Chemical Pathology Flashcards
1
Q
What are the roles of calcium?
A
- Part of the skeleton (99% of body calcium in skeleton)
- Metabolic: Action potentials and IC signalling
2
Q
Serum calcium is found in which 3 forms?
A
(1% of body calcium in serum)
- Free (“ionised”) ~50%- biologically active
- Protein-bound ~40%- albumin
- Complexed ~10%- citrate/phosphate
3
Q
What is the total serum Ca2+?
A
- 2.2- 2.6 mmol/L
4
Q
What is “Corrected” Ca2+?
A
- serum Ca2+ + 0.02*(40 - serum albumin in g/L)
- calcium levels important in muscle depolarisation and thus in the control of nerve and muscle
5
Q
What is the significance of corrected Ca2+?
A
- If you have a low albumin, the bound calcium will be low but the free calcium will be normal thus the corrected calcium refers to that
- The corrected calcium tells you that the problem is with the albumin and that the ionised calcium will be also be normal
6
Q
What does chronic calcium deficiency lead to?
A
- Loss of calcium from bone in order to maintain circulating calcium
- Plasma concentration must thus be maintained despite calcium and vitamin D deficiency
7
Q
How does the parathyroid gland respond to low calcium?
A
- Hypocalcaemia detected by parathyroid gland
- Parathyroid gland releases PTH
- PTH obtains Ca2+ from 3 sources
- Bone
- Gut (absorption)
- Kidney (reabsorption and renal 1 alpha hydroxylase activation)
8
Q
What two key hormones are involved in calcium homeostasis?
A
- PTH
- Vitamin D
9
Q
What is PTH and what is its roles?
A
- 84 aa protein
- Only released from parathyroids
Roles
- Bones & renal Ca2+ resorption
- Stimulate 1,25(OH)2 vit D synthesis (1 alpha hydroxylation)
- Also stimulates renal Pi wasting
10
Q
What are the stages of vitamin D synthesis?
A
- Sun converts 7-dehydrocholesterol to Cholecalciferol (D3)
- D3 is converted to 25-hydroxycholecalciferol in the liver (25 alpha hydroxylase)
- 25-OH D3 is converted to 1,25-dihydroxycholcalciferol in the kidneys (1 alpha hydroxylase)
- 1,25(OH)2 D3 is the physiologically active form
11
Q
What is ergocalciferol?
A
- Vitamin D2- a plant vitamin
12
Q
Where else is 1 alpha hydroxylase expressed?
A
- Rarely, this enzyme can be expressed in lung cells of sarcoid tissue
13
Q
What are the roles of 1,25(OH)2 vitamin D?
A
- Intestinal Ca2+ absorption
- Intestinal Pi absorption
- Critical for bone formation
14
Q
What are the roles of the skeleton? (Orthopaedic view)
A
- Structural framework
- Strong
- Relatively lightweight
- Mobile
- Protects vital organs
15
Q
What are the roles of the skeleton? (Metabolic view)
A
- Metabolic role in calcium homeostasis
- Main reservoir of calcium, phosphate and magnesium
16
Q
What are some metabolic bone diseases?
A
- Osteoporosis
- Osteomalacia
- Paget’s disease
- Parathyroid bone disease
- Renal osteodystrophy
17
Q
What is vitamin D deficiency?
A
- Defective bone mineralisation
- Childhood -> Rickets
- Adulthood -> Osteomalacia
- Vitamin D deficiency in the UK
- More than 50% adults have insufficient vitamin D
- 16% have severe deficiency during winter and spring
18
Q
What are the risk factors of vitamin D deficiency?
A
- Lack of sunlight exposure
- Dark skin
- Dietary
- Malabsorption
19
Q
What are the clinical features of vit D deficiency?
A
- Osteomalacia
- Bone & muscle pain
- Increased risk
- Biochem: low Ca2+ and Pi, raised ALP
- Looser zones
- Rickets
- Bowed legs
- Costrochondral swelling
- Widened epiphyses at the wrists
- Myopathy
20
Q
Outline osteomalacia
A
- Bone is demineralised
- Caused by vitamin D deficiency
- Renal failure
- Anticonvulsants induce breakdown of vitamin D
- Lack of sunlight
- Chappatis
21
Q
Outline osteoporosis
A
- Cause of pathological fracture
- Occurring more often as people live longer
- Loss of bone mass
- Bone slowly lost after age 20
- Residual bone normal in structure
22
Q
How does osteoporosis compare to osteomalacia?
A
- Reduction in bone density (bone mineralisation is normal)
- BIOCHEMISTRY NORMAL
- Asymptomatic until fracture. Then its too late
- Typical fracture: neck of femur, vertebral, wrist (Colle’s)
23
Q
How is osteoporosis diagnosed?
A
- DEXA scan
24
Q
What is the T-score?
A
- SD from mean of young healthy population (useful to determine risk)
- Osteoporosis - T-score < - 2.5
- Osteopenia - T-score between -1 and -2.5
25
What is the Z-score?
- SD from mean of aged-matched control (useful to identify accelerate bone loss in younger patients)
26
What are causes of osteoporosis?
