Chemical pathology Flashcards
(400 cards)
1
Q
How is urate made?
A
Purines –> intermediaries (via Xanthine Oxidase) –> Urate
2
Q
What are the pathways in producing purines?
A
De novo synthesis and (PAT) recycling/salvage pathways (HPRT or HGPRT)
3
Q
What are the key enzymes involved?
A
PAT (rate limiting step), HGPRT
4
Q
What is Lesch-Nyhan syndrome? What are the Sx/Ix?
A
X-linked complete deficiency of HGPRT enzyme –> ↓ purine recycling –> ↑ de novo pathway –> ↑ urate (hyperuricaemia) Hyperuricaemia, Development delay, Choreiform movements
5
Q
Tx of Gout?
A
Acute gout (↓ inflammation): NSAID, Colcichine, Glucocorticoids Chronic gout: (treat ↑ urate): Drink water, Allopurinol (inhibits XO, C/I Azathioprine as blocks its metabolism so ↑ effect), Probenecid (uricosuric –> ↑ renal excretion)
6
Q
Ix for Gout?
A
Bloods: raised urate, tap effusion + view under polarised light (2 filters to look for birefringence)
7
Q
Gout vs Pseudogout
A
GOUT: monosodium urate crystals, needle-shaped, negative birefringence, perpendicular to axis of red compensator PSEUDOGOUT: calcium pyrophosphate crystals, rhomboid shaped, positive birefringence, parallel to axis of red compensator
8
Q
Types of lipoproteins (largest to smallest) + function
A
Chylomicrons (largest) VLDL - main carriers of TG LDL - main carriers of cholesterol HDL (smallest)
9
Q
Main enzyme involved in cholesterol synthesis
A
HMG-CoA reductase –> ↑ cholesterol synthesis This enzyme is downregulated by dietary cholesterol
10
Q
Function of LDLs and HDLs
A
LDL: Transport cholesterol from Liver –> tissues HDL: Transport cholesterol from Tissues –> Liver
11
Q
Function of CETP (cholesterylester transfer protein)
A
Converts cholesterol esters from HDL –> VLDL and TG from VLDL –> HDL
12
Q
Absorption of cholesterol
A
Cholesterol (in diet) –> GI epithelium –> hydrolysed into bile acids (re-cycles) OR esterifised into Cholesterol ester Cholesterol ester + TG + ApoB –> VLDL –> LDL –> binds to LDL receptor –> LDL particle is endocytosed into cells
13
Q
Absorption of triglycerides
A
TG –> Chylomicrons –> hydrolysed into Free Fatty Acids –> taken up by Liver and Aidpose tissue FFA re-synthesised into TG
14
Q
Types of dyslipidaemia
A
Hypercholesteralaemia Hypertriglycidaemia Mixed hyperlipiademia Hypolipidaemia
15
Q
Types of primary hypercholesterolaemia
A
Familial hypercholesterolaemia Type II (autosomal dominant mutation in LDL-R, ↑ risk of CVD) Polygenic hypercholesterolaemia (many loci) Familial hyper-a-lipoproteinaemia (CETP deficiency –> ↑ HDL –> longevity) Phytosterolaemia (↑ plant sterols)
16
Q
Signs of hypercholesterolaemia
A
Arcus, Atheroma, Tendon xanthoma, Eruptive xanthoma
17
Q
Types of primary hypertriglyceridaemia
A
Familial Type I: deficiency of Lipoprotein lipase or ApoC II deficiency (↑ chylomicrons) Familial Types IV: unknown –> ↑ synthesis of TG (↑ VLDL) Familial Types V: ApoA V deficiency (↑ VLDL and ↑ Chylomicrons)
18
Q
DDx types of primary hypertriglyceridaemia
A
Overnight fridge test
19
Q
Types of primary mixed hyperlipidaemia
A
Familial combined hyperlipidaemia Familial hepatic lipase deficiency Familial dys-B-lipoproteinaemia (type III)
20
Q
Causes of secondary hyperlipidaemia
A
Pregnancy, Hypothyroidism, Diabetes, Obesity, Primary biliary cirrhosis, Alcohol
21
Q
Types of hypolipidaemia
A
AB-lipoproteinaemia Hypo-B-lipoporteinaemia Tangier disease Hypo-a-lipoproteinaemia
22
Q
Components of atherosclerosis
A
Necrotic core containing foam cells (full of cholesterol) and cholesterol cystals (foam cells die) with a thin fibrous cap
23
Q
Pathophysiological of atherosclerosis
A
LDL crosses endothelium –> oxidased and phagocytosed by Macrophages –> esterified to become Foam cells –> die and release lipids –> Necrotic core
24
Q
Types of lipid regulating drugs
A
Statins –> ↓ LDL, ↑ HDL, ↓ TG Fibrates (Gemfibrozil) –> ↓ TG Ezetimibe –> ↓ cholesterol absorption Resin –> binds to bile acids –> ↓ re-absorption
25
Tx of Obesity
Hypocaloric diet, Exercise, Orlistat (stearrhoea), GLP-1 analogue (exenatide), Bariatric surgery (Gastric banding, Roux-en-Y gastric bypass = stomach to Jejenum, Bilippancreatic diversion)
26
Causes of metabolic acidosis (3) + examples + compensation
↑ H+ production: e.g. DKA ↓ H+ excretion: e.g. renal failure Bicarbonate loss: e.g. gastro-intestinal fistula COMPENSATE: Hyperventilation (↑ RR)
27
Causes of respiratory acidosis (3) + examples + compensation
↓ venilation (e.g. Opiate overdose --\> respiratory depression) ↓ perfusion Impaired gas exchange (e.g. COPD) COMPENSATION: long term renal compensation (↑ H+ excretion, ↑ Bicarb regeneration)
28
Causes of metabolic alkalosis (3) + examples
Loss of H+ HypoK Ingest Bicarb NO COMPENSATION: would compensate by ↑ CO2 but this would involve stopping breathing, resp centres stop this
29
Causes of respiratory alkalosis (3) + examples
Hyperventilation (voluntary, anxiety, artificial ventilation - CPAP, stimulation by drugs) COMPENSATION: long term renal compensation (↓ H+ excretion, ↓ Bicarb regeneration)
30
How do kidneys compensate for acidosis?
