Chemical Pathology Flashcards
What is the chemical structure of porphyrin molecules?
It is a cyclic compound with 4 pyrrole rings connected by methenyl bridges.
The 4 nitrogen molecules at the centre can bind metal (iron) ions.
What are the symptoms of porphyria?
Skin lesions (exposure to light causes them to release free radicals = itching and rash) - not in AIP
Neurovisceral sx - ALA and PBG in excess
How are porphyria’s classified?
1) According to the organ the metabolites accumulate the most in.
O Erythtopoeitic = CEP and EPP
O Hepatic = AIP, HC, VL, PCT
2) acute/non-acute
O Acute = AIP, HC, VP
O Non-acute = PCT, CEP, EPP
What are the phases of acute porphyria and what do these said phases include?
Latent phase - enzyme defect
Acute phase - excessive ALA and PBG production
How do you treat an acute porphyria attack?
Supportive - fluids and electrolyte balance, IV haem arginate, pain relief, anti-emetics, adequate carb intake
What is an acute porphyria attack commonly mistaken for and why is this dangerous?
Acute abdomen, the pt will be taken to theatre and they will die
Which enzyme is deficient in Congenital erythropoietic porphyria?
Uroporphyrinogen III cosynthase
What are the clinical features of congenital erythropoeitic porphyria?
O Severe photosensitivity with scarring in infancy
O alopecia + hypertrichosis
O brownish/ pink teeth → red under uv light
O haemolytic anaemia
What tests do you request if you suspect congenital erythropoeitic porphyria and what results would you expect?
Urine: uro> copro I
Faeces: copro> proto
RBC’s: uro + copro
What enzyme is deficient in erythropoeitic protoporphyria?
Ferrochelatase
How does erythropoeitic protoporphyria present?
O mild anaemia
O porphrin gallstones
O liver cirrhosis and liver failure
O skin lesions (milder than CEP)
What tests would you request for EPP and what results would you expect?
Faeces: proto > copro
RBC’s: proto
What enzyme is deficient in Porphyria cutania tarda?
Uroporphrinogen decarboxylase
What are the clinical features of porphyria cutania tarda?
Oskin lesions only
O hypertrichosis
Ohyperpigmentation
What may provoke sx in PCT?
Ooestrogens
Oalcohol abuse
O Iron overload
(They learn to avoid these)
What would you test for in suspected pct?
Urine: uro>copro
Fecal: isocopro
What are some clinical features of an acute porphyria attack?
O git: abode pain, constipation, vomiting
O CVS: ↑ HR, hypertension
O CNS: convulsions, depression, psychosis
O peripheral neuropathy: pain, stiffness, weakness, numbness, pins + needles
Predisposing factors of porphyria acute attack
O anaesthesia
O alcohol
O oestrogens
O premenstrual
O carbamazepines
O sulphonamides
O stress / infection
What enzyme is deficient in acute intermittent porphyria?
PBG deaminase
Symptoms of AIP
Mostly asymptomatic
Neurovisceral sx in acute attack
What tests would you request in suspected AIP and expected? Results
Latent phase: ALA<PBG
Acute phase: ALA<PBG, uro from PBG
What enzyme is deficient in varigate porphyria?
Protoporphrinogen oxidase
What clinical sx of VP?
Latent phase: Asymptomatic / skin lesions
Acute phase: Neurovisceral sx
What tests would you order for VP?
O urine:
> acute - ALA, BPG, copro> uro
Ofaecal:
> acute- proto> copro
> latent -proto> copro
What enzyme is deficient in hereditary coproporphyria?
Coproporphyrinogen oxidase
What is the clinical presentation of hereditary coproporphyria?
OLatent phase: rarely skin lesions
OAcute phase: neurovisceral sx
What tests would you order and what results would you expect in hereditary coproporphyria?
O urine:
> acute - ALA, PBG, copro > uro
O fecal:
> latent- copro> proto
> active - copro> proto
What is the cause of 2° porphyria?
When its not due to an enzyme deficiency but something else causing excess porphrin production
O lead toxicity - inhibits ALA dehydrates, ferochelatase, coproporphrinogen oxidase
O liver disease
O chronic kidney failure
O bleeding stomach/ duodenum
O toxin exposure
What is the minimum volume of water that needs to be excreted by the kidneys for adequate waste removal?
500ml/24hrs
What is the physiological response to water loss?
O vasopressin release = water retention by kidneys
O hypothalamic thirst centre stimulated
O water ICF →ECF down conc. Gradient
What systems are responsible for sodium and water homeostasis?
RAAS
ADH/Vasopressin
How is water and sodium regulated?
①↓ effective blood volume
>↓ CO
> systemic vasodilation (sepsis)
>↓ECF (blood loss)
② vasopressin released → kind absorb water
③↑ sympathetic NS
> systemic vasoconstriction →↑BP
> arterial vasoconstriction →↓GFR =↑ water retained = blood volume
④RAAS activation = ↑ sodium + water retention
What causes pseudohyponatraemia?
Excess lipids/proteins
What is important to remember when correcting hyponatraemia?
Acute = emergency → treat rapidly (MEDICAL EMERGENCY)
Chronic = increase the sodium slowly as the body has adapted to this level
What are complications of acute hyponatraemia?