- Childhood illness: failure to obtain peak bone mass
- Menopause
- Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional
- Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings
- Drugs: steroids
- Others eg genetic, prolonged intercurrent illness
27
What are some treatments for osteoporosis?
- Lifestyle: weight-bearing exercise, stop smoking, reduce EtOH
- Drugs:
- Vitamin D/Ca
- Bisphosphonates (eg alendronate) –↓ bone resorption
- Teriparatide (PTH derivative) – anabolic
- Strontium – anabolic + anti-resorptive
(Oestrogens – HRT)
- SERMs eg raloxifene
28
What are symptoms of hypercalcaemia?
- Polyuria/polydipsia
- Constipation
- Neuro - confusion/seizures/coma
- Unlikely unless Ca2+ > 3.0 mmol/L
- Overlap with Sx of hyperPTH
29
What is the hormonal response to hypercalcaemia?
- PTH release should be suppressed
30
What are causes of hypercalcaemia?
- If PTH is suppressed
- Malignancy
- Others (rare): sarcoid, vitamin D excess, thyrotoxicosis, milk akali syndrome
- If PTH is not suppressed
- Primary hyperparathyroidism (common)
- Familial hypocalciuric hypercalcaemia (rare)
31
Outline primary hyperparathyroidism
- Commonest cause of hypercalcaemia
- Parathyroid adenoma/hyperplasia/carcinoma
- Hyperplasia associated with MEN1
- Women > men
- Increased serum Ca, increased or inappropriate PTH, decreased serum Pi, increased urine Ca (due to hypercalcaemia)
- BONES (PTH bone disease) and STONES (renal calculi)
- Hypercalcaemia -> abdominal MOANS (constipation, pancreatitis), psychiatric GROANS (confusion)
32
What causes familial hypocalciuric (/benign) hypercalcaemia (FHH/FBH)?
- CaSR mutation
- Higher "set point" for PTH release -> mild hypercalcaemia
- Reduced urine Ca2+
33
What are the 3 types of hypercalcaemia in malignancy?
- Humoral hypercalcaemia of malignancy (e.g. small cell lung cancer)
- PTHrP
- Bone metastases (e.g. breast cancer)
- Local bone osteolysis
- Haematological malignancy (e.g. myeloma)
- cytokines
34
What are other causes of non-PTH driven hypercalcaemia?
- Sarcoidosis (non-renal 1 alpha hydroxylation)
- Thyrotoxicosis (thyroxine -> bone resorption)
- Hypoadrenalism (renal Ca2+ transport)
- Thiazide diuretics (renal Ca2+ transport)
- Excess vitamin D (eg sunbeds…)
35
What is the treatment of hypercalcaemia?
- Fluids
- Bisphosphonates (if cause known to be cancer) otherwise avoid.
- Treat underlying cause
36
What are clinical signs of hypocalcaemia?
- Neuro-muscular excitability
- Trosseau's sign
- Convulsions
- Hyperreflexia
37
What are causes of (low) PTH-derived hypocalcaemia?
- Surgical (inc. post-thyroidectomy)
- Auto-immune hypoparathyroidism
- Congenital absence of parathyroids (e.g. diGeorge syndrome)
- Mg deficiency (PTH regulation)
38
What are causes of non-PTH driven hypocalcaemia? (secondary hyperthyroidism if PTH is raised)
- vitamin D deficiency - dietary, malabsorption, lack of sunlight
- chronic kidney disease (1 alpha hydroxylation)- can progress to tertiary hyperparathyroidism
- PTH resistance ("pseudohypoparathyroidism")
39
What is Paget's disease?
- Focal disorder of bone remodeling
- Focal PAIN, warmth, deformity, fracture, SC compression, malignancy, cardiac failure
Pelvis, femur, skull and tibia
- Elevated alkaline phosphatase
- Nuclear med scan / XR
- Treatment = Bisphosphonates for pain
40
What are some other metabolic bone disorders?
- In primary hyperparathyroidism
- Loss of cortical bone -> # risk
- Osteitis fibrosa
- Renal osteodystrophy
- Due to secondary hyperparathyroidism + retention of aluminium from dialysis fluid
- Both rare due to modern Rx of underlying disorders
41
What is hyponatraemia?
- Serum sodium < 135 mmol/L
| - Commonest electrolyte abnormality in hospitalized patients
42
What is the underlying pathogenesis of hyponatraemia?
- Increased extracellular water
43
What is ADH?
- A hormone which resaborbs water
- Acts on V2 receptors (collecting duct)
- Insertion of aquaporin-2
- V1 receptors
- vascular smooth muscle
- vasoconstriction (higher concentrations)
- alternative name ‘vasopressin’
44
What are the two main stimuli for ADH secretion?
- Serum osmolality (mediated by hypothalamic osmoreceptors).
| - Blood volume/pressure (mediated by baroreceptors in carotids, atria, aorta)
45
What is the effect of increased ADH secretion on serum sodium?
- Hyponatraemia
46
What is the first step in the clinical assessment of a patient with hyponatraemia?