↑ renal excretion of H+ and ↑ bicarb regeneration
31
Explain switch in stimulus for COPD
Impaired gas exchange (e.g. COPD) --\> Respiratory acidosis ----- Eventually, brainstem ignores ----- With exertion, COPD becomes breathless due to hypoxia (as hypercapnia is ignored) Renal compensation (Bicarb reabsorption, Excrete H+ ions)
32
List Dx in newborn screening program (9)
Cystic fibrosis (immunoreactive trypsinogen) Hypothyroidism (TSH) Sickle cell PKU (Phenylalanine levels) MCADD (acylcarnitine levels by tandem mass spec) Maple syrup urine disease Isovaleric aciduria Glutaric aciduria Homocystinuria
33
PKU enzyme deficiency, Sx and Tx
PKU = Phenylalanine hydroxylase deficiency Asymptomatic, Moderate-Severe LD if untreated Alternative meals for PKU
34
Define sensitivity, specificity, NPV, PPV
Sensitivity = true positive / total disease present Specificity = true negative / total disease absent NPV = true negative / total negative results PPV = true positive / total positive results
35
Cystic fibrosis - Ix, mutation
Gutherie test: ↑ immunoreactive trypsinogen Sweat test: Cl- \> 60 Genetic testing: autosomal recessive, delta(F508) is most common
36
MCADD - Pathogenesis, Ix
Fatty acid oxidation defect --\> cannot liberate acetyl CoA from fat --\> dies of hypoglycaemia Ix: Hypoketotic hypoglycaemia (cannot make ketones as cannot breakdown fat), Hepatomegaly, Cardiomyopathy
37
Red flag for urea cycle disorder
↑ Hyperammnoaemia + ↑ Glutamine (excess ammonia added to glutamate to make glutamine)
38
Tx for hyperammonaemia
Remove ammonia (sodium benzoate, dialysis), ↓ ammonia production (low protein diet)
39
Red flag for organic aciduria
Hyperammonaemia + Metabolic acidosis + High anion gap
40
Isovaleric acidaemia - Aet, Sx, Ix
Aetiology: deficiency of isovaleryl CoA-dehydrogenase --\> ↑ isovaleryl CoA, ↓ Leucine Sx: Funny smelling urine (maple syrup urine disease), ↑ hyperammonaemia, myoclonic jerks, ketoacidotic coma Ix: serum ammnoia, serum amino acids, urine organic acids, glucose, lactate, blood spot carnitine profile
41
Galactosaemia - Aet, Sx, Ix
Aetiology: Gal-1-PUT deficiency Sx: Conjugated ↑ BR, Hypoglycaemia, Hepatomegaly Ix: urine reducing substances - ↑ galactose Tx: galactose free diet
42
Red flag for mitochondrial disorders
Multiple organ systems affected, ↑ CK, ↑ Lactate
43
Examples of mitochondrial disorders
Barth, MELAS, Kearns-Sayre disease
44
Peroxisomal disorders - Sx, Ix
Aetiology: defective metabolism of very-long chain FA Sx: Seizures, hypotonia, dysmorphic signs (large fontnaelle), calcified stippling (x-ray) Ix: Very long-chain FA profile
45
Lysosomal stroage disease
Aetiology: autosomal recessive --\> ↑ stroage of material in cells Sx: Organomegaly, Dysmorphia Ix: Urine mucopolysaccharides Treatment: BM transplant, exogenous enzyme
46
Differences in neonatal renal function c.w. adults
Function maturity reached by 2 years old ↓ GFR (relative to SA) Shorter PCT --\> ↓ reabsorption Short LoH --\> ↓ concentrating ability DCT relatively aldosterone insensitive
47
Fluid differences in neonates c.w. adults
↑ water loss due to ↑ SA:V ratio, ↑ skin blood flow, ↑ trans-epidermal fluid loss All babies lose 10% BW in first weight of life
48
Electrolyte differences in neonates c.w. adults
↑ requirements: ↑ fluid (6x), ↑ Na+ (3.5x), ↑ K+ (2x) Hypernatraemia is common in first 2 weeks of life (after 2 weeks --\> ↑ Na+ indicates dehydration)
49
Neonatal causes of fluid overload
Bronchopulmonary dysplasia Necrotising enterocolitis
50
Neonatal causes of Hypernatraemia
Normal in first 2 weeks of life IVH Sodium bicarbonate when treating acidosis
51
Neonatal causes of Hyponatraemia
CAH Caffeine/Theophylline (when treating apnoea)
52
Osteopenia of prematurity
Inability to get enough Calcium ex utero, Ca (last to go), ↓ PO4, ↑↑ ALP, Tx with Ca supplements
53
Transient hyperphosphataemia of infancy
↑↑ ALP in absence of liver or bone disease, returns to normal within weeks-months
54
Pathological neonatal jaundice
Jaundice \< 24 hours (haemolysis, jaundice) Jaundice \> 14 days (hepatobiliary failure) Conjugated hyperBR at any stage of infancy
55
Define porphyria
Deficiency of haem biosynthesis pathway --\> build-up of haem precursors
56
Rate limiting step in Haem biosynthesis pathway
ALA synthase
57
Classify porphyria based on presentation/onset
Acute --\> Neuro-visceral symptoms +/- Cutaneous symptoms Chronic --\> Cutaneous symptoms (blistering or non-blistering)
58
Mechanisms of symptoms of porphyria
5-ALA is neurotoxic Porphyrinogen (precursors) oxidised by UV light in skin --\> cutaneous skin lesion
59
Porphyrinogens vs Porphyrins
Porphyrinogen: colourless, unstable (readily oxided to porphyrin) Porphyrin: coloured, water soluble --\> urine, insoluble --\> faeces
60
Acute porphyrias (4) + enzymes involved
ALA dehydratase = Plumboporphyria --\> PBG synthase deficiency = ALA dehydratase deficiency --- Neurocutaneous lesions Acute intermittent porphyria --\> HMB synthase deficiency --- Neurocutaneous lesions --- Intermittent symptoms (triggered by CYP450 inducers) --- Tx: IV Haem arginate Hereditary coproporphyria --\> Coproporphyrinogen oxidase deficiency --- Neurocutaneous lesions + Skin lesions Variegate porphyria --\> Protoporphyrinogen oxidase deficiency --- Neurocutaneous lesions + Skin lesions
61
Porphyrias - neurovisceral symptoms + Ix
Psychosis, Abdo pain, Motor neuropathy, Constipation, Hyponatraemia (due to ↓ renin), Bulbar palsy, Coma Ix: Urinary PBG
62
Porphyrias - cutaneous symptoms + Ix
Blistering (vesicles, skin crusting) or Non-blistering (photosensitive rash, burning, itching, oedema) Ix: Urine and Faecal and Plasma porphyrins + Red cell protoporphyrins
63
Chronic porphyrias (4) + enzyme involved
Congenital erythropoietic porphyria --\> Uroporphyrinogen III synthase --- Blistering Porphyria cutanea tarda --\> Uroporphyrinogen decarboxylase --- Blistering Erythropoietic protoporphyria --\> Ferrochetolase --- Non-blistering
64
Most common porphyria
Porphyria cutanea tarda --\> Uroporphyrinogen decarboxylase
65
Most common porphyria in children
Erythropoietic protoporphyria --\> Ferrochetolase
66
ALA synthase deficiency
X-linked sideroblastic anaemia (it does NOT cause porphyria)
67
Thyroid physiology (iodide to T4)
Iodine absorbed in GIT (blocked by perchlorate) and converted to Iodide In Thyroid gland, TPO converts iodide to iodine -- thyroglobulin within colloid Iodine --\> mono- --\> di- --\> T3 --\> T4 In periphery, T4 converted to T3 TSH acts to ↑ iodine uptake into thyroid, ∑ conversion, ∑ movement of T4 into basememnt mebrane, ∑ excretion of T4 into blood
68
Causes of Hypothyroidism
Primary - Hashimoto's thyroiditis (autoimmune, anti-TPO antibodies, anti-TG antibodies, plasma cell infiltration) - Primary atrophy hypothyroidism: difficuse lymphocytic infiltration + atrophy (small thyroid), no antibodies - Iodine deficiency (common worldwide) - Post thyroidectomy - Drugs (Lithium, amiodarone, anti-thyroid drugs) Secondary - pituitary adenoma
69
Ix + Tx of Hypothyroidism
↓ T4, ↑ TSH in primary hypothyroidism T4 (titrated until normal TSH)
70
Subclinical hypothyroidism - Ix