Cerebral oedema ( water goes intracellularly as ↓ extracellular sodium )
> N & V
> confusion
> coma
> death
How do you diagnose syndrome of inappropriate ADH?
Diagnostic criteria: (exclude other causes of hyponatraemia )
o hyponatraemia and low serum osmolality
o normal ECF volume
o urine not excessively diluted ( osmolality>100 )
o normal kidney, adrenal, thyroid fxn
o pt not on any drug that may cause hyponatraemia
What investigations needed in hyponatraemia?
O blood
> glucose
> lipids
> total protein
> potassium
> osmolality
> urea + creatinine
> TSH + T4
> haematocrit
O urine
> sodium
> osmolality
What are the causes of hyponatraemia?
O hyperglycaemia
O too much iv fluids
O congestive heart failure
Ocarcinoma of bronchus
Odiuretic therapy
When is hypernatraemia unlikely to occur?
O pts with access to water
O ability to drink
O intact thirst mechanism
O alert
How does the brain adapt to high/ low levels of sodium?
Hypernatraemia:
O brain produces idiogenic osmolytic molecules intracellularly to prevent water moving extracellularly
Hyponatraemia
O brain secretes idiogenic molecules to extracellular space to prevent watermoving intracellularly = cerebral oedema
What are some causes of hypokalaemia?
① intracellular shift ( alkalosis, insulin admin, refeeding syndrome,↑ k excretion )
② renal causes ( diuretics, AKI, tubular disorders )
③ extravenal ( diarrhoea, vomiting )
④↓ intake
What causes hyperkalaemia?
①spurious
> haemolysis
> EDTA contamination
> old sample
② transcellular movement
> acidosis
> tissue damage
>rhabdomyelitis
> k-sparing diuretics
>AKI +CKD
> mineral corticoid deficiency
③ excessive intake
> slow k
> parental infusion
What are some functions of calcium?
Obone + teeth structure
O2nd messenger system
O neuromuscular junction - Release neurotransmitters
O muscle contractions
O cofactor in coagulation factors
How do you calculate adjusted calcium?
① if [ alb ] < 40: [ca] + 0,02 X ( 40 - [alb] )
② if [alb] > 45: [ Ca] - 0,02 X( [ alb]- 45 )
What are the indications for measuring ionized calcium?
O hypercalcaemia of malignancy
O severe pancreatitis
O chronic kidney disease + dialysis
O transplantation
O massive transfusion
O extracorporeal transfusion
O critical illness
O hyperparathyroidism
O post-op parathyroïdectomy
What do you have to keep in mind when taking blood for ionized calcium measurement?
①stasis free blood taking method, fill tube maximally
② to the lab in 30mins so that centrifugation can occur within 1 hr
③ avoid removing test tube cap ( co2 into tube ↑ acidity = change ionized calcium levels )
④ keep sample on ice
What hormones regulate calcium homeostasis?
O PTH
O calcitonin
O vitamin D
What are the affects ofPTH On its target organs?
①bone
> ↑ osteoclast activity =↑ [Ca] plasma
> rapid release calcium
② kidneys
> ↑ calcium reabsorption
>↓ phosphate reabsorption
>↓ bicarb reabsorption = acidosis
What are the effects of calcitonin?
O inhibits osteoclast activity:↓ calcium reabsorption
What is fibroblast growth factor 23 (fgf 23 ) and what does it do?
It is a phosphotonin. it is secreted by osteoclasts when there is a ↑ phosphate + calcitriol and causes the kidneys to excrete more phosphate = phosphaturia. ( inhibits cotransporter )
= ↓ serum calcitriol and phosphate
Causes of hypercalcaemia
OPrimary hyperparathyroidism
O malignancy
O sarcoidosis
O Tb
O thyrotoxicosis
O persistent hyperparathyroidism after rents transplant
O vitamin D toxicity
What are the clinical features of hypercalcaemia
O git
>N&V
> abdominal pain
> constipation
> pancreatitis
O CVS
> ECG changes (↓ qt interval,↑ Pr interval)
> arrhythmias
O neuropsychiatric
> confusion
> lethargy, depression
> hypotonia, hyporeflexia, muscle weakness
O renal
> polyuria, polydipsia
> Kidney stones
>↓ GFR
Causes of hyperphosphataemia
O vit D intoxication
O chronic kidney injury + renal insufficiency
O hypoparathyroidism
O excess intake
O catabolic States eg: tumor lysis syndrome
What are complications of hyperphosphataemia?
O inhibits 1 alpha hydroxylation of 1,25 OH D in the kidneys
O phosphate may combine with calcium (opposite charges) → metastatic calcium deposits in tissues + hypocalcaemia
Management of hyperphosphataemia?
Treat the underlying cause
Phosphate binders
What are the causes of hypophosphataemia?
O↓ absorption ( malabsorption, vomiting, phosphate binding agents )
O redistribution ( DKA , resp alkalosis, enteral feed with inadequate phosphate )
O ↓ excretion via kidneys ( hyperparathyroidism)
Clinical effects of hypophosphataemia?
O mild sx
O it severe - muscle weakness (ATP is phosphate dependent)
O chronic hypophosphataemia = rickets, osteomalacia
Presentation of hypomagnesaemia?
O muscle weakness
O arrhythmias
O tetany
O ataxia
O delirium
O convulsions
O agitation
Causes of hypomagnesaemia?