- Clinical assessment of volume status
| - Hypovolaemic? Euvolaemic? Hypervolaemic?
47
What are the clinical signs of hypovolaemia?
- Tachycardia
- Postural hypotension
- Dry mucous membranes
- Reduced skin turgor
- Confusion/drowsiness
- Reduced urine output
- Low urine Na+ (<20)
48
What are the clinical signs hypervolaemia?
- Raised JVP
- Bibasal crackles (on chest examination)
- Peripheral oedema
49
What are the causes of hypovolaemic hyponatraemia?
- Diarrhoea
- Vomiting
- Diuretics
- Salt losing nephropathy
50
What are the causes of euvolaemic hyponatraemia?
- Hypothyroidism
- Adrenal insufficiency
- SIADH
51
What are the causes of hypervolaemic hyponatraemia?
- Cardiac failure
- Cirrhosis
- Nephrotic syndrome
52
What are causes of SIADH?
- CNS pathology
- Lung pathology
- Drugs (SSRI, TCA, opiates, PPIs, carbamazepine)
- Tumours
- Surgery
53
What investigations would you order in a patient with euvolaemic hyponatraemia?
- ? Hypothyroidism: Thyroid function tests
- ? Adrenal insufficiency: Short Synacthen test
- ? SIADH: Plasma & urine osmolality (low plasma & high urine osmolality)
54
How would you manage a hypovolaemic patient with hyponatraemia?
- Volume replacement with 0.9% saline
55
How would you manage a hypervolaemic patient with hyponatraemia?
- Fluid restriction
| - Treat the underlying cause
56
How would you manage a euvolaemic patient with hyponatraemia?
- Fluid restriction
| - Treat the underlying cause
57
Describe severe hyponatraemia
- Reduced GCS
- Seizures
- Seek expert help (Treat with Hypertonic 3% saline)
58
What is the most important point to remember while correcting hyponatraemia?
- Serum Na must NOT be corrected > 8-10 mmol/L in the first 24 hours
- Risk of osmotic demyelination (central pontine myelionlysis)
- quadriplegia, dysarthria, dysphgia, seizures, coma, death
59
What drugs can be used to treat SIADH?
If water restriction is insufficient
- Demeclocycline
- Reduces responsiveness of collecting tubule cells to ADH
- Monitor U&Es (risk of nephrotoxicity)
- Tolvaptan
- V2 receptor antagonist
60
What is hypernatraemia?
- Serum [Na+] > 145 mmol/L
- Unreplaced water loss
- Gastrointestinal losses, sweat losses
- Renal losses: osmotic diuresis, reduced ADH release/action (Diabetes insipidus)
- Patient cannot control water intake e.g. children, elderly
61
What investigations would you order in a patient with suspected diabetes insipidus?
- Serum glucose (exclude diabetes mellitus)
- Serum potassium (exclude hypokalaemia)
- Serum calcium (exclude hypercalcaemia)
- Plasma & urine osmolality
- Water deprivation test
62
How do you treat hypernatraemia?
- Fluid replacement
- Treat the underlying cause
- Correct water deficit
- 5% dextrose
- Correct extracellular fluid volume depletion
- 0.9% saline
- Serial Na+ measurements
- Every 4-6 hours
63
What are the effects of of diabetes mellitus on serum sodium?
- Variable
- Hyperglycaemia draws water out of the cells leading to hyponatraemia
- Osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia
64
What is the most abundant intracellular cation?
- Potassium
65
What is the serum concentration of potassium?
- 3.5-5.0 mmol/L
66
Which hormones are involved in renal regulation of potassium?
- Angiotensin II
| - Aldosterone
67
How does aldosterone control potassium secretion?
- Aldosterone number of open Na+ channels in the luminal membrane
- Increased sodium reabsorption makes the lumen electronegative & creates an electrical gradient
- Potassium is secreted into the lumen
68
What are the stimuli for aldosterone secretion?
- Angiotensin II
| - Potassium
69
What are the main causes of hyperkalaemia?
- Renal impairment: reduced renal excretion
- Drugs: ACE inhibitors, ARBs, spironolactone
- Low Aldosterone
- Addison’s disease
- Type 4 renal tubular acidosis (low renin, low aldosterone)
- Release from cells: rhabdomyloysis, acidosis
70
What is the main the ECG change associated with hyperkalaemia?
- Peaked T waves
71
How would you manage a patient with hyperkalaemia?
- 10 ml 10% calcium gluconate
- 50 ml 50% dextrose + 10 units of insulin
- Nebulized salbutamol
- Treat the underlying cause
72
What are the causes of hypokalaemia?
- GI loss
- Renal loss
- Hyperaldosteronism, (Excess cortisol)
- Increased sodium delivery to distal nephron
- Osmotic diuresis
- Redistribution into the cells
- Insulin, beta-agonists, alkalosis
- Rare causes: Renal tubular acidosis type 1& 2, hypomagnesaemia
73
What are the clinical features hypokalaemia?
- Muscle Weakness
- Cardiac arrhythmia
- Polyuria & polydipsia (nephrogenic DI)
74
What screening test would you order in a patient with hypokalaemia and hypertension?