T4, ↑ TSH, asymptomatic (incidental) May progress to Primary hypothyroidism, esp if anti-TPO antibody +ve Only treat if ↑ cholesterol levels
71
Thyroid function in pregnancy
↑ hCG (similar to TSH), ↑ T4, ↑ Thyroglobulin, ↑ Thyroid-binding globulin
72
Most important test for Thyroid disease
TSH
73
Sick euthyroid syndrome
Sick (e.g. sepsis) --\> ↓ T4/T3, ↑/ TSH --\> with aim of ↓ BMR
74
Causes of Hyperthyroidism + Ix
↑ uptake - Grave's disease (diffuse enlargement, exothalphmos, pre-tibial myxoedema, thyroid acropathy) - Toxic multi-nodular goitre - Single toxic adenoma ↓ uptake - Subacute de Quervains thyroiditis (initial hyperthyroid, then hypothyroid) - Post-partum thyroiditis Ix: Technetium scan
75
Tx of Hyperthyroidism
Thionamides (Carbimazole, propylthiouracil) Radioactive iodine (release radiation to destroy thyroid gland, S/E thyroid storm - Tx: β blocker) Potassium perchlorate: ↓ iodine absorption in GI tract β blockers
76
Tx of thyroid carcinoma
Surgery Radioactive iodine T4 --\> suppresses TSH so tumour does not growth
77
Marker of recurrence of thyroid cancer
Thyroglobulin
78
5 types of thyroid neoplasia
Papillary (most common) - Psammoma bodies Follicular Medullary - from parafollicular C cells, MEN2, produces Calcitonin Lymphoma - MALT origin Anaplastic
79
Normal range of calcium
2.2 - 2.6 mmol / L
80
Why do you use corrected Calcium
If ↓ albumin --\> ↓ total Ca2+ ∴ look at corrected Ca2+
81
Vitamin D synthesis pathway
Cholesterol --\> D3 (from skin or diet) --\> 25-hydroxylase produces 25-OH D3 (in Liver, inactive form) --\> 1α-hydroxylase produces 1,25 (OH)2 Vitamin D3 (in Kidney, active form, enzyme controlled by PTH)
82
Rate limiting step in Vit D synthesis
1 α hydroxylase (controlled by PTH)
83
Vitamin D2
Ergocalciferol (in plants) Tip = "ER" = 2
84
Vitamin D3
Cholecalciferol (in mammals) Tip: "CHO" = 3
85
Effects of 1, 25 Vitamin D (2)
↑ intestinal Ca2+ absorption and ↑ intestinal PO4 absorption
86
Effects of PTH (3)
↑ 1α-hydroxylase --\> ↑ Vitamin D --\> ↑ intestinal Ca2+ absorption and ↑ intestinal PO4 absorption ↑ renal absorption of Ca2+ + ↓ renal PO4 resorption (phosphate trashing hormone) Activates osteoclasts --\> consume bone to release Ca2+ ∴ Osteoblasts repair bone --\> ↑ ALP
87
Vitamin D deficiency vs Osteoporosis
Vitamin D deficiency: defective bone mineralisation (↓ Vit D, ↓ Ca2+, ↑ PTH) - secondary hyperparathyroidism Osteoporosis: loss of bone mass, normal bone mineralisation (NORMAL biochemistry)
88
Causes of Vitamin D deficiency
Dietary deficiency, Lack of sunlight, Renal failure
89
Pathophysiology of Vitamin D deficiency
↓ Vit D --\> ↓ Ca2+ --\> ↑ PTH --\> ↑ bone resorption by osteoclasts --\> ↓ bone mineralisation = Osteomalacia
90
Types of Vitamin D deficiency (age) + Sx
Vitamin D deficiency in children = Rickets (bowed legs, widened epiphyses) Vitamin D deficiency in Adults = Osteomalacia (Looser's zone = pseudofracture, ↑ risk of fractures)
91
Tx of Vitamin D deficiency
Vitamin D, adjust dose to Ca2+ levels
92
Causes of Osteoporosis
Excess breakdown: Cushing's syndrome, Hyperthyroidism Deficient production: oestrogen deficiency, Old age Dietary
93
Sx of Osteoporosis
Asympatomic UNTIL fracture
94
Dx of Osteoporosis
DEXA scan Osteoporosis = T score \< -2.5 Osteopenia = T score -1 & -2.5 -1 \< Normal \< 1
95
DEXA Z score vs T score
T score = SD from young healthy population (determine fracture risk) Z score = SD from mean age-matched controls (identify accelerated bone loss) Tip: Z is at the end of the alphabet so it is the old people who are leftover in society
96
Tx for Osteoporosis
Vitamin D / Ca2+ Bisphosphonates (Alendronate) - creates special C-N bond not found in nature, not biodegradable, GI S/E Teriparatide (PTH derivative) Strontium - anabolic (many S/E) SERMs (Raloxifene) Denosumab - binds to RANK ligand --\> ↓ maturation of osteoclasts --\> ↓ bone resorption
97
Symptoms of Hypercalcaemia
Stones - renal stones Bones - bone pain Abdo Moans - constipation, pancreatitis Psychic Groans - depression Thrones - polyuria/polydipsia Band keratopathy (deposition in front of eye)
98
Classify causes of Hypercalcaemia
PTH driven (↑ or inappropriate normal PTH) or non-PTH driven (↓ PTH - appropriately supressed)
99
Treatment of Hypercalcaemia
Fluids ++++++ (1L/1hr then 1L/8 hour --\> overal 3-6L/24hr) +/- Furosemide (if elderly, to ↓ risk of pulmonary oedema) If malignancy --\> Bisphosphonates (otherwise avoid as it makes diagnosis harder later!) Treat underlying cause
100
Symptoms of Hypocalaemia
CATs go numb (neuronal excitability) - Convulsions - Arrhythmias - Tetany (Trosseau's sign/BP cuff, Chvostek's sign/Facial tetany) - Parasthesia
101
Classify causes of Hypocalcaemia
↑ PTH (non-PTH driven i.e. secondary hyperparathyroidism, appropriate response to ↓ Ca2+) or ↓ PTH (lack of PTH-driven)
102
Tx of hypocalcaemia
Calcium, Vitamin D (usually activated form, unless Vit D deficiency)
103
DDx ↑ Ca2+, ↑/ PTH
Primary hyperparathyoidism (parathyroid adenoma) Familial benign hypercalcaemia (mutation in Ca sensing receptor - CaSR - higher set point for PTH release, benign)
104
DDx ↑ Ca2+, ↓ PTH
= Secondary hypoparathyroidism - Malignancy ---- Hypercalcaemia of Malignancy (small cell lung cancer releases PTHrP) --- Bone mets (invades bone --\> releases Ca2+) --- Multiple myeloma (cytokines --\> release Ca2+) - Sarcoidosis (ectopic 1α-hydroxylation) - Vitamin D excess Tip: DDx by giving steroids (if normalised, the cause is sarcoidosis)
105
DDx ↓ Ca2+, ↑ PTH
Secondary hyperparathyroidism (LOWEST CALCIUM) - Vitamin D deficiency (↓ Vit D --\> ↓ Ca2+ --\> ↑ PTH) - Chronic Kidney Disease (failure of 1α-hydroxylation) - may progress to tertiary hyperPTH - Pseudohypothyroidism = PTH resistance (↓ Ca2+, ↑ PTH, skeletal abnormalities - abnormal 4th metacarpal)
106
DDx ↓ Ca2+, ↓ PTH
Primary hypoparathyroidism - Surgery = post-thyroidectomy - Autoimmune (rare) - Congenital absence (e.g. DiGeorge syndrome) - Mg2+ deficiency (required for PTH synthesis)
107
↑ Ca2+, ↓ PO4, ↑ PTH, ↑/ ALP, Vitamin D
Primary hyperPTH (or Tertiary hyperPTH)
108
↑ Ca2+, ↓ PO4, PTH, ↑/ ALP, Vitamin D
Primary hyperPTH (or Tertiary hyperPTH)
109
↓ Ca2+, ↑ PO4, ↑ PTH, ↑ ALP, Vitamin D
Secondary hyperPTH (Vitamin D deficiency, CKD, Pseudohypoparathyroidism)
110
Ca2+, ↑ PO4, ↑ PTH, ↑ ALP, Vitamin D
Secondary hyperPTH (Vitamin D deficiency, CKD, Pseudohypoparathyroidism)
111
↓ Ca2+, ↓ PO4, ↑ PTH, ↑ ALP, ↓ Vitamin D
Vitamin D deficiency
112
↓ Ca2+, ↑ PO4, ↓ PTH, ALP, Vitamin D
Primary hypoparathyroidism
113
, Ca2+, PO4, PTH, ↑ ALP, Vitamin D
Paget's disease
114
, Ca2+, PO4, PTH, ALP, Vitamin D
Osteoporosis
115
Primary hyperparathyroidism (↑ PTH)
Parathyroid adenoma --\> ↑ PTH --\> ↑ Ca2+ --\> no negative feedback Bloods: ↑ Ca, ↑ PTH
116
Secondary hyperparathyroidism (↑ PTH)
Vitamin D deficiency --\> ↓ Ca2+ --\> secondary ↑ PTH Bloods: ↓ Ca, ↑ PTH
117
Tertiary hyperparathyroidism (↑ PTH)
CKD --\> ↓ 1α-hydroxylase --\> ↓ Vitamin D --\> ↓ Ca2+ --\> secondary ↑ PTH Long-standing CKD, ↑ PTH --\> parathyroid hyperplasia After renal transplant, parathyroid hyperplasia becomes autonomous (no -ve feedback) --\> ↑ PTH, ↑ Ca2+ Bloods: ↑ Ca, ↑ PTH (same as Primary hyperPTH) Clue lies in the history
