Chemical Pathology- Part 2 (p85-100- Adrenals, calcium, enzymes, nutrition, metabolic disorders, sugar, paeds + renal) Flashcards
What are the common causes of Cushing’s syndrome?
Pituitary tumour- Cushing’s disease 85%
Adrenal tumour 10%
Ectopic ACTH producing tumour 5%
Iatrogenic steroid use
Common symptoms and signs of Cushing’s?
Moon face Buffalo hump Striae Acne HTN Diabetes Muscle weakness- proximal myopathy Hirsutism
What are the investigations to diagnose Cushing’s?
Low dose dexamethasone- 0.5mg- will fail to suppress cortisol in all causes of Cushing’s
High dose dexamethasone 2mg- will suppress pituitary cushing’s
How do you treat Cushing’s?
Treat underlying disease- e.g. surgical removal of lesion
What causes Addison’s?
Autoimmune TB Tumour mets Adrenal Haemorrhage Amyloidosis
What are the symptoms and signs of Addison’s?
Increased K+ Decreased Na+ + Glucose Postural hypotension Skin pigmentation Lethargy Depression
What investigations are used to diagnose Addison’s?
SynACTHen test
How do you treat Addison’s?
Hormone replacement- hydrocortisone/fludrocortison if primary lesion
What causes Conn’s?
Adrenal tumour
What are the symptoms and signs of Conn’s?
Uncontrollable HTN
Raised Na+
Decreased K+
What investigations are used to diagnose Conn’s?
Aldosterone:Renin ratio high
How do you treat Conn’s?
Aldosterone antagonists/potassium sparing diuretics- spironolactone, eplerenone, amiloride
What causes phaeo?
Adrenal medulla tumour leading to increased adrenaline
What are the symptoms and signs of phaeo?
Hypertension
Arrhythmias
Death if untreated
What investigations are used to diagnose phaeo?
Plasma and 24h urinary metadrenaline measurement/catecholamines + VMA (vanillylmandelic acid)
How do you treat phaeo?
Alpha blockade
Beta blockade
Surgery when blood pressure is well controlled
What is phenytoin used to treat?
Seizures
What is digoxin used to treat?
Arrhythmias
What is lithium used to treat?
Relapse of mania in BPAD
What are the signs of phenytoin toxicity?
Ataxia and nystagmus
Treated with omission or reduction of dose
What are the signs of digoxin toxicity and how is it treated?
Arrhythmias
Heart block
Confusion
Xanthopia (seeing yellow)
Treated with digibind aka digoxin immune Fab
What are the signs of lithium toxicity?
Tremor (early) Lethargy Fits Arrhythmia Renal failure- treated with haemodialysis
What are the signs of gentamicin toxicity?
Tinnitus
Deafness
Nystagmus
Renal failure
Treated with omission or reduction of dose
What are the signs of theophyline toxicity?
Arrhythmia
Anxiety
Tremor
Convulsions
Treated with omission or reduction of dose
Normal plasma range of calcium?
2.2-2.6mmol/l
How does calcium exist in the blood in terms of bound/free etc?
45% ionised (free- biologically active)
50% bound to albumin, therefore affected by albumin level- use corrected calcium
What does Parathyroid Hormone (PTH) do?
Increased tubular 1a hydroxylation of vit D (25(OH)D) to form calcitriol
Mobilises calcium and PO4 from bone
Increased renal calcium reabsorption
Increased renal phosphate excretion
What does calcitriol (1,25 (OH)2D) do?
Increased calcium and phosphate absorption from the gut
What causes PTH release?
Decreased plasma Ca
What is the primary defect in 1’ hyperparathyroidism?
Increase of PTH (80% parathyroid adenoma)
What is the primary defect in 2’ hyperparathyroidism?
Renal osteodystrophy
What is the primary defect in 3’ hyperparathyroidism?
Autonomous PTH secretion post renal transplant
What is the primary defect in hypoparathyroidism?
Low levels of PTH
1’- DiGeorge syndrome
2’- Post-thyroid surgery
What is the primary defect in Rickets/osteomalacia?
Vit D deficiency
What is the primary defect in osteoporosis?
Bone loss
What would you see in 1’ hyperparathyroidism in terms of Ca, PO4, PTH, ALP + Vit D?
Increased Ca Decreased PO4 Increased/Normal PTH Increased/Normal ALP Normal Vit D
What would you see in 2’ hyperparathyroidism in terms of Ca, PO4, PTH, ALP + Vit D?
Decreased/Normal Ca Increased PO4 Increased PTH Increased ALP Normal Vit D
What would you see in 3’ hyperparathyroidism in terms of Ca, PO4, PTH, ALP + Vit D?