O PPI’s
O diuretics
O malabsorption
O refeeding syndrome
O cirrhosis
O alcoholism
O drug toxicity
What are the dangers of hypermagnesaemia
O > 7,5 mmol/dl, can cause resp paralysis + cardiac arrest
On the other hand, can be useful to prevent bronchospasm in ICU pts ( btw 3-4 mmol/dl )
What causes secondary hyperparathyroidism?
O kidney injury
O vitamin D deficiency
=↓ synthesis calcitriol =↓ serum calcium = ↑ PTH
What ph does the stomach need to be for pepsinogen activation
Ph=3
What are the cells in the stomach and what do they secrete?
O parietal cells - HCl + intrinsic factor
O G-cells - gastric
O chief cells - pepsinogin
O d-cells - somatostatin
Vasoactive intestinal polypeptide - where is it secreted and what does it do?
O Regulates GI motility and secretions
Motion - where is it secreted and what does it do?
In the GI - stimulates motility
Gastric inhibitory peptide _ where is it secreted and what does it do?
O In the duodenum + jejunum - stimulates insulin release in response to ↑ glucose
Pancreatic polypeptide location + fxn
O released by the pancreas to inhibit exocrine fxn
Secretin location+ fxn
Duodenum + jejunum - stimulates pancreatic bicarb secretion
Define diarrhoea
Loose stool passage > 3 times per day
Differentiate chronic vs acute diarrhoea
Acute = <2 weeks (does not need to be investigated further )
Chronic = > 4 weeks
Classify diarrhoea
O small bowel - malabsorption, enzyme deficiency, crohns disease, bile salt malabsorption
O large bowel - crohns, ulcerative colitis
O pancreas - chronic pancreatitis, carcinoma, cystic fibrosis
O endocrine - gastronoma, carcinoid tumor
O other - laxatives, drugs,
What tests would you order to investigate chronic diarrhoea?
O FBC,U&E,LFT,ESR
O Ca, mg, na, K, PO4, albumin, folate, vitb12, iron
O fecal occult blood, fecal mc+s, fecal elastase, fecal calprotectin,
How do you further categorize chronic diarrhoea?
①secretary
> infection
> endocrine ( TSH, gastrin,
②osmotic
> lactose intolerance (hydrogen breath test)
> mg, carbs
How do you determine if its secretory or osmotic chronic diarrhoea?
① Osmotic gap of stools:
290 -2( [Na] + [k] )
> 125 = osmotic
< 50 = secretory
② Fecal ph < 5.6 = carb malabsorption
③ fecal laxative screening
Mg+phenyolphthalene
How is H. Pylori diagnosed?
Urea breathe test ( C14 labeled urea taken orally)
Stool antigen test
What is zollinger - Ellison syndrome
There is a gastrin producing tumor = ↑ acid secretion
How do you diagnose zollinger Ellison syndrome?
basal acid output (BAO)
= ng tube used to measure acid production over hr →> 15mmol/hr
What is coeliac disease?
Sensitivity to gliadin in all glutens = inflammation of small intestine → malabsorption
How do you diagnose coeliac disease?
O serology
> IgA EMA
> IgA tTG
O confirm with 3 duodenal biopsies
> HLA DQ2 / DQ8 in > 99% coeliac pts
What is fecal calprotectin?
O It is a protein found in the cytosol of leukocytes
O not digested by bower enzymes: ↑ amounts in faeces when inflammation
O used to differentiate irritable bowel syndrome to inflammatory bowel disease → avoid unnecessary colonoscopy
What is alpha 1 antitrypsin and why is it important?
It is a small protein that can be found in stool in protein loosing enteropathy because it is resistant to gut bacteria: not broken down
Causes of hypercalcaemia?
Malignancy
Hyperparathyroidism
Causes of hypercalcaemia?
Malignant disease
① widespread skeletal metastasis
② homeostatic malignancy
③ num eral hypercalcaemia of malignancy
Primary hyperparathyroidism
① sporadic
②familial
Less common
① vit D toxicity
Common drugs needing assessment for toxicology
Paracetamol
Lead
Iron
Ethanol
Salicylates (aspirin)
When do you take your sample for therapeutic monitoring?
When the drug is at a steady state (after about 5 half-lives)
Drugs with narrow therapeutic index
Phenytoin
Warfarin
Digoxin
Lithium
Phenytoin signs of toxicity and mechanism
Seizures - zero order kinetics cause phenytoin receptors to become saturated at therapeutic range therefore accumulates after that as can’t be eliminated
How does digoxin act and what is it used for
Inhibits Na/K ATPase pump
To treat a fib
Therapeutic range of digoxin
0,5-2 microgram/L for AF
Signs of digoxin toxicity
N&V
Dysrhythmias
Treatment of digoxin toxicity
Anti-digoxin antibodies
Another name for paracetamol
Acetaminophen
What metabolises paracetamol
Glucurodination and sulphation
Signs and sx of paracetamol poisoning
<24hr = nausea, vomiting, anorexia
24-48hr = abdo pain, ↑INR,
>48hr = jaundice, encephalopathy, AKI
What is the best marker of paracetamol poisoning severity
Prothrombin time
Treatment of paracetamol poisoning
① drug screen, liver + renal fxn
② N acetalcysteine ASAP
③ activated charcoal within 1hr of ingestion
④ 5% dextrose ( risk hypoglycaemia due to liver damage)
Signs of salicylate toxicity
①tinnitus
② resp alkalosis
③ then metabolic acidosis + N&V and electrolyte disturbances
Treatment of salicylate toxicity
Alkali is action of blood so that salicylate can ionise and be excreted in the urine.