118
Primary hypoparathyroidism (↓ PTH)
Causes: Surgical, Autoimmune, Congenital agenesis (DiGeorge) Bloods: ↓ Ca2+, ↓ PTH
119
Secondary hypoparathyroidism (↓ PTH)
Suppressed by ↑ Ca Bloods: ↑ Ca2+, ↓ PTH
120
Pseudohypoparathyroidism
PTH resistance, skeletal abnormalities Bloods: ↓ Ca2+, ↑ PTH
121
Pseudopseudohypoparathyroidism
Clinical abnormalities of pseudohypoparathyroidism NORMAL biochemistry
122
Paget's disease
↑ bone turnover / remodelling --\> ↑ ALP Focal bone pain, bone warmth, fracture, bone scan: hot bone Bloods: Ca, PO4, ↑ ↑ ALP Tx: Bisphosphonates
123
Which deaths need to be reported to Coroner (3)
Violent, Unnatural/Sudden or Cause of death is unknown
124
Forensic samples
Ante-mortem blood - drugs before death PM blood (most important) - drugs at time (some may be broken down) Urine Stomach contents (drugs not yet absorbed) Vitreous humour (similar conc to blood) Hair (tape recording of drug use with time) Liver (drugs) Bile (opiates concentrate here) Items found near person
125
Drugs with respiratory depressant effects (3)
Alcohol, Opiates, BDZ
126
Duration of substance still undetectable (blood, urine, hair)
Blood \< 12 hr, Urine 2-3 days, Hair 1cm/month (only specimen which gives long-term drug history)
127
Actions for ADH/Vasopressin + receptors
V2 - acts on collecting tubules to ↑ AQP2 --\> ↑ water reabsorption --\> ↓ Na+ V1 - vasoconstriction (smooth muscle)
128
Stimuli for ADH secretion
↑ serum osmolality - medicated by hypothalamic osmoreceptors ↓ BP (or ↓ blood volume) - mediated by baroreceptors
129
True hyponatraemia vs False
True hypontraemia has LOW osmolality
130
Classification of hyponatraemia
Hypovolaemic / Euvolaemic / Hypervolaemic
131
Sx of hyponatraemia
N&V, Confusion, Seizures, Coma, Death
132
Clinical features of Hypovolaemia
↓ BP, ↑ HR, Dry mucous membranes, ↓ skin turgor, ↓ urine output ↓ urine Na+ (most important / most sensitive) - Na+ retained by kidneys to maintain BP
133
Clinical features of Hypervolaemia
Pulmonary oedema, Peripheral oedema, ↑ JVP
134
Causes of Hypovolaemic hyponatraemia
Diarrhoea Vomiting Diuretics Due to: hypovolaemia --\> ↑ ADH secretion --\> ↑ water retention (only partially compensates for volume loss) --\> ↓ Na+ (overall ↓ Na+)
135
Ix of Hypovolaemic hyponatraemia
Clinically hypovolaemic ↓ urine Na+
136
Tx of Hypovolaemic hyponatraemia
Fluids (0.9% saline)
137
Causes of Euvolaemic hyponatraemia
Hypothyroidism (--\> ↓ cardiac contracility --\> ↓ BP --\> ↑↑ ADH) Addison's (--\> ↓ cortisol --\> ↓ BP --\> ↑ ADH) SIADH (--\> ↑↑ ADH) Due to: excess ADH --\> ↑ water retention --\> ↓ Na+ (excess ↑ water retention --\> ↑ ANP --\> lose Na+ and water in urine so volume normalises - so no oedema)
138
SIADH - causes
CNS pathology - ANY Lung pathology - ANY Tumours - ANY Drugs Surgery
139
SIADH - Ix
↓ plasma osmolality (hyponatraemia) ↑ urine osmolality (↑ ADH --\> ↑ water retention --\> urine concentrates)
140
Ix of Euvolaemic hyponatraemia
TFTs, synACTHen test, plasma osmolality, urine osmolality
141
Tx of Euvolaemic hyponatraemia
Fluid restriction Treat underlying cause If SIADH --\> Demeclocycline (↑ ADH resistance) + Tolvaptin (V2 receptor antagonist) + Furosemide
142
Causes of Hypervolaemic hyponatraemia
Tip FAILURES - Cardiac failure (↓ CO --\> ↓ BP) - Liver failure (↑ NO as less broken down --\> vasodilation --\> ↓ BP) - Nephrotic syndrome (lose albumin --\> ↓ oncotic pressure --\> fluid enters tissues --\> ↓ BP) Due to: ↓ BP --\> ↑ ADH --\> ↑ water retention --\> ↑ fluid volume --\> oedema
143
Ix of Hypervolaemic hyponatraemia
Clincially fluid overloaded
144
Tx of Hypervolaemic hyponatraemia
Fluid restriction Treat underlying cause
145
Tx of severe hyponatraemia
Hypertonic saline (2.7%) - under specialist guidance Only indicated if ↓ GCS or Seizures
146
Rate of correcting hyponatraemia
1 mmol/L per hour OR \< 10 mmol/L per 24 hours (monitor 4 hourly)
147
Dangers of correcting hyponatraemia too quickly
Central pontine myelinolysis (paralysis, dysarthria, seizures, coma, death)
148
Sx of hypernatraemia
Thirst, Confusion, Seizures, Ataxia, Coma
149
Classification of hypernatraemia
Hypovolaemic / Euvolaemic Tip: 3 Ds of Hypernatraemia (Diarrhoea, Diabetes mellitus, Diabetes insipidus)
150
Causes of hypovolaemic hypernatraemia
GI losses - Diarrhoea Skin losses Renal losses - Diabetes mellitus (osmotic diuresis)
151
Causes of euvolaemic hypernatraemia
Inability to access water (children, elderly) Diabetes insipidus
152
Types of diabetes insipidus
Central DI: no ADH release - due to Hypophysitis (inflammation) or Pituitary adenoma (less common) Nephrogenic DI: ADH resistance - due to: Hypercalcaemia, Hypokalaemia, Lithium
153
DDx types of diabetes insipidus
Measure urine osmolality (& plasma osmolality) Fluid deprived: normal will ↑ urine osmolality, rest remain same Give DDAVP: only central DI will ↑ urine osmolality, nephrogenic DI will remain same
154
Tx of hyperntraemia
Fluid replacement (5% dextrose if euvolaemic, 0.9% saline if hypovolaemic)
155
Dangers of correcting hypernatraemia too quickly
Cerebral oedema
156
NONE
NONE
157
RAAS
Angiotensinogen (Liver) --\> A-I by Renin --\> AT-II by ACE (in Lung) --\> Aldosterone (by Adrenaline) Aldosterone --\> Na+/H2O re-absorption and K+ excretion
158
Stimuli for Aldosterone release
Angiotensin II ↑ K+
159
Causes of Hyperkalaemia (8)
↓ GFR (Renal failure) - most common cause ↓ Renin (NSAIDs, Type 4 renal tubular acidosis) ACE inhibitors ARBs Addison's disease (↓ aldosterone) MR antagonists (Spironolactone = K+ sparing diuretic) Acidosis (K+ moves out of cells as H+ moves into cells, to compensate for acidosis) Rhabdomyolysis (damage to muscle cells --\> release of K+)
160
ECG findings of Hyperkalaemia
Tented T waves, Absent p waves, Widened QRS, Bradycardia Eventually --\> VF
161
Management of Hyperkalaemia
K+ \> 6.5 or ECG changes - 10ml 10% Calcium gluconate (stabilise myocardium) - 100ml 20% Dextrose + 10 units Insulin (drives K+ into cells) - Nebulised salbutamol (drive K+ into cells) - Treat underlying cause K+ 5.3 - 6.5 --\> consider haemolysed sample
162
Causes of Hypokalaemia (12)
(1) GI loss - Diarrhoea - Vomiting (2) Renal loss ------\> ↑ urinary [K+] - Hyperaldosteronism (↑ aldosterone) - Cushing's syndrome (excess cortisol --\> binds to MR --\> aldosterone-like effect) - Osmotic diuresis - ↑ Na+ delivery to distal nephron ----- Lack of Na+ reabsorption in LoH (Na/K/Cl channel) ---------- Bartter syndrome ---------- Loop diuretics (e.g. Furosemide) ----- Lack of Na+ reabsorption in DCT (Na/Cl- channel) ---------- Gitelman syndrome ---------- Thiazide diuretics (e.g. Bendroflumethiazide) (3) Restriction into cells - Alkalosis - Insulin - β agonists
163
Clinical features of Hypokalaemia
Muscle weakness Arrhythmia Polyuria/Polydipsia (nephrogenic DI)
164
Ix + Cause of ↓ K+ and ↑ BP
Ix = aldosterone : renin ratio (↑ in Primary hyperaldosteronism = Conn's syndrome) normally, expect ↓ renin (suppressed)
165
Tx of Hypokalaemia