Increased Ca Decreased PO4 Increased PTH Increased/Normal ALP Normal Vit D
What would you see in hypoparathyroidism in terms of Ca, PO4, PTH, ALP + Vit D?
Decreased Ca Increased PO4 Decreased PTH Decreased/Normal ALP Normal Vit D
What would you see in Rickets/Osteomalacia in terms of Ca, PO4, PTH, ALP + Vit D?
Decreased Ca Decreased PO4 Increased PTH Increased ALP Decreased Vit D
What would you see in Paget’s in terms of Ca, PO4, PTH, ALP + Vit D?
Normal Ca Normal PO4 Normal PTH Increased ALP Normal Vit D
What would you see in osteoporosis in terms of Ca, PO4, PTH, ALP + Vit D?
Normal Ca Normal PO4 Normal PTH Normal ALP Normal Vit D
What are the causes of hypocalcaemia with increased phosphate?
CKD
Hypoparathyroidism (inc post-thyroid surgery)
Pseudohypoparathyroidism
Hypomagnesaemia
What are the causes of hypocalcaemia with normal or decreased phosphate?
Osteomalacia
Acute pancreatitis
Overhydration
Respiratory alkalosis
Symptoms of hypocalcaemia?
Perioral paraesthesia
Carpopedal spasm
Neuromuscular excitability- Chvostek’s + Trousseau’s
What is Chvostek’s sign?
Abnormal reaction due to stimulation of facial nerve due to existing nerve hyperexcitability in hypocalcaemia
What is Trousseau’s sign?
Carpopedal spasm caused by inflating the blood-pressure cuff to a level above systolic pressure for 3 minutes in hypocalcaemia
What is the treatment of mild and severe hypocalcaemia?
Mild- give calcium
Severe- 10% calcium gluconate IV
Causes of hypercalcaemia?
Dehydration
Primary or tertiary hyperparathyroidism
With raised ALP and phosphate- Bone mets, thyrotoxicosis + sarcoidosis
With normal ALP and raised phosphate- myeloma, excess vit D, sarcoid, milk alkali syndrome
Symptoms of hypercalcaemia?
Stones (renal) Bones (Pain) Groans (psych) Moans (abdo pain) Polyuria Muscle weakness
How do you treat hypercalcaemia?
Correct dehydration
Bisphosphonates
Correct cause e.g. chemo for cancer
What are the RFs for renal stones?
Dehydration
Abnormal urine PH (meat intake, renal tubular acidosis)
Increased excretion of stone constituents
Urine infection
Anatomical abnormalities
What are the common constituents of renal stones?
Calcium- mixed 45% Calcium oxalate 35% Calcium phosphate 1% Triple phosphate "Struvite" 10% Uric acid 5% Cysteine 1-2%
Which types of renal stones are radiolucent?
Uric acid
Cysteine
Which renal stones have a ‘staghorn’ appearance
Triple phosphate “Struvite”
What marker would be 10x upper limit of normal serum levels in acute pancreatitis?
Amylase
What is Creatine Kinase a marker of?
Muscle damage
Which creatine kinase is a marker of skeletal muscle damage and which is a marker of cardiac muscle damage?
CK-MM = skeletal muscle
CK-MB (1+2)= cardiac muscle
What causes raised CK levels physiologically?
Race- Afro-Caribbean
What causes raised CK levels pathologically?
DMD (>10x ULN)
MI (>10x ULN)
Statin myopathy
Rhabdomyolysis
Where is alkaline phosphatase high in concentrations?
Liver
Bone
Intestine
Placenta
What are the physiological causes of raised ALP?
Pregnancy (3rd trimester)
Childhood during growth spurt
What are the pathological causes of raised ALP (Bone + Liver)?
>5x ULN- Bone- Pagets, Osteomalacia Liver- Cholestasis, Cirrhosis <5x ULN- Bone- tumours, fractures, osteomyelitis Liver- infiltrative disease + hepatitis
What is the biomarker of myocardial injury?
Troponin I/T
When do you test Troponin?
6h and 12h post onset of chest pain
How long does Troponin remain elevated for?
3-10d
What is one international unit?
The quantity of enzyme that catalyses 1uMol of substrate in a minute- measure of MASS or CONCENTRATION
What does PCSK9 do?
Binds LDLR and promotes its degradation leading to raised LDL
Loss of function mutation leads to low LDL- novel LDL-therapy is Anti-PCSK9 MAb
Which vitamins are fat soluble?
ADEK
Which vitamins are water soluble?
B1 (thiamine), B2 (riboflavin), B6 (pyroxidine), B12 (cobalamin), C, Folate, B3 (Niacin)
What does Vit A deficiency lead to?
Colour blindness
What does Vit D deficiency lead to?