NaHCO3, hydration, avoid hypoglycaemia, urine pH mustn’t exceed 8
Signs of iron toxicity
Circulatory collapse
encephalopathy
Renal failure
Liver necrosis
Treatment of iron toxicity
Desferroxamine
Fluids
Avoid hypoglycaemia
Lead toxicity blood levels that sx start
> 0,5
Sx of lead toxicity
Abdominal pain
N&V
Encephalopathy
Convulsions
Coma
Interferes with porphrin pathway
Lead toxicity tests
Urine - coporporphyrinogen III
Urine Aminolaevulinic acid
Treatment of lead toxicity
Chelation therapy (DMSA)
What electrolyte changed occur in insulin deprivation?
Hyperkalaemia
Hyperphosphataemia
(Insulin cellular uptake of these)
Electrolyte changes in insulin therapy?
Hypokalaemia
Hypophosphataemia
Hypomagnesaemia
Pathophysiology of T2 DM
Increased lipolysis
Increased gluconeogenesis
Decreased in retain
Increased resorption of glucose in the kidneys
Decreased insulin production
Insulin resistance
Increased glucagonp
Normal fasting glucose
<6.1
2-hr glucose tolerance test
Fast overnight
75g glucose in 200ml water
Measure glucose before and after 2hrs
>11,1 = DM
DM HbA1C
> 6.5% or >48mmol/L
When can you NOT use HbA1C
New onset DM
Rapidly changing glucose levels
Sever Anaemia (low Hb <6.5)
Abnormal RBC lifespan
No HbA
Pregnancy
How do you diagnose GDM
Oral glucose tolerance test >7.8
What is the DKA triad
Hyperglycaemia
Ketones
Acidotic
Biochemical abnorms in DKA
Hyperglycaemia
Hyperkalaemia
Hyponatraemia
Hyperphosphataemia
Metabolic Acidosis
Dehydration
Kidney injury
How do you treat DKA?
IV saline
Insulin
Vit K, phosphate and magnesium
Check U&E and blood glucose every 6hrs
Monitor fluid status with CVP
What is hyperosmolar hyperglycaemic state and treatment
No ketones, high blood glucose
DM2
Minimal acidosis
Treatment = fluids +low dose insulin
Whipples tried
Hypoglycaemic sx
Hypoglycaemia
Sx resolve after glucose load
Causes of fasting hypoglycaemia
Chronic kidney disease
Chronic liver disease
Cancer
Endocrine disease
Alcohol/drugs
Hyperinsulinaemia
What is the expected pCO2 formula for METABOLIC ACIDOSIS?
Expected pCO2 = 1,5 x [HCO3] + 8
(range +/-2)
What is serum protein electrophoresis used for?
It shows the levels of various proteins in the blood (albumin, alpha 1+2, beta and gamma)
Can help diagnose varies pathologies ie myeloma = spike in gamma
What is serum immunofixation?
Helps identify which of the proteins from gel electrophoresis have spiked within the protein section
What does hypoalbuminaemia indicate
CHRONIC liver disease, liver cirrhosis
What is the serum ascites albumin gradient calculation and how does it help?
Serum albumin - ascites albumin (indicates if exudate/transudate)
What does a high gradient SAAG indicate?
> 1,1
Portal HT, non-peritoneal cause of ascites, malnutrition, liver cirrhosis
<1,1
Peritoneal cause of ascites eg cancer, TB
Which cofactors in the clotting cascade are dependent on Vit K
2, 7,9,10
What markers of liver disease guide you towards alcohol induced
AST:ALT >2
Gamma GT increased
Increased triglycerides
Increased serum IgA
Red cell macrocytosis
What type of bilirubin causes bilirubinuria?
Conjugated
Lab findings in haemolytic jaundice?
Urine urobilinogen
Increased AST and LDH
Increased reticulocytes
Increased unconjugated bilirubin
Positive Coombs test
What is delta bilirubin?
Conjugated bilirubin bound to albumin elevated in pts with long-standing obstructive jaundice/hyperbilirubinaemia
Sources of ALP (explained isolated increase)
GIT
LIVER
BONE
PLACENTA
TUMORS
Why does liver cirrhosis cause increased ammonia?
Liver converts ammonia to urea for excretion by kidneys therefore urea cycle affected by liver disease
Can lead to hepatic encephalopathy
Formula for expected CO2 at compensated metabolic alkalosis
0,7 x [HCO3] +20 (+-5)
AG formula
[Na] + [K] - [Cl-] - [HCO3]
Causes of metabolic acidosis
DKA
Lactic acidosis
Kidneys unable to resort HCO3
Kidneys unable to excrete H+
Ingestion alcohol/salicylates
Causes of metabolic alkalosis
Potassium depletion
Volume depletion (pyloric stenosis, gastric aspiration)
Chronic alkali intake
Causes of respiratory acidosis
Airway obstruction
Depression of resp centre (anaesthesia, cerebral trauma)
Neuromuscular disease (Guillian Barre)
Pulmonary disease (severe pneumonia, pulmonary fibrosis)
Causes of respiratory alkalosis
Increased respiratory drive (high altitude, severe anaemia)
Voluntary hyperventilation
Mechanical overventilation
What is the normal amount of protein excreted in the urine?