Serum K 3.0 - 3.5 --\> check K+ +/- oral KCl Serum K \< 3.0 --\> IV KCl (max rate 10 mmol/hr) Treat underling cause
166
Henderson-Hasselback equilirium
H + HCO3 CO2 + H2O
167
Osmolality equation
Osmolarity = 2(Na+K) + Urea + Glucose (NR 275-295)
168
Anion gap equation
Anion gap = Na + K - Cl - Bicarb (NR = 14-18)
169
Osmolar gap
Osmolality (measured) - Osmolarity (calculated) NR \< 10 Elevated osmolar gap = presence of abnormal/extra solute (ethylene glycol, ethanol, methanol, mannitol)
170
Causes of ↑ anion gap (excess anions) (5)
Ketones, Methanol, Ethanol, Lactate, Metformin overdose
171
Osmolality vs Osmolarity
osmolality = total number of particles in a solution (units = mmol/kg) osmolarity = 2(Na+K)+U+G, units = mmol/L
172
Alkalosis is associated with what electrolyte abnormality
Hypocalaemia
173
Hyperglycacemia Hyperosmolar State (HHS) - Aetiology, Ix, Tx = Hyperglycaemia Hyperosmolar Non-ketotic Coma (HONKC)
More common in T2DM Long-term uncontrolled diabetes (undiagnosed) --\> ↑ ↑ blood glucose --\> ↑ symptomatic (polyria, polydipsia, glycosuria) --\> ↑ water loss --\> VERY DEHYDRATED Overall: ↑ ↑ blood glucose, ↑↑ Na+ (i.e. ↑ osmolality) Hypernatraemia --\> coma Tx: normal saline (↓ Na+ slowly to avoid cerebral oedema)
174
Metformin overdose causes …
Lactic acidosis (Metformin blocks lactate --\> glucose)
175
Defintion of Diabetes
Fasting PLASMA glucose \> 7.0 mmol/L (must be plasma glucose, plasma is excreted from blood by centrifuging and removing red cells) or OGTT 2hr \> 11.1 mmol/L or HbA1c \> 48 mmol/mol (\>6.5%) - NR is \< 42 mmol/mol
176
Defintion of impaired glucose tolerance
Fasting PLASMA glucose \< 7.0 mmol/L OGTT 2hr \> 7.8-11.1 mmol/L
177
7 classes of Diabetes drugs
Metformin Sulphonylurea SGLT2 inhibitor α-glucosidase inhibitor Thiazolidinediones GLP-1 analogues Gliptins (DPPG-4 inhibitor)
178
Mechanism of Metformin
MOA: ↓ insulin resistance
179
Example of Sulphonylurea + Mechanism
Example: Glibencamide MOA: ↑ insulin secretion (insulin secretagogue) S/E: Hypoglycaemia
180
Example of SGLT2 inhibitor + Mechanism
Example: Empaglifozin MOA: SGLT2 inhibitor --\> urinary glucose re-absorption --\> ↑ urinary glucose (glycosuria)
181
Example of α-glucosidase inhibitor + Mechanism
Example: Acarbose MOA: delays gut transit --\> prolongs absorption of sugars --\> gives pancreas more time to produce sufficient insulin S/E: Flatus
182
Example of Thiazolidinediones + Mechanism
Example: Pioglitazone MOA: PPAR-γ receptor agonist (on Fat cells) --\> ↓ peripheral insulin resistance
183
Example of GLP-1 analogues + Mechanism
Example: Exenatide, Liraglutide MOA: ↑ insulin, ↓ glucagon, ↑ satiety
184
Example of Gliptins + Mechanism
Example: Sitagliptin, Linagliptin MOA: ↑ half-life of endogenous GLP-1
185
Layers of the adrenal (4) + hormones
Zona glomerulosa --\> Aldosterone Zona fasciculata --\> Cortisol Zona reticularis --\> Sex steroids Medulla --\> Catecholamines
186
Adrenal vasculature
L adrenal vein --\> L renal vein R adrenal vein --\> IVC Arteries on outside (picks up aldosterone --\> cortisol --\> sex steroids --\> adrenaline --\> central vein)
187
Macroscopic appearance of adrenals
Golden-yellow outer cortex Inner red-grey medulla Mercedes-Benz sign
188
Causes of adrenal atrophy
Addison's disease, TB, Chronic cortisteroid use
189
Causes of adrenal enlargement
Cushing's syndrome or Idiopathic adrenal hyperplasia
190
Schmidt's syndrome
Schmidt's syndrome = Addison's disease + Primary hypothyroidism
191
Primary hypothyroidism - Ix
↓ T4, ↑ TSH
192
Addison's disease - Causes, Dx
Addison's disease = ↓ cortisol, ↓ aldosterone --\> ↓ Na, ↑ K, ↓ glucose Causes - Autoimmune - TB Ix: Short synACTHen test - Normal: ↑ Cortisol - Addisons: ↓ Cortisol
193
Phaeochromocytoma - Ix, Tx, RF, Staining, rule of 10s, location
Phaeochromocytoma = adrenal medullary tumour secreting catecholaemines Ix: ↑ 24 hr urinary catecholaemines Tx: α blockade (phenolamine), then β-blockade, then surgery RF: MEN2(A/B), VHL, NF1 Chromaffin staining: dichromate fixative turns brown with catecholaemines 10% bilateral, 10% extra-adrenal (paraganglia - carotid bodies, aortic bodies, bladder wall), 10% in children, 10% malignant
194
Primary hyperaldosteronism - Causes, Sx, Ix
Conn's syndrome (2/3) Bilateral adrenal hyperplasia (1/3)
195
Bilateral adrenal hyperplasia - causes
Cushing's syndrome or Idiopathic adrenal hyperplasia
196
Conn's syndrome - Sx, Ix
Conn's syndrome = tumour of zona glomerulosa --\> produces Aldosterone ↑ Aldosterone --\> ↑ Na+, ↓ K+, Hypertension (in a young individual), ↓ Renin Hypertension + Hyperkalaemia --\> CONN'S
197
Benign adrenal mass - Epi
10% general population have incidental non-functioning adrenal mass
198
Cushing's syndrome - causes
Exogenous steroids - most common Pituitary adenoma (Cushing's disease) - 85% Ectopic ACTH (lung cancer) Adrenal adenoma (zona fasciculata)
199
Cushing's syndrome - Ix
Diurnal cortisol (9am cortisol, midnight cortisol) - Normal: ↑ 9am cortisol, ↓ midnight cortisol (if asleep) - unreliable if awake - Cushing's: ↑ 9am cortisol, ↑ midnight cortisol (if asleep) - only reliable in well individuals (no stress) Low-dose dexamethasone supression test - Normal: LOW cortisol - Cushing's: Cortisol remains HIGH ------- If remains high --\> Inferior Petrosal Sinus Sampling (IPSS) ------- If we remove pitutiary, guessing would be correct 85% of time ------- If MRI pituitary, 10% will have small pitutiary incidentoma ACTH - Adrenal adenoma :↓ ACTH - Exogenous steroids :↓ ACTH - Pituitary adenoma: ↑ ACTH - Ectopic ACTH (lung cancer):↑ ACTH High dose dexamethasone suppression test - 80% of Pituitary adenoma will supress (but so will 20% of ectopic ACTH)
200
How to DDx Cushing's syndrome
Inferior Petrosal Sinus Sampling (IPSS) - confirms pitutiary origin of pathology (i.e. Cushing's disease) - only done to exclude pituitary-cause of ACTH
201
High dose dexamethsone suppression test - results
80% of Cushing's disease (pituitary-dependent) will supress BUT 20% of ectopic ACTH (lung cancer) will also suppress ∴ now do IPSS
202
Obese with Cushing's syndrome Ix
↑ 9am cortisol ↓ midnight cortisol (if asleep) Low dose dexamethasone supression test: ↓ cortisol If midnight cortisol incorrectly performed when awake --\> ↑ midnight cortisol Sent for MRI (10% have benign pituitary incidentoma) --\> pituitary removed --\> now hypopit....
203
Stain for amyloid
Congo Red (apple green birefringence)
204
DDx Rosette (histology)
- Adrenal neuroblastoma - Pancreatic neuroendocrine tumour - Medulloblastoma (CNS)
205
Should you aggressively manage BP and lipids?
Aggressive management of BP and lipids --\> ↑ survival
206
Options for statin intolerant patients
Ecetemibe Plasma exchange Evolocumab (PCSK9 monoclonal antibody --\> ↓ LDL receptor recycling --\> ↑ LDL receptors --\> ↓ circulating LDLs)
207
Benefits of Evolucumab
↓ LDL cholesterol ↓ non-fatal MI BUT no effect on cardiovascular death
208
Does good glucose control prevent complications
YES - but benefits only seen after 15 years in newly diagnosed T2DM ∴ should start good glucose control ASAP
209
How long do benefits of good glucose control last?