- Aldosterone: Renin ratio
75
How would you manage a patient with hypokalaemia?
- Serum potassium 3.0-3.5 mmol/L
- Oral potassium chloride (two SandoK tablets tds for 48 hrs)
- Recheck serum potassium
- Serum potassium < 3.0 mmol/L
- IV potassium chloride
- Maximum rate 10 mmol per hour
- Rates > 20 mmol per hour are highly irritating to peripheral veins
- Treat the underlying cause e.g. spironolactone
76
How do you work out osmolality?
- 2(Na + K) + U + G
77
How do you work out anion gap?
- Anion gap = Na + K – Cl – bicarb
78
What is Schmidt's syndrome?
- Addison’s disease and primary hypothyroidism occur together more commonly than by chance alone
79
What is the test for Addison's?
- Short SYNACTHEN test.
- Measure cortisol + ACTH at start of test
- Administer 250 micrograms synthetic ACTH by IM injection.
- Check cortisol at 30 and 60 minutes
80
What are potential abnormal adrenal masses?
- Phaeochromocytoma
(Adrenal medullary tumour secreting adrenaline).
- Conn’s syndrome (adrenal tumour secreting aldosterone)
- Cushing’s syndrome (secretes cortisol)
81
What is a phaeochromocytoma?
- Adrenal medullary tumour that secretes adrenaline, and can cause severe hypertension, arrhythmias and death.
- THUS A MEDICAL EMERGENCY
- Urgent alpha blockade with phenoxybenzamine.
- Add beta blockade.
- Finally arrange surgery.
82
What is Conn's syndrome?
- Conn’s syndrome.
- The adrenal gland secretes high levels of aldosterone autonomously. This will cause hypertension and this will in turn suppress the renin at the JGA
83
What is the test for Cushing's?
- Dexamethasone suppression. This will usually suppress cortisol levels to undetectable levels.
- Not so in Cushing’s.
84
What are causes of Cushing's syndrome?
- Being on oral steroids for something else
- Pituitary dependent Cushings disease (85%)
- Ectopic ACTH (5%)
- Adrenal adenoma (10%)
85
Describe pituitary sinus sampling
- Distinguishing from ectopic ACTH
- Needs excellent angiography
- Not always available
86
What are the normal ranges in acid/base equations?
- pH: 7.35 - 7.45
- CO2: 4.7 - 6kPa
- Bicarbonate: 22 – 30 mmol/l
- O2: 10 – 13kPa
87
What are the causes of metabolic acidosis?
- Lactate build up DKA
- Renal tubular acidosis
- Intestinal fistula
88
What are the causes of metabolic alkalosis?
- Pyloric stenosis
- Hypokalaemia
- Ingestion of bicarbonate
89
What are the causes of respiratory acidosis?
- Lung injury – pneumonia,
- COPD
- Decreased ventilation – Morphine OD
90
What are the causes of respiratory alkalosis?
- Mechanical Ventilation
| - Anxiety/ panic attack
91
What is a mnenomic for elevated anion gap metabolic acidosis?
- Ketoacidosis (DKA, alcoholic, starvation)
- Uraemia (renal failure)
- Lactic Acidosis
- Toxins (ethylene glycol, methanol, paraldehyde, salicylate)
92
What is the normal glomerular filtration rate?
- 120ml/min
| - Age related decline approximately 1ml/min per year
93
What is clearance?
- The volume of plasma that can be completed cleared of a marker substance in a
unit of time
- If marker is not bound to serum proteins, freely filtered at the glomerulus, and not secreted/reabsorbed by tubular cells, Clearnce = GFR
94
What is the gold standard measure of GFR?
- Inulin.
- But requires steady state infusion and difficult to
assay so it is reserved for research purposes only
95
What are clinically viable measures of GFR?
- 51Cr-EDTA
- 99Tc- DTPA
- Iohexol
96
What are endogenous markers of GFR?
- Creatinine
| - Urea
97
How do you work out clearance?
- (U x V)/P
- U = Urinary conc
- P = Plasma conc
98
What are characteristics ideal for measuring clearance?
- Not plasma protein bound
- Freely filtered at glomerulus
- Not modified by tubules
99
Describe creatinine as an endogenous marker for GFR
- Derived from muscle cells (small amount from intestinal absorption)
- Freely filtered
- Creatinine is actively secreted into urine by tubular cells
- Generation is not equivalent in different individuals
- Muscularity
- Age
- Sex
- Ethnicity
100
What is Cockcroft Gault?
- eCCr = (1.23 x (140-age) x weight) / serum creatinine
- Adjust by 0.85 if female
- Estimates creatinine clearance (not GFR)
- May overestimate GFR, especially when <30ml/min
101
What is the MDRD equation? (modification of diet in renal disease study)
- eGFR = 186 x ( Creat x 0.0113) -1.154 x Age -0.203
- Adjust by 0.742 if female
- Requires age, sex, serum creatinine and ethnicity
- May underestimate GFR if above-average weight and young
102
What are alternative endogenous markers of GFR?