Osteomalacia/Rickets
What does Vit E deficiency lead to?
Anaemia/neuropathy
?Malignancy/IHD
What does vit K deficiency lead to?
Defective clotting
What does excess vit A lead to?
Exfoliation
Hepatitis
What does excess vit D lead to?
Hypercalcaemia
What does vit B1 (thiamine) deficiency lead to?
Beri-Beri
Neuropathy
Wernicke syndrome
How do you test vit K?
PTT
What does B2 (riboflavin) deficiency lead to?
Glossitis
What does B6 (pyroxidine) deficiency lead to?
Dermatitis/anaemia
What does B6 excess lead to?
Neuropathy
How do you test B2 (riboflavin)?
RBC glutathione reductase
How do you test B6 (pyroxidine)?
RBC AST activation
What does B12 deficiency lead to?
Pernicious anaemia
How do you test B12?
Serum
What does vit C deficiency lead to?
Scurvy
What does excess vit C lead to?
Renal stones
What does folate deficiency lead to?
Megaloblastic anaemia
Neural tube defect
What does B3 (niacin) deficiency lead to?
Pellagra- 3Ds (Dementia, dermatitis, diarrhoea)
What does iron deficiency lead to?
Hypochromic anaemia
What does iron excess lead to?
Haemochromatosis
What does iodine deficiency lead to?
Goitre
Hypothyroid
What does zinc deficiency lead to?
Dermatitis
What does copper deficiency lead to?
Anaemia
How do you test copper?
Cu
Caeroplasmin
What is the Guthrie blood spot test and what does it test for?
Heel prick in neonates to screen for serious conditions, mainly metabolic e.g. CF, phenylketonuria, congenital hypothyroidism, medium chain acylcoA dehydrogenase deficiency
What causes phenylketonuria?
Phenylalanine hydroxylase deficiency
How do you screen for phenylketonuria?
Phenylalanine levels
What happens in cystic fibrosis?
Mutation in CFTR- viscous secretions -> ductal blockages
How do you screen for cystic fibrosis?
Immune reactive trypsin
If positive -> DNA mutation detection
What happens in medium chain acylcoA dehydrogenase deficiency?
Fatty acid oxidation disorder
How do you screen for medium chain acylcoA dehydrogenase deficiency?
Acylcarnitine levels by tandem mass spectrometry
What is the definition of specificity?
The probability in % that someone without the disease will correctly test negative
TN/FP+TN
What is the definition of sensitivity?
Probability that someone with the disease tests correctly positive
TP/TP+FN
What is the definition of PPV?
Probability that someone who tests positive actually has the disease
TP/TP+FP
What is the definition of NPV?
Probability that someone who tests negative actually doesn’t have the disease
TN/TN+FN
What are the 5 different groups of metabolic conditions?
1- Accumulation of toxins 2- Reduced energy stores 3- Large molecule synthesis 4- Defects in large molecule metabolism 5- Mitochondrial
Give examples of metabolic conditions with accumulation of toxins?
Organic acidaemias
Urea cycle disorders
Aminoacidopathies (e.g. PKU + maple syrup urine disease)
Give examples of metabolic conditions with reduced energy stores?
Glycogen storage disorders (Von Gierke’s)
Galactossaemia
Fatty acid oxidation disorders (MCADD)
Give examples of metabolic conditions with large molecule synthesis problems?
Peroxisomal disorders
Glycosylation disorders
Give examples of metabolic conditions with defects in large molecule metabolism?
Lysosomal disorders e.g. Tay Sachs disease
Give examples of metabolic mitochondrial conditions?
MELAS
Kearn’s
Sayre
POEMS
What are the key features of organic acidaemias?
High urea + ketones
Metabolic acidosis
Funny smells
How do you treat organic acidaemias?
Low protein diet, acylcarnitine + haemofiltration
What are the key features of urea cycle disorders?
High ammonia leading to encephalopathy + developmental delay
Resp alkalosis
Vomiting
?Diarrhoea
How do you treat urea cycle disorders?
Low protein diet- stops urea formation
What are the key features of aminoacidopathies?
High phenylalanine Blue eyes Fair hair/skin Retardation MSUD- sweaty feet
What are the key features of glycogen storage disorders?
Hypoglycaemia + lactic acidosis
Hepatomegaly
Developmental delay
Hepatoblastoma risk
How do you treat glycogen storage disorders?
Regular CHO
Key features of galactossaemia?
Increased Gal-1 phosphate levels cause cataracts
Hypoglycaemia
Neonatal jaundice
How do you treat galactossaemia?
Treat with low lactose/galactose
Key features of fatty acid oxidation disorders?