Despite stopping intense control, benefits last 10-30 years = Legacy effects
210
Should you intensely controly BMs in long-standing diabetics
Sudden tight control in long-standing diabetic patients (with knacked coronary arteries) will prevent some complications (nephropathy) BUT will ↑ mortality
211
Which drugs should be used in long-standing sub-optimal T2DM
SGLT2 inhibitor (empagliflozin) or GLP-1 analogue (liraglutide)
212
Step-up management of T2DM
(1) Metformin If not reach HbA1c target within 3 months --\> (2) + 2nd agent If long-standing sub-optimally controlled T2DM --\> add SGLT2 inhibitor (Empagliflozin)
213
Management of Hypoglycaemia
Alert + Orientated --\> oral carbohydrate (rapid + long acting) Drowsy/Confused + Swallow intact --\> Gel glucose (sublingual) Unconscious OR concerns about swallow --\> IV 50ml 50% glucose +/- 1mg Glucagon (takes 20min to work)
214
Whipple's triad
Low glucose \< 4 mmol/L Symptoms of Hypoglycaemia - Adrenergic: Tremor, Palpitation, Sweating, Anxeity - Neurological: Confusion, Seizures - Asymptomatic (if recurrent --\> impaired awareness) Relieved with glucose administration
215
Response to hypoglycacemia (in order of timing)
In order of timing: ↓ Insulin, ↑ glucagon, ↑ adrenaline, ↑ cortisol ↑ glycogenolysis, ↑ gluconeogenesis, ↑ liposis --\> ↑ Glucose, ↑ FFA (--\> ketones)
216
C-peptide (formation, marker, feedback)
β-cells produce pro-insulin --\> C-peptide and Insulin (equimolar amounts) C-peptide is marker of insulin production (longer half life) If ↑ insulin --\> ↓ production --\> ↓ C-peptide (-ve feedback)
217
DDx ↓ insulin, ↓ C-peptide
Hypoinsulinaemic hypoglycaemia - i.e. endogenous insulin production is switched off in response to hypo (something else causes hypo) - Fasting / Starvation - Strenuous exercise - Addison's - Liver failure - Anorexia nervosa (limited endogenous glycogen stores)
218
↓ Glucose, ↓ insulin, ↓ C-peptide, ↓ FFA, ↓ Ketones
Non-islet cell tumour hypoglycaemia - Paraneoplastic tumour secretes Big IGF-2 which has same effect as insulin - ↓ suppresses endogenous insulin production --\> ↓ insulin, ↓ C-peptide
219
Hypoglycaemia + ↓ Ketones
Fatty acid oxidation defect (e.g. MCADD) Normally, hypoglycaemia --\> ↓ insulin, ↑ glucagon --\> ↑ glucose, ↑ FFA --\> ketones (but this doesn't happen)
220
Exampes of ketone bodies
3-hydroxybutyrate, Acetoacetate, Acetone (pear-drop smeall in DKA)
221
DDx ↑ insulin, ↑ C-peptide
Hyperinsulinaemic hypoglycaemia - i.e. endogenous insulin drives hypo - Insulinoma - Sulphonylurea (↑ insulin effect) - Islet cell hyperplasia - Familial hypoglycaemia (glucokinase activating mutation)
222
Dx insulinoma
Must exclude sulphonylurea abuse - Ix Sulphonylurea drug screen - in order to diagnose insulinoma
223
DDx ↑ insulin, ↓ C-peptide
Exogenous insulin
224
Autoimmune hypoglycaemia
Anti-insulin receptor Ab and Anti-insulin Ab
225
Post-prandial hypoglycaemia
Food intake --\> hypoglycaemia (in insulin sensitive individuals)
226
Portal triad
Hepatic artery, Hepatic vein, Bile duct
227
Hepatic lobule flow
Blood flows from portal triad --\> Sinusoids (endothelium is discontinuous with Space of Disse where metabolism occurs) --\> central vein Bile flows in opposite direction
228
Zones of Liver (differences of metabolism)
Zone 1 (around portal triad, best O2), Zone 2, Zone 3 (least O1, most metabolically active cells)
229
Van den Bergh reaction
Direct reaction measures conjugated BR Adding methanol --\> measure total BR Indirectly measure unconjugated BR
230
BR cycle
BR in bile --\> Bowel --\> converted to sterobilinogen --\> re-absorbed as Urobilinogen --\> Urine
231
Gilbert's syndrome
Autosomal recessive --\> ↓ activity of UDPGT enzyme
232
Hepatitis A
Faecal-oral transmission (contaminated water), Acute IgM reponse, Then IgG response (can only get Hepatitis A once)
233
Hepatitis B
HbSAg = +ve indicates active infection (acute or chronic) anti-HBs = +ve indicates vaccination or previous exposure/cleared anti-HBc = previous exposure/cleared IgM anti-Hbc = +ve acute infection IgG anti-Hbc = +ve indicates chronic infection eAg +ve = highly infectious eAb +ve = not very infectious
234
Histological features of Alcohol hepatitis
Fatty change Mallory Denk bodies (damaged hepatocyte intermediate filaments) Megamitochondria Inflammation (PMN neutrophils) Fibrosis (collagen-staining)
235
Histological features of NASH
Same as Alcoholic hepaitis Clues in the history - alcohol
236
Liver failure results in
↓ synthetic function --\> ↓ clotting, ↓ albumin ↓ clearance of BR and ammonia --\> encephalopathy
237
Macroscopic changes of Alcoholic liver disease
Pale (fatty), Nodular (regenerating hepatocytes), Fibrous cuffs around nodules
238
Types of shunting
Intrahepatic shunting - Fibrosis blocks normal flow of blood ∴ intra-hepatic shunting bypasses hepatocytes --\> central vein (toxins enter systemic circulation) Extrahepatic shutning - Caput medusae - Oesophgeal varices - Ascites - Splenomegaly Tx: β-blockers, spleno-renal shunt (bypass liver + toxins enter systemic circulation)
239
Courvoisier's law
Jaundice + palpable gallbladder = Pancreatic cancer Gallstones --\> non-palpable, shrunken, small, fibrotic gallbladder
240
Define GFR + NR
Glomeruar filtration rate = flow from glomerulus to Bowman's capsule NR \> 90 ml/min
241
Ideal marker for GFR
Not bound to serum proteins Freely filtered Not secreted or absorbed IF ALL TRUE --\> Clearance = GFR
242
Define clearance
Clearance = [urine] x V / [plasma] = volume of plasma which is completed cleared of a substance in a unit of time
243
Markers of GFR (5)
Inulin Cr-EDTA Blood urea Serum creatinine Cystatin C
244
Gold standard marker for GFR
Inulin BUT not used clinically (difficult measuring inulin concentration), only used in Research
245
Exogenous marker of GFR used clinically
Cr-EDTA (single injection GFR measurement, measure radioactivity in plasma samples) BUT only used prior to chemotherapy (requires accurate GFR measurement)
246
Endogenous markers of GFR
Blood urea (highly dependent on nutritional state ∴ limited clinical value) Creatinine - geneartion depends on muscle mass, age, sex and ethnicity, actively secreted by tubular cells and non-linear relationship with GFR Cystatin C - difficult to acquire this assay (only used if eGFR 45-59 and normal albumin-to-Creatinine ratio), influenced by thyroid dysfunction
247
Equation to estimate GFR using Creatinine
CKD-EPI --\> used to calculate eGFR
248
How to quantify proteinuria
Urine Protein:Creatinine Ratio (PCR) 24 hour urine collection no longer used
249
Urine dipstick: haematuria
-ve reliably excludes haematuria +ve suggests blood OR myoglobinuria (rhabdomyolysis)
250
Urine dipstick: protein
Sensitive for albumin (poor sensitivity for Bence Jones proteins)
251
Urine dipstick: leucocyte esterase
-ve result is clinically significant
252
Urine dipstick: nitrite
Detects bacteria (esp Gram -ve) -ve result does NOT exclude UTI (not all bacteria produce nitrites)
253
Urine microscopy
Looks for Crystals (stones) RBC (stones, UTI) WBC (UTI, glomerulonephritis) Casts (glomerulonephritis) Bacteria (UTI)
254
Calcium oxalate crystals suggest
Anti-freeze poisoning Ethylene glycol is metabolised to calcium oxalate --\> precipitates as crystals in renal tubules/ureters
255
1st line Ix for renal stones
CT KUB
256
Staghorn calculi - cause, component
Due to recurrent UTI with urease-producing bacteria (proteus, klebsiella, pseudomonas, Enterobacter) Composed of magnesium ammonium phosphate
257
Use of USS KUB
Hydronephrosis suggests AKI Small, shrunken kidneys suggest CKD
258
Use of DMSA scan