- Cystatin C
- 13.6kD protein
- Cysteine protease inhibitor
- Constitutively produced by all nucleated cells
- Constant rate generation
- Freely filtered
- Almost completely reabsorbed and catabolised by tubular cells
103
Describe measurement of renal function in practice
- Serum creatinine is an insensitive marker of GFR
- Other endogenous blood markers (ie Cystatin C) are better
- Constant rate infusion GFR measurement is a research tool
- Single injection GFR measurement is reserved for specific situations
- In practice, estimated GFR / CCr is the best compromise
104
What is Urine protein:creatinine ratio?
- Quantitative assessment of amount of proteinuria
| - Measurement of creatinine corrects for urinary concentration
105
Describe 24 hour urine collection
- Cumbersome and messy
- Highly inaccurate without specific patient education
- Estimation of proteinuria superceded by urinary PCR
106
What are examples of urine examination and their uses?
- Single sample
- Dipstick testing
- Microscopic examination
- Proteinuria quantification
- Electrolyte estimation
- 24hour collection
- Creatinine clearance estimation
- Stone forming elements
- (Proteinuria quantification)
- (Electrolyte estimation)
107
Describe urine dipstick testing
- pH
- 4.5 to 8.0
- Specific gravity
- 1.003 to 1.035
- (Bowmans space 1.007 to 1.010)
- Protein
- Sensitive to albumin, not BJPs
- Zero, Trace, 1+ to 4+
- Blood
- Leucocyte esterase
- Negative result is significant
- Nitrite
- Detects bacteria, esp. Gm negatives
108
Describe urine microscopy
- Centrifuge at 3000rpm
- 5-10 minutes
- Examine sediment for:
- Crystals
- Red blood cells
- White blood cells
- Casts
- Bacteria
109
What are the different types of renal imaging?
- Plain KUB films
- Intravenous urogram (IVU)
- KUB ultrasound
- Cross-sectional imaging (CT and MRI)
- Functional imaging (static and dynamic renograms)
110
What is normal liver function?
- Intermediary Metabolism
- Protein Synthesis
- Xenobiotic Metabolism
- Hormone Metabolism
- Bile Synthesis
- Reticulo-endothelial
111
What is intermediary metabolism?
- Enzyme-catalysed processes within cells that extract energy from nutrient molecules and use that energy to construct cellular components
- Glycolysis
- Glycogen storage
- Glucose synthesis
- Amino-acid synthesis
- Fatty acid synthesis
- Lipoprotein metabolism
112
Describe Xenobiotic metabolism in the liver
- Chemical modification
- P450 Enzyme System
- Acetylation / de-acetylation
- Oxidation / Reduction
-->
- Conjugation
- glucuronate
- sulphate
- Excretion
113
Describe Vitamin D metabolism in the liver
- Vitamin D
- hydroxylation
- Steroid Hormone
- conjugation
- excretion
- Peptide Hormone
- catabolism
114
What are the constituents and functions of bile?
Constituents
- Water
- Bile salts/acids
- Bilirubin
- Phospholipids
- Cholesterol
- Proteins
- Drugs and Metabolites
Function
- Excretion
- Micelle formation
- Digestion`
115
Describe the reticulo-endothelial function in the liver
- Kupffer Cells
- Clearance of infection and LPS
- Antigen presentation
- Immune modulation
- cytokines etc.
- Erythropoesis
116
What are the LFTs?
- Alanine Transaminase
- Aspartate Transaminase
- Alkaline Phosphatase
- Gamma glutamyl transferase
117
What are the markers of liver cell damage?
LFTs
- ALT
- AST
- ALP
- GGT
118
What are the markers of synthetic function?
- Albumin
- Clotting (INR)
- Glucose
- Bilirubin
119
Describe ALT
- Found primarily in the liver, more sensitive than AST for hepatocyte damage
- Raised when hepatocytes die. AST:ALT =1 supportive of
viral hepatitis
120
Describe AST
- Found in the Liver, cardiac and skeletal muscle, and the kidney and brain
- AST:ALT = 2 is supportive of alcoholic hepatitis
121
Describe ALP
- Found in the liver, bones, placenta
- Raised with cholestasis (either intrahepatic or extrahepatic) and
bone disease, ↑++ in pregnancy
122
Describe GGT
- Found in hepatocytes and biliary cells, also found in the kidney and pancreas.
- Elevated in chronic alcohol use
- Also bile duct disease and metastases. Used to confirm hepatic source of ↑ALP
123
Describe albumin (Synthetic hepatocellular dysfunction)
- Average adult synthesises 200mg/kg of albumin per day
- Important serum protein which binds many hormones, calcium and other metabolites.
- Hypoalbuminaemia is common in hospital patients as acute illness/systemic inflammation and malnutrition can contribute to a reduced albumin
- Hypoalbuminaemia in critically ill patients is a poor prognostic factor
124
Describe clotting factors (Synthetic hepatocellular dysfunction)
- The liver synthesises Factor V, VII, IX, X, XII, XIII and fibrinogen and prothrombin
- In practical terms INR (International normalised ratio) is measured, this is the prothrombin time standardised for age and population expressed as a ratio of ‘normal’.