Less than 150mg/24hrs
What are the categories of proteinurea?
Persistent(1+ or more) = CKD
> 300mg/day (corrected for creatinine)
Benign
Why do we test microalbuminurea and why does it help us?
Detects albumin at very low concentrations (more sensitive than dipstix)
Measures from 30-300mg/day
Indicates early nephropathy
What are the mechanisms of proteinurea?
Secretory (kidneys or urinary tract secrete proteins)
Overflow (excess protein, kidney can’t resorb all)
Glomerular (permeability increased)
Tubular (impaired/saturated absorption)
What is urine protein electrophoresis and how does it help us?
It’s used to determine what category of proteinurea we are dealing with.
Causes of increased creatinine
Rhabdomyolysis
AKI
Diet
Patient stature
Drugs
Analytical interference
Causes of low plasma creatinine
Elderly and infants
Chronic illness
Analytical interference
Vegetarians
What is the formula for creatinine clearance?
[Urine creatinine] x (urine flow rate) / plasma creatinine concentration = ml/min
GFR Formula
eGFR = 175 x [sCr x 0,011312]^-1,154 x age^-0,203
When can eGFR be misleading?
> AKI
pregnancy
increased volume of distribution eg oedema of heart failure
malnutrition
extreme of age
meat fish meal
decreased or increased muscle mass
What has been found more useful that creatinine in estimating kidney function?
Cystatin C
Why is Cystatin C better than eGFR?
Not influenced by mass or sex
Single reference range for men and female under 50
Improved accuracy
BUT influenced by malignancy, hyperthyroidism and steroid tx
Explain the exogenous pathway of fat metabolism
Enterocyte absorbs fat with apo B48. The chylomicron is then transported via lymph, through thoracic duct into circulation. It gains apo E, C1,2 and 3 from HDL. Hydrolysis of the chylomicron allows fatty acids to be released and absorbed by fat and muscle tissue. Glycerol to the liver. Now the chylomicron is dense cholesterol. Apo C’s are given back to HDL. This is removed from circulation by the liver.
Explain the endogenous pathway of fat metabolism
The liver releases VLDL with only apo-100. It gains C1-3 and E app’s from HDL. The triglyceride is hydrolysed by LPL and fatty acids are released and taken up by fat and muscle. The VLDL reduces in size (IDL now). Some of the IDL is removed by receptor mediated pathways and it is now LDL (by hepatic lipase). The uptake of LDL is dependent on LDL receptors.
Function of HDL
The precursor for HDL (nascent HDL) is released by the liver with Apo A1+2 apo, apo E and phospholipids. It is disc shaped. These molecules absorb free cholesterol to become HDL3. hDL3 is esterified by LCaT which allows it to have more carrying capacity for cholesterol. The cholesterol esters move to the centre and it becomes spherical.
HDL3 accepts apo C2+3 and phospholipids from cholesterol and VLDL and then at HDL2.
The cholesterol in HDL2 is exchanged with chylomicron and VLDL for triglycerides. (Mediated by CETP)
VLDL now with cholesterol esters is removed by the liver.
Classify dyslipidaemias
Primary
Secondary (exclude first)
Describe the pathophysiology of familiar hypercholesterolaemia
There is a mutation in the gene coding for the LDL receptors. (Apo B100) It is a dominant gene. 1 mutation = receptors working @ 50%. 2 mutations = 0 receptors working.
Heterozygous = 7.5-12mmol/L total (>4.5 LDL)
Homozygous = up to 20mmol/L
What does familial dysbetalipoproteinaemia present with typically?
Fat deposits in palmar crease and tuberous xanthomata.
Excess IDL and chylomicron remnants which can’t be cleared
List Causes of secondary dyslipidaemias NB
Diabetes
Obesity
Excess alcohol intake
Hypothyroidism
Nephrotic syndrome
Cholestasis
Chronic renal failure
Drugs
What is the Framingham risk score used for?
What does it consist of? NB
Used to determine LDL treatment target
Defines the risk of suffering CV event in the next 10y without treatment.
Low risk <3%
Mod 3-15%
High 15-30%
Very high >30%
Includes gender, age, systolic BL, TG, HDL, smoker status
When do you NOT use the Framingham risk score?
If the patient has already suffered a CV event
OR
Strong family history of CV event
→ treat
Who qualifies for a lipogram?
anyone above 40y old
What is the formula to calculate LDL?
Total cholesterol - (HDL + TG/2.2)
Invalid if TG >4.5
Why do we treat hyperlipidaemia?
Decrease risk CV event and pancreatitis
What are paraneoplastic endocrine syndromes?
When hormones or hum oral factors are secreted by the tumor
What are the most common paraneoplastic endocrine syndromes.
Cushing Syndrome
Syndrome of inappropriate ADH
Hypercalcaemia of malignancy
What are the effects of ectopic vasopressin secretion?
Dilutional hyponatraemia
With water retention
(SIADH)
What are the sx of hyponatraemia?