Look for anatomical defects
259
Use of renal biopsy
Gold standard for diagnosis
260
Define AKI
↑ serum Creatinine (↑ 0.3mg/dl) ↓ urine volume (\<0.5ml/kg/hr)
261
AKI vs CKD
AKI: acute ↓ GFR, reversible, Tx aims to reverse disease process CKD: long standing ↓ GFR, irreversible, Tx aims to prevent worsening disease + prevent complications of CKD
262
DDx AKI vs CKD
Renal biopsy (AKI will likely show acute tubular necrosis)
263
Types of AKI
Pre-renal, Intrinsic, Post-renal
264
Causes of pre-renal failure
Acute blood loss Hypotension Oedematous states (ascites, pleural effusion) Renal artery stenosis Drugs (NSAIDs, Calcineurin inhibitors, ACEi, ARBs, Diuretics)
265
ACEi and renal artery stenosis
Kidney compensates for renal artery stenosis by constricting/dilating other renal arteries/arterioles to maintain GFR ACE inhibitor disrupts these compensatory mechanisms --\> acute AKI
266
Causes of post-renal failure
Intra-renal obstruction Ureteric obstruction Prostatic / Urethral obstruction Blocked urinary catheter
267
USS to DDx likely location of post-renal failure
If single kidney has dilated calyces, obstructive uropathy --\> issue in ureter If both kidneys affected, problem in bladder or lower down
268
Causes of Intrinsic AKI
Vascular disease (e.g. vasculitis) Glomerular disease (e.g. glomerulonephritis) Tubular disease - Ichaemic (most common) - prolonged pre-renal AKI --\> acute tubular necrosis - Endogenous toxins (rhabdomyolysis --\> myoglobinuria, Ig in multiple myeloma) - Exogenous toxins (contrast, nephrotoxic drugs) Interstitial disease (e.g. analgesic nephropathy)
269
Mechanisms of renal injury
Inflammation (glomerulonephritis, vascultisi) Protein deposition OR infiltration (amyloidosis, lymphoma, myeloma)
270
Nephrotoxic drugs
Aminoglycosides (gentamicin, amikasin), aciclovir
271
Signs of ATN
Epithelial cell casts in urine
272
Causes of CKD
Diabetes Atherosclerosis Hypertension Chronic glomerulonephritis Obstructive uropathy Polycystic kidney disease
273
Normal kidney function
Homeostatic function (excretion of water-soluble waste, water balance, electrolyte balance, acid-base) Hormonal funcion (EPO, RAS, Vitamin D)
274
Consequences of CKD
Failure of acid base homeostasis --\> Metabolic acidosis, Hyperkalaemia (failure to excrete H+ ions, K+ leaves cells to swap for H+ to maintain elec neutrality) ----- Tx: oral sodium bicarbonate Failure of hormonal function --\> Anaemia, Renal bone disease ----- Tx: EPO ----- Tx: Phosphate bindiners, activated Vitamin D, Cinacalcet (suppresses PTH), Dialysis ↑ risk of CVD - Vascular calcification - different to traditional lipid-rich atheromas - Uraemic cardiomyopathy (LV hypertrophy, dilatation, dysfunction) Uraemia
275
Major cause of hyperkalaemia in CKD
Dietary intake (milk, chocolate, dried fruit, tomatoes)
276
Types of renal bone disease
Osteitis fibrosa - due to HyperPTH --\> resorption of calcified bone (replaced by fibrosis tissue) Osteomalacia - due to Vitamin D deficiency --\> demineralisation of bone osteoid Adyanmic bone disease - complication of Tx of HyperPTH, supression of PTH --\> LOW bone turnover and LOW osteoid
277
Types of renal replacement therapy
Haemodialysis - through fistula, in hospital Peritoneal dialysis - at home, less effective Transplantation - pelvic kidney
278
Contraindications for renal transplant
Untreated malignancy Untreated HIV infection Active infection Life expectancy \< 2 years
279
Indications for dialysis as an emergency
Pulmonary oedema Refractory hyperkalaemia Metabolic acidosis Uraemic encephalopathy Drug toxicity (e.g. Lithium)
280
Smith's fracture
Smith's fracture = Reverse of Colles's fracture (i.e. fracture if forward, not backwards) Fallen on hand inflexed (land on back of hand)
281
DDx haematuria
Renal stones - painful haematuria Glomerulonephritis - painless haematuria, autoimmune Subacute bacterial endocarditis - microscopic haematuria
282
Ix for renal stones
Abdo X-ray: detects Calcium renal stones (radio-opaque), quick, misses non-calcified renal stones (uric acid, gout = radiolucent) OR Abdo USS: detects ALL renal stones, need to book
283
Ix of choice if found renal stones
Calcium (N.B. PTH is un-interpretable without Ca)
284
Complications of hypercalcaemia
Renal stones (calcium), Pancreatitis, Osteitis fibrosa et cystica (↑ osteoclast activation --\> osteolytic lesions --\> fractures)
285
Which organism causes UTI in Calcium renal stones
Proteus maribilius
286
Risk factors for renal calcium stones
Dehydration, Hypercalacemia, Hyperparathyroidism, Hypercalciuria
287
Tx of renal stones
Watchful waiting (most stones pass), Lithotrypsy (USS waves), Cystopscopy (look and pull), Lithotomy (open and remove)
288
Parathyroidectomy - Ix to open or not?
Technicium scan + USS results concordant --\> do not need to open neck If NOT concordant --\> surgical open neck to visual all 4 parathyroids + remove largest parathyroid
289
CXR of Sarcoidosis
Bilateral hilar lympadenopathy
290
Histology of Sarcoidosis
Non-caseating granuloma
291
Histology of TB
Caseating granuloma
292
DDx of non-caseating granuloma
Sarcoidosis, Crohn's disease, PBC
293
ECG territories + arteries
II, III, aVF = RCA I, aVL, V5, V6 = LCA V1-V4 = LAD
294
Anterior pitutary hormones (6) + their hypothalmic control
GHRH --\> GH TRH --\> TSH & Prolactin LHRH --\> FSH/LH CRH --\> ACTH N.B. Prolactin is controlled by TRH (+ve) and Dopamine (-ve)
295
Define macroadenoma and microadenoma
MRI pituitary macroadenoma \> 1cm (visual field defects) and microadenoma \< 1cm (10% general population)
296
Ix for Macroadenoma
MRI + visual field assessment
297
Causes of ↑ prolactin
Prolactinoma, DA antagonists (anti-psychotics), Pregnancy
298
Components of combined pitutiary function test (CPFT)
Tip: it's gonna get LIT ---- LHRH --\> stimulates LH/FSH ---- Insulin --\> induce hypoglycaemia --\> stimulates ACTH and GH ---- TRH --\> stimulates TSH and Prolactin Assess function of anterior pituitary
299
Contraindications to pituitary function test (3)
IHD, Epilepsy, untreated hypothyroidism (impairs GH and cortisol response)
300
Interpreting pitutiary function test
Direction of change (rise, fall) is important - rather than absolute numbers Glucose \< 2.2mM required for test to be valid (adequate hypoglycaemia) Prolactin \> 6000 suggests Prolactinoma
301
Treatment for Pituitary failure
Hormone replacement - Hydrocortisone (most urgent) - Thyroxine - Oestrogen replacement - GH replacement N.B. Do not need to give Fludrocortisone (aldosterone replacement) as Pituitary does NOT control Aldosterone (RAS does!)
302
Treatment for prolactinoma
Dopamine agonists (Cabergoline, Bromocriptine) +/- Surgery
303
Non-functioning pitutiary adenoma
Non-functioning adenoma compresses stalk --\> pituitary failure Prevent DA reaching pitutiary ∴ ↓ negative inhibition to produce prolactin --\> hyperprolactinaemia
304
Acromegaly - Ix
GH: ↑ IGF-1: ↑ OGTT: - normal: ↓ GH - Acromegaly: ↑ GH (unknown why)
305
Stimulate GH relase
Exercise, Insulin (gold standard)
306
Acromegaly - Tx
Pituitary surgery Pituitary radiotherapy Cabergoline Octerotide
307
Should you use prednisolone vs hydrocortisone
Prednisolone mimics circadian rhythm of cortisol release more closely than hydrocortisone (rapidly metabolised, needs multiple doses)
308
Does pituitary failure cause hypotension?
NO - pitutiary failure causes ↓ GH, ↓ Prolactin, ↓ TSH, ↓ FSH/LH, ↓ ACTH (--\> ↓ Cortisol) Cortisol does not control BP Addison's disease --\> ↓ cortisol + ↓ aldosterone (--\> ↓ BP) Aldosterone controls BP Pituitary does NOT control aldosterone (RAS does!)