- Deranged clotting is not diagnostic of hepatocellular dysfunction on its own as it could be due to multiple other aetiologies – for example iatrogenic (therapeutic warfarinisation), hereditary thrombophillia, acquired consumption
(DIC)
125
What is Alpha-feto protein? (AFP)
- glycoprotein MW 69 000 /albumin superfamily
- Fetal transport-immune regulation/tolerance in fetal life made by yolk sac, GI epithelium and liver
- In adult concentration low / no known function
used in diagnosis of hepatocellular carcinoma (but may rise too late or not at all)
- Also raised in hepatic damage/regeneration raised in pregnancy and testicular cancer
126
What is jaundice?
- Elevated serum bilirubin manifesting as yellowing of the skin or sclera (icterus)
127
What is bilirubin?
- Bilirubin is a breakdown product of heme, and the majority is produced by breakdown
of haemoglobin.
- Normal metabolism of bilirubin involves conjugation in hepatocytes, and subsequent secretion into the bile ducts and then the GI tract
- Conjugated bilirubin is metabolised further in the GI tract into urobilinogen
- Urobilinogen is then partially reabsorbed and excreted in the kidneys as Urobilin
- The rest of the urobilinogen is converted to stercobilin which is the brown pigment in faeces.
- Disorder of bilirubin metabolism can therefore be pre-hepatic [raised bilirubin production], hepatic [decreased ability to conjugate bilirubin] or post hepatic [decreased ability to excrete conjugated bilirubin].
128
What are pre-hepatic causes of jaundice?
- Haemolysis
| - Congestive heart failure
129
What are lab findings of pre-hepatice jaundice?
- Elevated unconjugated bilirubin
- Rediced haemoglobin
- Reduced haptoglobin
- Raised LDH
130
What are hepatic causes of jaundice?
- Acute or chronic liver failure
- Gilbert syndrome
- Crigler-Najjar syndrome
- Viral Hepatitis
- Alcoholic Hepatitis
- PBC
131
What are lab findings of hepatic jaundice?
- Elevated Unconjugated bilirubin
- Raised Aminotransferases
- Synthetic dysfunction may be
present
132
What are post-hepatic causes of jaundice?
- Obstruction of the biliary tree from any cause (Think intraluminal – Stones, strictures, Luminal – Mass/Neoplasm,
- Inflammation e.g. PSC/PBC,
- Extra-luminal – Pancreatic Ca, cholangio Ca
133
What are lab findings of post-hepatic jaundice?
- Elevated conjugated bilirubin
| - Elevated bilirubin in the urine [Dark urine pale stools]
134
Where is ALP found in high concentrations?
- Present in high concentrations in liver, bone, intestine and placenta
135
How to differentiate raised ALP due to liver disease or due to bone disease?
- We can differentiate liver from bone ALP either by seeing if there is a rise in gamma-GT (liver ALP rises with this)
- Electrophoresis
- Bone-specific assay of ALP
136
What are causes of raised ALP?
- Physiological: Pregnancy (3rd trimester), Childhood (during growth spurt)
- Pathological:
- >5x the upper limit of normal = Bone (Pagets, osteomalacia) Liver (Cholestatis, Cirrhosis)
- <5x the upper limit of normal = Bone (tumours, fractures, osteomyelitis), Liver (infiltrative disease, hepatitis)
- ALP not raised in osteoporosis unless complicated by fractures
137
Describe amylase as an enzymatic marker of pancreatitis
- Secreted by exocrine pancreas
- High serum amylase activity in acute pancreatitis
- Usually > 10 times upper limit of normal
- Remember salivary isoenzyme exists
- Small increases may be seen in other acute abdomen states
138
What is the most widely used marker for muscle damage?
- Creatine Kinase
139
What are the three forms of creatine kinase?
- CK-MM- skeletal muscles
- CK-MB (1 & 2) – cardiac muscles
- CK- BB – brain – activity minimal even in severe brain damage
140
What are raised levels of CK due to?
- Physiological: Afro-Caribbean (<5x upper limit of normal)
| - Pathological: Duchenne Muscular Dystrophy (>10xULN), MI (>10xULN), Statin related myopathy, Rhabdomyolysis
141
What is the spectrum for statin related myopathy?
- Myalgia to rhabdomyolysis
142
What are the risk factors for statin related myopathy?
- Polypharmacy ( fibrates – gemfibrosil, cyclosporin, other drugs metabolised by the CYP 3A4 system)
- High dose
- Genetic predisposition
- Previous history of myopathy with another statin
143
What is troponin?
- A myocardial injury biomarker
- Measure at 6 hours and then at 12 hours post onset of chest pain/post MI (100% Se and 98% Sp at
12-24 hours).
- Remains elevated for 3 - 10 days
144
What is an IU?
- International unit
- 1 international unit is the quantity of enzyme that catalyses 1uMol of substrate in a minute (at a given temp and pH)
- It is a measure of enzyme MASS or CONCENTRATION, not activity
145
What is the diagnostic criteria for acute MI?
