young age. What would the infant be suffering with?
*organomagaly (connective tissue, solid organs, cartilage, bone and nervous tissue)
*consequent dysmorphia and regression
May be detected on urine - mucopolysaccharides / oligosaccharides
Treatment requires bone marrow transplant.
what is the ‘classic’ presentation of mitochondrial disorders?
chronic muscle weakness with hyperlactataemia.
at what age do glycogen storage disorders usually present?
3-6 months
what are common disorders seen in low birthwright neonates?
- Intraventricular haemorrhage
- Patent ductus arteriosus
- Central pontine myelinolysis
- Bronchopulmonary dysplasia (RDS)
- necrotising enterocolitis
in neonates presenting with jaundice, what are we most worried about?
Kernicterus may develop if total bilirubin exceeds 340 mol/l in the term neonate; this
what happens in neonates with hypercalcemia?
High foetal ionised calcium concentration causes suppression of the foetal parathyroid. Transient post-natal hypocalcaemia is the norm.
what can cause hypernatremia in neonate?
beyond 2 weeks of age - usually dehydration
before 2 weeks of age -often due to drugs, skin loss of ECF, RR, not having as developed kidneys…
what can cause hyponatremia in the neonate?
CAH - congenital adrenal hyperplasia. Increased levels of 17-OH-progesterone and a blockage from creating aldosterone/cortisol….
- hyponatremia
- hyperkalemia
- marked dehydration
- hypoglycemia
- females have ambiguous genitalia from birth
what can cause neonatal jaundice in under 24 hours of age?
Always pathological -
Haemolytic disease (ABO, rhesus etc)
G-6-PD deficiency
Crigler-Najjar syndrome
what are some causes of conjugated hyperbilirubinemia, presenting with prolonged neonatal jaundice?
hepatitis sepsis inherited metabolic disorders biliary atresia choledocal cyst polysplenia, ascending cholangitis in TPN
what is the biochemistry in osteopenia of prematurity in neonates?
Calcium: within reference range
Phosphate <1mmol/L
Alk phos >1200 U/l ( 10 x adult ULN)
Vitamin D rarely measured in neonate
how does the hypothalamic-THYROID axis work?
*TSH controls iodine uptake and conversion by thyroid to iodide. This iodinates tyrosine which joins with itself to form thyroxine - T3/T4
- hypothalamus releases TRH to stimulate pituitary to release TSH which stimulates the above in thyroid. Thyroid releases the T3/T4 … converted by type 1 monodeiodinase which makes it tri-iodothyronine and causes effects
- The T4 provides negative feedback to TSH from pituitary which provides negative feedback to hypothalamus
what is the biochemistry in hypothyroidism?
Since T4 is not eliciting negative feedback effect on pituitary - TSH is high.
T4/T3 is low - not producing enough in hypothyroidism.
Can use TRH stimulating test to distinguish if cause is pituitary or hypothalamus. If TRH stimulating test leads to increase in TSH - problem is in the hypothalamus not producing TRH. If it does NOT lead to increase - TSH cannot be stimulated in pituitary… so pituitary is the problem
what happens to thyroid biochemistry when somebody is severely ill?
‘sick euthyroid’
TRH: normal
TSH: high-normal (trying to stimulate thyroid), later on will decrease
T3/T4: low
what side effects do we worry about if somebody with previous hyperthyroidism is placed on PTU or carbimazole?
Rare SE of agranulocytosis (<1%). Warn to stop if sore throat or fever and check FBC. Routine tests of no value
what are the two types of differentiated thyroid carcinomas and how do we investigate thyroid cancer?
Papillary thyroid cancer
Follicular thyroid cancer
Give thyroglobulin - ought to suppress TSH. If continues to express TSH – must be malignant cells
who gets medullary carcinoma of the thyroid and what investigative test can help determine it?
MTC can be sporadic, familial, associated with MEN
- C cells of thyroid
- CEA antigen test
what is lesch-nyan syndrome?
a complete deficiency of HGPRT enzyme involved in purine catabolism.
While babies present as quite normal at birth, they quickly develop to have developmental delay apparent by 6 months and choreiform movements by 1 year. They have mental retardation in growth and uncontrollable self-mutilation urges in childhood/adolescence. Bloods - Hyperuricaemia
what is the pathophysiology of gout?
- Monosodium urate crystals build up into exquisitely acutely painful tophi on joint (red,hot, swollen)
- post-pubertal males, post-menopausal females
- Usually ‘big toe joint’ (1st MTP)
- Can be acute (Podagra) or chronic (Tophaceous)
the way you manage an acute gout flare-up is different from chronic condition. What is the management of acute gout?
-NSAIDs
-Colchicine
-Glucocorticoids
Do NOT attempt to modify plasma urate concentration
what is the management of chronic gout (between flare ups)
allopurinol (unless on Azathioprine!)
hydration/dietary changes
how do we tell the difference between gout and pseudogout?
gout- Monosodium urate crystals; negatively birefringent
pseudogout- calcium pyrophosphate dihydrate crystals; positively birefringent ( along axis)
what is pseudogout and who gets it?
- osteoarthritis patients
- self limiting in 1-3 weeks (no need for chronic allopurinol, etc)
- calcium pyrophosphate crystals (not urate)