Hypoglycaemia
Cardiomyopathy
Rhabdomyolysis
Low ketones
How do you treat fatty acid oxidation disorders?
Regular carbs
What are the key features of peroxisomal disorders?
Poor feeds Seizures Retinopathy Hepatomegaly Mixed hyperbiliribinaemia
How do you screen for glycosylation disorders?
Measure serum transferrins
What are the key features of lysosomal disorders?
Very slow progress
Neuroregression
Hepatomegaly
Cardiomyopathy
How do you test for lysosomal disorders?
Test urine mucooligopolysaccharides + WBC enzyme levels
How is DM diagnosed?
Typical symptoms plus one of fasting glucose >7, OGTT >11.1 or random glucose>11.1, or without symptoms but with 2 of the above tests
NICE also recommends you use HbA1C>48
What is the definition of impaired glucose tolerance?
Random or OGTT >7.8 but <11.1
What is the definition of impaired fasting glucose?
Fasting glucose >6.1 but <7
In which type of DM are DKA more common?
Type 1
In which type of DM are hyperosmolar hyperglycaemic state (HHS) more common?
Type 2
What are the HHS criteria?
pH >7.3
Osmolarity >320mOsm
Blood Glucose > 30mM
Develops over few dats
What are the DKA criteria?
pH<7.3
Plasma glucose >11mM
Blood ketones >3mM
DKA- rapid
What are causes of hyperinsulinaemic hypoglycaemia?
Iatrogenic insulin
Sulfonylurea excess
Insulinoma
What are causes of hypoinsulinaemic hypoglycaemia?
+ve ketones- alcohol binge, no food, pituitary insufficiency, Addison’s, liver failure
-ve ketones- Non-pancreatic neoplasms- fibrosarcomata, fibromata
What would you see in blood tests for non-islet tumour hypoglycaemia?
Low glucose, insulin, C-peptide, FFA and ketones
What causes non-islet tumour hypoglycaemia?
Tumour causes paraneoplastic syndrome secreting big IGF-2 which binds to IGF-1 and insulin receptors
What common problems originate from low birth weight?
Respiratory distress syndrome Retinopathy of prematurity Intraventricular haemorrhage Patent ductus arteriosus Necrotising enterocolitis (inflammation of bowel wall)- necrosis and perforation
Why does renal function differ in babies compared to adults?
Functional maturity only at 2yo
Low GFR for SA
Less reabsorption due to short proximal tubule
Reduced concentrating ability due to short loops of Henle + DCTs
Persistent sodium loss due to distal tubule being aldosterone insensitive
Why is there high insensible water loss in babies compared to adults?
High SA:BW ratio
Skin blood flow is increased
Metabolic/respiratory rate is higher than adults
Transepidermal fluid loss (skin not the best barrier)
However hypernatraemia common in first 2w of life
What would you suspect with jaundice within first 24h of life?
Acute haemolysis or sepsis
What would you suspect with jaundice after 2wks of life?
Hepatobiliary failure
What is normal GFR?
120ml/hr
What is renal clearance defined as?
Volume of plasma that can be completely cleared of a marker substance in a unit of time
What is the gold standard measure of GFR?
Inulin
What is the problem with the use of inulin?
It requires steady state infusion and it is difficult to assay so reserved for research
Which measure is used in clinical practice to measure renal function?
Creatinine- an endogenous marker
What is the problem with the use of creatinine?
Very variable between individuals and muscular ppl have high creatinine
What is the definition of an AKI?
A rise in serum creatinine over 26.5 in 48h or to 1.5x baseline in 48h
Can also be defined as urine output of less than 0.5ml/kg/hr
What are the different causes of AKI?
Pre-renal- reduced renal perfusion with no structural abnormality
Renal- vascular, glomerular, tubular, interstitial
Post-renal- characterised by obstruction to urinary flow
What emergency indications are there for dialysis?
Pulmonary oedema Refractory hyperkalaemia Metabolic acidosis Uraemic encephalopathy Drug toxicity e.g. lithium
5 stages of CKD?
1- kidney damage with GFR>90 2- mild decrease in GFR 60-89 3- Moderate decrease in GFR 30-59 4- Severe decrease in GFR 15-29 5- End stage <15 or dialysis
Commonest causes of CKD?
Diabetes Atherosclerotic renal disease HTN Chronic glomerulonephritis Infective or obstructive uropathy PKD
What are the 4 main consequences of CKD?
- Progressive loss of homeostatic function- acidosis + hyperkalaemia
- Progressive failure of hormonal function- anaemia (loss of EPO synthesis) + Renal bone disease (2’ hyperparathyroidism due to low vit D)
- CVD- vascular calcification + atherosclerosis and uraemic cardiomyopathy
- Uraemia and death