Either one of the following
- Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) with at least one of the following:
- (a) ischemic symptoms
- (b) pathologic Q waves on the ECG
- (c) ECG changes indicative of ischemia
- (d) coronary artery intervention
- Pathological findings of an acute MI
146
What are biomarkers of heart failure?
- Atrial natriuretic peptide – secreted by the atria
| - Brain natriuretic peptide – secreted by the ventricles
147
When is BNP released?
- Released in response to ventricular stretch
148
What are some of the roles of BNP?
Reducing
- systemic vasoconstriction
- sodium retention
- renal sympathetic activity
149
Describe BNP levels with regards to heart failure
- Levels of <100 are highly specific for excluding heart failure, >400 is highly sensitive for heart failure
- Confounding factors to interpretation include CKD
- NT-proBNP is more sensitive than BNP and has greater prognostic value
150
What is the acute management of hypoglycaemia in adults?
- Alert and orientated: oral carbohydrates, rapid acting; juice/sweets, longer acting; sandwich
- Drowsy/confused but swallow intact: buccal glucose, e.g. hypostop/glucogel, start thinking about IV access
- Unconscious or concerned about swallow: IV access, 50ml, 50% glucose mini-jet OR 100mls 20% glucose
- Deteriorating/refractory/insulin induced/difficult IV access: consider IM/SC 1mg Glucagon
151
What are symptoms of hypoglycaemia?
- Adrenergic
- Tremors
- Palpitations
- Sweating
- Hunger
- Neuroglycopaenic
- Somnolence
- Confusion
- Incoordination
- Seizures, coma
152
How is low glucose counter-regulated?
- Decreased insulin and increased glucagon
- Reduced peripheral intake of glucose
- Increase glycogenolysis
- Increase gluconeogenesis
- Increase lipolysis
- Low neuronal glucose sensed in hypothalamus leads to sympathetic activation (catecholamines) and ACTH, cortisol and GH production
- This leads to increased glucose and FFA production (which leads to increased ketone bodies)
153
How can glucose be measured?
- Lab glucose
- Grey top (flouride oxalate)
- Venous sample
- 2 mls blood
- Gold std to make the diagnosis
- Delay in results
- Blood glucose meter
- Point-of-care device
- Instant result
- Capillary blood
- Poor precision at low glucose levels
- Often poorly maintained
154
What are causes of hypoglycaemia without diabetes?
- Fasting or reactive?
- Critically unwell
- Organ failure
- Hyperinsulinism
- Post gastric-bypass
- Drugs
- Extreme weight loss
- Factitious
155
What are causes of hypoglycaemia with diabetes?
May be related to
- Medications
- Inadequate CHO intake / missed meal
- Impaired awareness
- Excessive alcohol
- Strenuous exercise
- Co-existing autoimmune conditions
156
What are some diabetic medications?
- Oral hypoglycaemic
- Sulphonylureas
- Meglitinides
- GLP-1 agents
- Insulin
- Rapid acting with meals: inadequate meal
- Long-acting : hypo’s at night or in between meals
- Other drugs
- B-blockers, salicylates, alcohol ( inhibits lipolysis)
157
Describe diabetes and co-morbidities
- Co-existing renal / liver failure alters drug clearance, and reduced doses needed.
- Rarely concurrent Addison’s can result in hypos (polygladular autoimmune syndrome)
- Caveats
- Poor awareness can occur due to autonomic neuropathy
- Very serious problem at night, and an indication for continuous glucose monitoring
- A very good HbA1c level in a diabetic, may be due to recurrent hypos.
- End of the honeymoon period
158
What is C-peptide?
- C-peptide levels are a good marker of beta-cell function
- Also good to help differentiate the cause of hypoglycaemia
- Half-life, ~ 30 minutes Renal Clearance
159
What type of hypoglycaemia is linked with low insulin and low C-peptide?
- Hypoinsulinaemic hypoglycaemia
160
What type of hypoglycaemia is linked with high insulin and high C-peptide?
- Hyperinsulinaemic hypoglycaemia
161
What type of hypoglycaemia is linked with high insulin and low C-peptide?
- Exogenous insulin
162
What is neonatal hypoglycaemia?
- Explainable
- Premature, co-morbidities, IUGR, SGA
- Inadequate glycogen and fat stores
- Should improve with feeding
- Pathological
- Inborn metabolic defects
163
What is neonatal hypoglycaemia with suppressed insulin + C-peptide?
- FFA raised, but low ketones
- Inherited metabolic disorders
- FAOD : no ketones produced
- GSD type 1 ( gluconeogentic disorder)
- Medium chain acyl coA dehydrogenase def.
- Carnitine disorders
- Expect high FFA
- Expect detectable ketone bodies ( beta hydroxybutyrate, acetoacetate /acetone)
- Good differentiators in neonatal hypoglycaemia
- Insulin / C-peptide
- FFA
- KB
- Lactate
- Hepatomegaly
164
What causes inappropriate levels of insulin?
- Islet cell tumours – insulinoma
- Drugs; insulin, sulphonylurea
- Islet cell hyperplasia
- Infant of a diabetic mother
- Beckwith Weidemann syndrome
- Nesidioblastosis
165
What is an insulinoma?