Asymptomatic
Drowsiness
Confusion
Fits
Coma
Which tumors increase ADH concentration
Small cell Ca of bronchus
Carcinoid tumors
Breast cancers
Pancreatic adenocarcinomas
What is the pathophysiology of hypercalcaemia in malignancy?
PTH secreting peptides are released bY the tumor which stimulates the kidney to reabsorb more calcium (the PTH peptides from the tumor are not regulated)
Some tumors have osteoclast activating cytokines (myeloma)
And prostaglandins produced by metastasis (breast Ca)
How do malignant diseases harm the kidneys?
Hypercalcaemia, cytotoxic drugs, urinary tract obstruction, antibiotics, Bence Jones proteinurea, kidney infiltration, tumor lysis syndrome (TLS)
What is tumor lysis syndrome?
Cytotoxic drugs break down tumors causing massive tumor necrosis and
Hyperkalaemia
Hyperphosphataemia
Hyperuricaemia
Hypocalcaemia
How do you prevent tumor lysis syndrome?
Fluids, allopurinol to inhibit Uris acid synthesis, careful fluid and electrolyte monitoring
Where do gastroenteropancreatic neuroendocrine tumors arise from?
Neuroendocrine cells derived from the embryological gut
What is carcinoid syndrome?
When vasoactive amines such as serotonin and peptides such as ACTH are secreted into circulation from a tumor.
Another name for serotonin
5 hydroxytryptamine (5 HT)
Symptoms of carcinoid syndrome
Pellagra like skin lesions (decreased nicotinic acid production - it’s diverted to make serotonin)
GI - N&V, diarrhoea, colicky pain
CVS - flushing, pulm stenosis
Resp - bronchospasm
How do you screen for carcinoid syndrome?
24hr urine 5-hydroxyindk,eacetic acid (5-HIAA) = metabolite of serotonin
Chrimogranin A (less specific)
What is an ideal tumor marker?
One that can be used for
Screening
Diagnosis
Prognosis
Treatment monitoring
Recurrence detection
What is used to screen for Down syndrome?
Alpha fetoprotein (produced by yolk sac and embryonic liver and gut)
What tumors does raised alpha fetoprotein indicate?
Hepatocellular Ca (but not specific)
Testicular germ cell tumors
What tumor marker suggests colorectal cancer?
CEA (carcinoembryonic antigen)
Not sensitive or specific
What may elevated hcg indication? (Extremely sensitive)
Choriocarcinoma (malignant prolif of hydatidiform mole)
Classify acute coronary syndrome using tropoin and ECG
Unstable angina = normal troponin and nonspecific ECG
Non ST elevation MI = increased troop in and ST depression
ST elevation MI = increased troponin and ST elevation
Pathogenesis of atherosclerosis
LDL trapped in subintimal space. Oxidises and attracts monocytes and macrophages to become foam cells.
Foam cells:
>secrete pro-inflam cytokines which attract leukocytes and cause endothelial damage
>secrete enzymes that erode plaque cap and increase risk of plaque rupture
>activate Th1 cells to products inflammatory cytokines
Pathogenesis of Acute MI
Plaque of artherosclerosis ruptures, platelets aggregate and thrombosis is stimulates by Tissue Factor
Vascular occlusion by clot with/without embolisation plus vascular spasm which restricts blood flow
What is STEMI
Abrupt total occlusion of major coronary artery causing transmural ischaemia/necrosis
Treatment of STEMI NB
<12 hrs after event = percutaneous coronary intervention (PCI)with stent placement
If >120min delay expected = start fibrinolytic treatment and transfer to PCI capable hospital
What is NSTEMI
Partial occlusion of major artery or total occlusion of minor artery causing partial thickness/subendocardial necrosis
What troponin subunits are specific to myocardium
Troponin I and T
How do you diagnose MI
1) test troponin (rise within 1-2hrs of onset)
2) use only highly sensitive troponin assay
3) repeat troponin over several hours to aid injury mechanism (occlusive or non-occlusive)
If first trop is normal but pt still unwell, might be an evolving AMI or unstable angina
4) repeat in 1-3hrs: >50% = diagnostic
5) NB FOR TEST: High and very high risk Framingham risk pts = involve cardiology
Pitfalls of troponin
> causes rise and falls in coronary occlusion on serial testing
can’t distinguish between injury mechanisms (occlusion, inflam, toxic)
decreased clearance in kidne6 failure (monitor trends if creat>200)
Point of care testing of trop pitfalls
Not highly sensitive
: will miss cases (but better than nothing in rural setting)
Layers of the adrenal gland from outside in
Capsule
Zona glomerulosa
Zona fasciculata
Zona reticular is
Medulla
What is the diurnal rhythm?
It shows how cortisol levels in the blood differ at different times of the day physiologically.
Lowest = midnight
Highest = 8am
Causes of increased glucocorticoid
ACTH dependent
>pituitary (Cushing)
>ectopic
>ACTH therapy
ACTH independent
>adrenal adenoma
>adrenal carcinoma
>glucocorticoid therapy (steroid to)
>micronodular hyperplasia
How do you test for Cushing Syndrome?