309
Posterior pituitary hormones
ADH/Vasopressin, Oxytocin
310
Use of enzymes
Identify disease, detect tissue injury, markers of therapeutic response, enzymes to measure other substances
311
Release of enzymes following tissue injury (location)
Small amount of intracellular enzymes normally reponse (normal cell turnover) Tissue injury --\> release of cytosolic enzymes, then sub-cellular enzymes
312
Define iso-enzyme
Different forms of the same enzyme
313
Which tissues produce ALP
Liver, Bone, Placenta, Intestine
314
DDx iso-forms of ALP
Electrophoresis or bone-specific assay of ALP
315
Physiological causes of ↑ ALP
Pregnancy, growth spurt
316
Pathological causes of ↑ ALP (from bone)
Paget's (highest ALP), Osteomalacia, Tumours, Fractures, Osteomyelitis
317
Pathological causes of ↑ ALP (from liver)
Cholestasis (highest ALP), Cirrhosis, Infiltrative disease of liver, Hepatitis
318
Enzyme markers in acute pancreatitis
↑ Amylase, ↑ Lipase (more specific)
319
Causes of ↑ amylase
Acute pancreatitis, Salivary gland pathology (Mumps), acute abdomen states
320
3 isoforms of creatine kinase
Forms dimers, 3 isoforms --- CK-MM = Muscle (95%) --- CK-MB = Cardiac (5%) --- CK-BB = Brain (1%) N.B: mesauring CK measures all 3 isoforms (individual isoforms are NOT routinely measured)
321
Causes of ↑ CK
Muscle damage (falls, injection) Myopathy ----- Statin-related myopathy (onset within weeks of starting statin, spectrum from myalgia to rhabdomyolysis --\> AKI) ----- Ducheene muscular dystrophy ----- Polymyositis / Dermatomyosistis MI (non-specific marker) Ethnicity (Afro-Carribean)
322
Cardiac biomarkers for MI
(1) Myoglobin - rapid rise and fall (non-specific as found in all muscle fibres, found in cytoplasm) (2) Cardiac troponin (2nd to rise, found within contractile apparatus) (3) CK-MB (found in nucleus and mitochondria)
323
Current marker of choice for MI
Cardiac troponin (NOT an enzyme)
324
When to measure cardiac troponin
Measure at 6 hours and 12 hours AFTER onset of chest pain Lack of troponin rise excludes MI (98% specifcity and 100% sensitivity at 12 hours) Cardiac troponin rises 4-6 hours post MI, peaks at 12 hours and remains elevated for 10 days
325
Diagnostic criteria for MI
Rise and fall or Troponin OR rise and fall or CK-MB + 1 of following (ischaemic symptoms, pathological Q waves, ECG ischaemic changes, coronary artery intervention)
326
Biomarkers in heart failure
Atrial natriuretic peptide (secreted by atria) Brain natriuretic peptide (secreted by ventricles)
327
What do enzyme assays measure
Enzyme activity (NOT enzyme mass)
328
Define the unit of enzyme activity
1 international unit = quantity of enzyme required to catalyse the reaction of 1umol of substrate per minute (at a given tmperature and pH) Unit = U/L
329
Specific liver enzyme marker
GGT
330
Vitamin and Mineral markers
Vitamin A: serum Vitamin A (rare) Vitamin D: 25(OH)D3 = inactive form Vitamin E: serum Vitamin E (rare) Vitamin K: INR Vitamin B1: RBC transketolase (rare) Vitamin B2: Serum Vitamin B2 (rare) Vitamin B6: RBC AST activation (rare) Vitamin B12: Serum B12 Vitamin C: Serum Vitamin C (rare) Folate: RBC folate Niacin: no test available
331
Fat soluble vitamins
Vitamin A, D, E, K
332
Vitamin A deficiency
Colour blindness
333
Vitamin A excess
Exfoliation hepatitis
334
Vitamin D deficiency
Osteomalacia/Rickets
335
Vitamin D excess
Hypercalcaemia (and secondary hypoparathyroidism)
336
Vitamin E deficiency
Anaemia, Neuropathy
337
Vitamin K deficiency
Prolonged PT --\> bleeding
338
Types of Vitamin B1 deficiency (thiamine)
Wet Beri Beri and Dry Beri Beri
339
Wet Beri-Beri
Heart failure, Oedema
340
Dry Beri-Beri
Wernicke's encephalopathy (Ataxia, Confusion, Eye signs - opthalmoplagia)
341
Vitamin B2 deficiency (riboflavin)
Glossitis
342
Vitamin B6 deficiency (pyridoxine)
Dermatitis, Anaemia
343
Vitamin B6 excess
Neuropathy
344
Vitamin B12 deficiency (cobalamin)
Due to: Pernicious anaemia Peripheral neuropathy
345
Vitamin C deficiency (ascorbate)
Scurvy
346
Vitamin C excess
Renal stones
347
Folate deficiency
Megaloblastic anaemia, Neural tube defects
348
Niacin deficiency
Pellegra (Dermatitis, Diarrhoea, Dementia, Death)
349
Iron deficiency
Microcytic anaemia
350
Iron excess
Due to haemochromatosis Bronze diabetes, Infertility (iron deposition)
351
Iodine deficiency
Hypothyroidism, Goitre
352
Zinc deficiency
Dermatitis
353
Copper deficiency
Anaemia
354
Copper excess
Due to Wilson's disease Kayser-Flyscher rings, deposition in basal ganglia
355
Fluoride deficiency
Dental caries (tooth decay)
356
Fluoride excess
Flourosis (teeth staining)
357
Hunger hormone
Ghrelin
358
Satiety hormones
PYY, Leptin
359
Defintion of obesity
Based on BMI (\>25), Waist:hip ratio, Waist circumference
360
Types of protein
Indispensable proteins (only available from diet) "Conditoinally" indispensable proteins (required for certain parts of lifespan e.g. fetus) Dispensable proteins = human body can only produce 5 amino acids
361
Assessment of protein
Assessment of muscle bulk
362
Types of fat
Saturated (bad), Monounsaturated, Polyunsaturated (best), Trans-monosaturates (worst), Cis-monosaturates
363
Types of carbohydrates
Oligosaccharides (simple), Polysaccharides (complex), non-starch carbohydrates (fibre)
364
Metabolic syndrome pentad
Diabetes, ↑ waist circumference, insulin resistance, ↓ HDL levels, hypertension
365
Types of Malnutrition
Marasmus: due to low calorie intake --\> severe muscle wasting, no subcutaneous fat Kwashiorkor: due to lack of protein --\> oedematous, hepatomegaly, lethargic
366
Ix to decide whether to start statin therapy
Total plasma cholesterol, plasma LDL
367
6 liver functions
Intermediary metabolism (glycolysis, glycogen storage, gluconeogenesis) Protein synthesis (clotting factors, albumin) Xenobiotic metabolism (detoxification of drugs) Hormone metabolism (Vitamin D, steroid hormone, peptide hormone catabolism/recycling amino acids) Bile synthesis Reticulo-endothelial (Kupffer cells clear infection, Erythropoesis in thalassaemia)
368
Process of xenobiotic metabolism
(1) Chemical modification (redox, acetylation/de-acetylation, CYP450) (2) Conjugation (glucoronate, sulphate) (3) Excretion in bile
369
LFTs
ALT, AST, ALP, GGT
370
Markers of liver's synthetic function
Albumin, PT
371
AST \> ALT
Alcoholic hepatitis (alcoholicS)
372
ALT \> AST
ViraL hepatitis
373
↑ GGT
Chronic alcohol use, bile duct disease, liver mets, drugs
374
↑ ALP
Obstructive jaundice (gallstones, pancreatic cancer), Bile duct damage, viral hepatitis, alcoholic liver disease
375
Albumin half life
Long half life (20 days) ∴ ↓ albumin indicates long-term change
376
Causes of ↓ albumin
↓ production (chronic liver disease, malnutrition) Loss (in gut, in kidney) Sepsis (3rd spacing sepsis, albumin enters tissue spaces --\> oedema)
377
Clotting half life
T1/2 = hours ∴ acute marker of liver function
378
↑ AFP
Hepatocellular carcinoma (hepatic damage, pregnancy, testicular cancer)
379
If ↑ ALP, next Ix
USS If ducts dilated --\> gallstones, cancer If ducts not dilated --\> drugs, PBC, PSC, pregnancy
380
Why pale stools, dark urine
No BR enters gut --\> no sterco/urobilinogen --\> pale stools Conjugated BR backpressure into systemic circulation --\> water soluble so enters urine --\> dark urine (only conjugated BR is water soluble)
381
Isolated ALT + asymptomatic
Fatty liver
382
↑ serum bile acids
Cholestasis of pregnancy, PBC, PSC
383
Drug-induced cholestasis
Augmentin, Co-amoxiclav
384
Causes of ALT \> 1000
Toxins (paracetamol) Viruses (viral hepatitis, EBV, CMV) Ischaemia
385
Isolated ↑ unconjugated BR, normal LFTs
Gilbert's syndrome
386
NR of Na
135 - 145
387
NR of K
3.5 - 5.3
388
NR of Hb
M 13.5 - 18.0, F 11.5 - 16.0
389
NR of WBC
4-11
390
NR of Plt
150-400
391
NR of Urea
2-7
392
NR of Creatinine
55-120
393
NR of osmolality
275-295
394
MEN1 (3Ps)
Pituitary, Pancreatic, Parathyroid
395
MEN2A (2Ps, 1M)
Parathyroid, Phaeo, Medullary thyroid
396
MEN2B (1P, 2Ms)
Phaeo, Medullary thyroid, Mucocutaneous neurmas (& Marfanoid)
397
ALP stands for
Alkaline phosphatase (ALP)
398
ALT stands for
Alanine aminotransferase (ALT)
399
AST stands for
Aspartate aminotransferase (AST)
400
GGT stands for
Gamma glutamyl transferase (GGT)