> Low-dose dexamethasone suppression test
urinary free cortisol
late night salivary cortisol
Other tests when increased ACTH to determine origin
> potassium - hypokalaemic alkalosis (ectopic ACTH production due to increased output of mineralcorticoids)
selective venous sampling
pituitary function tests (to see if other hormones from the pituitary are affected = tumor?)
tumor markers
Glucose tolerance test (steroid induced diabetes)
What is Cushing disease?
An increase in serum cortisol levels leading to sx related to this
Causes of adrenal insufficiency?
① Primary (inside adrenal)
>autoimmune
>infective
>secondary tumor
>infiltration
>congenital adrenal hyperplasia
>drugs (eg etomidate)
② secondary due to pituitary
>congenital
>tumours
>infection
>trauma
>iatrogenic
>vascular lesions
Causes of primary hyperaldosteronism?
> idiopathic/bilateral adrenal hyperplasia
unilateral adenoma (Conns syndrome)
primary adrenal hyperplasia
aldosterone producing carcinoma
How do you investigate primary hyperaldosteronism?
> plasma aldosterone:renin ratio
urine 18 hydroxycortisol
genetic CYP11B2 testing
What causes secondary hyperaldosteronism?
Diuretics
What is a phaeochromocytoma?
A tumor releasing catecholamines
How do you investigate increased catecholamines?
> plasma free metadrenalines
urinary fractionated matadrenalines
Classify Congenital adrenal hyperplasia
Classic = early onset
No classic = late onset
What is the pathophysiology of congenital adrenal hyperplasia?
21 alpha hydroxylase deficiency is the most common cause = decreased aldosterone and increased androgens
Who should have a TFT?
① symptomatic
> fam hx
> features of thyroid disorder
> elderly with non-specific symptoms
> women in menopause with nonspecific sx
> pt taking myroxine
② pts at risk
> presenting with dm
> autoimmune disease
> treated hyperthyroidism
> down + Turner’s syndrome
> lithium + amiodarone
What is the proteins that T3 and T4 bind to in the plasma?
Thyroxine binding globulin
Albumin
Transthyretin
Mechanism of action of thyroid hormones
T4 and T3 dissociate from protein in plasma to cross the cell membrane and enter the nucleus where they promote mRNA and protein synthesis
What drugs affect thyroid function?
> steroids and dopamine - decrease TSH secretion
lithium, iodine, amiodarone - decrease thyroid hormone secretion, induce hyperthyroidism
PPI’s
oestrogens
Causes of low TSH in euthyroid patient?
> subclinical hyperthyroidism
treated hyperthyroidism
no thyroid all illness
pregnancy
ophthalmic Graves’ disease
treatment with dopamine or high dose steroids
Causes of high TSH in euthyroid patient?
> subclinical al hypothyroidism
recovery phase of non-thyroidal illness
When is TSH a good first line test vs when is it not a good first line test?
First line TSH okay
>asymptomatic patients
>monitoring pts on thyroxine
First line TSH not okay
>symptomatic patient not treated
>optimising tax in hyper or hypothyroidism
> screening and monitoring in pregnancy
>diagnosisi and monitoring of hypopituitarism
>diagnosis of TSHoma and Thyroid hormone resistance
How do you treat hypothyroidism?
T4 treatment (to normalise TSH (neg feedback) and to relieve sx of patient)
Annual follow up
Wait 6-8weeks before lab tests after changing dose
Classify causes of hypothyroidism?
Congenital
>thyroid aplastic
>dyshormogenesis
Acquired
>primary
• iatrogenic
° inflammatory ( autoimmune/transient)
>secondary
•hypopituitism
o iodine deficiency
• hypothalamic dysfunction
When do you treat subclinical hypothyroidism?
> if TSH >10
if TSH 4.5-10 but positive anti-TPO antibodies
Classify the causes of hyperthyroidism
> inflammatory (graves/thyroiditis)
toxic multinodular goitre
TSH-Oma
iodine induced ( toxic high intake of iodine in pts with autonomously functioning thyroid gland)
trophoblastic
How do you manage hyperthyroidism?
> radioiodine
carbimazole
thyroidectomy
Measurement of TSH not reliable in first 4-6months
What other lab tests are affected by hyperthyroidism?
> impaired glucose tolerance
hypocholesterolaemia
hypercalcaemia
abnormal LFT’s
increased SHBG
What other lab tests are affected by hypothyroidism?
> hyponatraemia
hypercholesterolaemia
hyperprolactinaemia
increased CK
deceased SHBG
When are thyroid function tests unreliable?
> nonthyroidal illness (thyroid abnormality twice as likely to be due to illness)
recovering from nonthyroidal illness
neonate (spike at birth and then gradual decrease)
pregnancy (trimester related reference ranges)
Causes for abnormal results in euthyroid patients
> abnormal TBG
genetic variants of albumin
assay interference
How do testes make testosterone? (Precursor and enzyme)
The enzyme 17B-HSD (17B hydroxysteroid dehydrogenase) converts androstenedione to testosterone
What is the active form of testosterone?
Dihydrotestosterone (5 alpha reductase)
What are the results of leydig cell dysfunction?
Decreased masculinisation and decreased sperm count
What are the results of serotonin cell dysfunction?
Normal masculinisation but decreased sperm count
Signs and symptoms of androgen deficiency?
> delayed puberty
decreased masculinisation
infertility
decrease bone mineral density
ED
reduced sexual desire
gynaecomastia
small testes
insulin resistance and T2 DM
First line tests for suspected androgen deficiency?
Total serum testosterone (FASTING at 9am)
LH
FSH
What are the sx experienced at different levels of testosterone?
<13 =decreased vitality and vigour
<11 =decreased morning erections
<8,5 =ED
<8 =decreased sexual thoughts
When must free testosterone be measured?
When there is a decrease SHBG
> obesity
DM
nephrotic syndrome
steroids
hypothyroidism
acromegaly
polymorphisms in SHBG gene
When there is an increased SHBG (decreases free testosterone)
>aging
>HIV
>cirrhosis and hepatitis
>oestrogen use
>hyperthyroidism
Second line tests for suspected hypogonadism?
> HCG stimulation test (Hypo-thalam pituitary axis)
stimulates leydig cells to increase testosterone (differentiate primary and secondary) = no response =primary testicular failure
> semen analysis
How do you treat testosterone deficiency
Testosterone replacement therapy (IM or implant)
Goal = 10-15nmol/L
What are the functions of oestrogens?
> female sexual characteristics (body shape, fat, hair pattern)
Prepare for pregnancy
maintenance of pregnancy
preparation for lactation
Functions of progesterone
> promotes implantation
decreased contractility of uterine muscle
decrease maternal immune response
What hormone indicates hypogonadism in females and how does it present?
Decreased 17B estradiol
Oligo/amenorrhoea
How do you test for uterine dysfunction?
Progesterone challenge test (try and elicit withdrawal bleed = only if adequately oestrogenized)
What is the pathophysiology of PCOS?
Ovaries produce excessive androgens = hyperandrogenism
Differential diagnosis for hirsutism?
Ovarian
>PCOS
>androgen secreting tumor
>post-menopausal
Adrenal
>congenital adrenal hyperplasia
>Cushing syndrome
>androgen secreting tumors
iatrogenic
>androgens
>pRogesterones
What is the Ferriman Gallwey score?
Used to score abnormal hair patterns
>8 = abnormal
Menopause pathophysiology
Increase FSH, Low oestrodiol
- osteoporosis
Adverse lipid changes = decrease HDL, increase LDL
Adrenal androgens take over
What is Kallman Syndrome?
Neurodevelopmental disorder caused by abnormal migration of olfactory and GnRH neurons through cribiform plate = by decreased GnRH leading to hypogonadism and anosmia.
Results in decreased FSH, LH, and testosterone.
Treatment of Kallmans syndrome?
Testosterone replacement therapy
Kleinefelter syndrome
XXY
decreased testosterone, increased FSH,LH and oestrogen
= gynaecomastea, tall, female body type
What is the pathology in osteomalacia and rickets?
Decreased mineralisation of bone, most commonly due to decreased supply of calcium
Causes of osteomalacia and rickets
Calciopenic
>nutritional calcium/VitD deficiency
>CKD
>anticonvulsants
Phosphopenic
>isolated phosphate loss
>generalized renal tubular disorders (Fanconi syndrome, renal tubular acidosis, hypophosphataemic rickets)
What is the function of fibroblast growth factor 23?
Inhibits calcitriol
Stimulates renal phosphate loss
What is hypophosphatasia?
A rare inherited disorder with features that resembles rickets in which the ALP is decreased.
Clinical features of osteomalacia and rickets?
Bone pain
Bone deformities
Proximal muscle weakness
Management of osteomalacia and rickets
Vit D supplementation
Ca and PO4 supplementation
Monitor ALP, PTH, Ca and phosphate = should normalise
What is osteoporosis?
Decrease in bone mass and abnormal micro architecture
BMD >2.5 std deviations below the mean, or by a pathological fracture
Pathology of osteoporosis
Increased osteoclast activity
Decreased osteoblast activity
How do you diagnose osteoporosis?
DEXA
WHO frax tool to estimate future risk of fracture with clinical knowledge and BMD
Bone remodelling process
Bone lining cells line quiescent bone surfaces. These cells are replaced by osteoclasts which reabsorb the bone. Once they are done, they apoptoses and are replaced by osteoblasts which lay down new osteoid 6-12 months)
What are markers of bone resorption
Collagen derivatives
>pyridinium cross links of collagen (urine)
>cross linking telopeptides of Type 1 collagen (serum)
Name markers of bone formation
> plasma osstoclacin
bone specific ALP
procollagen type 1 terminal peptides
What is the use of bone turnover markers?
Monitoring treatment and adherence
NOT diagnosing
What is pagets disease of bone
It is a disease of unknown aetiology caused by increased osteoclastic resorption if bone and the new bone that replaced it is disorganised
=deformed, painful bone
What blood test result is common in pagets?
Increased ALP
normal calcium and phosphate
What is CKD-MBD
Chronic kidney disease with mineral and bone disorder
Pathogenesis of CKD BMD
Decrease of nephrons leads to hyperphosphataemia. This causes a increase FBF23 and the. A decrease calcitriol synthesis = hypocalcaemia
Hypocalcaemia causes increased PTH (increases phosphate excretion but limited by poor kidney function)
Phosphate becomes so high that it exceeds solubility and phosphate and calcium form metastatic calcification.
How do you manage CKD BMD
Monitor calcium and phosphate, PTH, ALP
Oral phosphate binder
Oral calcitriol
PTH maintained at 2-4x normal