- 1-2/million/year
- Usually small solitary adenoma
- 10% malignant
- 8% associated with MEN1
- Diagnosis, based on biochemistry + localisation
- Treatment: resection
166
What is a non-islet cell tumour hypoglycaemia?
- Tumours that cause a paraneoplastic syndrome
- Secretion of ‘big IGF-2’
- Big IGF2 binds to IGF-1 receptor and insulin receptor
- Mesenchymal tumours ( mesothelioma /fibroblastoma)
- Epithelial tumours ( carcinoma)
167
What are autoimmune causes of hypoglycaemia?
- Autoimmune conditions: rare
- Antibodies to insulin receptors usually present with insulin resistance but rarely hypoglycaemia.
- Autoimmune insulin syndrome
- Ab’s directed to insulin, sudden dissociation may precipitate hypoglycaemia
- Japan
- Certain drugs : hydralazine, procainamide etc
168
Describe genetics and hypoglycaemia
- Glucokinase activating mutation
- Congenital hyperinsulinism
- KCNJ11 /ABCC8
- GLUD-1
- HNF4A
- HADH
169
What is reactive/post-prandial hypoglycaemia?
- Hypoglycaemia following food intake
- Can occur post-gastric bypass
- Hereditary fructose intolerance
- Early diabetes
- In insulin sensitive individuals after exercise or large meal
- True post-prandial hypo’s
- Difficult to define
170
Describe purine catabolism
- Purine ---> Hypo-Xanthine ---> Xanthine (by Xanthine Oxidase) ---> Urate (by Xanthine Oxidase) ---> Allantoin (by Uriease)
171
What are the plasma concentrations of monosodium urate?
- Men 0.12 – 0.42 mmol/l
| - Women 0.12 – 0.36 mmol/l
172
What is Lesch Nyhan Syndrome?
- Complete HGPRT deficiency
- Normal at birth
- Developmental delay apparent at 6/12
- Hyperuricaemia
- Choreiform movements (1 year)
- Spasticity, mental retardation
- Self mutilation (85%) aged 1-16
173
What are causes of hyperuricaemia due to increased urate production?
Primary
- Lesch Nylan Syndrome
- Partial HGPRT deficiency
- Glyocogen storage disorders
- Fructose intolerance
- PRPP synthetase overactivity
Secondary
- Myeloproliferative disorders
- Lymphoproliferative disorders
- Carcinomatosis
- Chronic haemolytic anaemia
- Gaucher's disease
- Severe psoriasis
174
What are causes of hyperuricaemia due to decreased urate excretion?
Primary
- FJHN
Secondary
- CRF
- Down Syndrome
- Diuretics
- Aspirin
175
What are causes of hypouricaemia due to decreased urate production?
- Xanthine oxidase deficiency
- Severe hepatic disease
- Allopurinol
176
What are causes of hypouricaemia due to increased urate excretion?
- Idiopathic hypouricaemia
- Fanconi syndrome e.g. idiopathic, cystinosis, myeloma
- Uricosuric drugs
- URATI inactivation
177
What is gout?
- Monosodium urate crystals
- Can be acute (Podagra) or chronic (Tophaceous)
- Males 0.5 – 3% prevalence
- Females 0.1 – 0.6% prevalence
- Post pubertal males and post menopausal females
178
What are clinical features of acute gout?
- Rapid build up of pain
- “Exquisite”
- Affected joint red, hot and swollen
- 1st MTP joint first site in 50%
- This joint is involved in 90% overall
179
How do you reduce inflammation when treating acute gout?
- NSAIDs
- Colchicine
- Glucocorticoids
- Do NOT attempt to modify plasma urate concentration
180
How do you manage hyperuricaemia?
- Drink plenty (water!)
- Reverse factors putting up urate
- Reduce synthesis with allopurinol
- Increase renal excretion with probenecid: “uricosuric”
181
What are the side effects of allopurinol?
- Interacts with azathioprine, making it more toxic on bone marrow etc.
- Azathioprine is metabolised to mercaptopurine and then to thioinosinate which interferes with purine metabolism.
- Allopurinol makes the mercaptopurine last longer.
182
How do you diagnose gout?
- Tap effusion
- View under polarised light
- Use red filter
- Negative birefringent crystals
183
What is pseudogout?
- Occurs in patients with osteoarthritis
- Pyrophosphate crystals
- Self limiting 1 – 3 weeks
184
What are different types of primary hypercholesterolaemia?
- Familial hypercholesterolaemia (type II)
- AD: LDLR, apoB, PCSK9 mutations
- AR: LDLRAP1 mutation
- Polygenic hypercholesterolaemia
- Several polymorphisms
- Familial hyper alpha-lipoproteinaemia
- CETP deficiency
- Phytosterolaemia
- ABC G5 & G8
185
What are different types of primary hypertriglyceridaemia?
- Familial Type I
- Lipoprotein lipase or apoC II deficiency
- Familial Type V
- apoA deficiency (sometimes)
- Familial Type IV
- increased TG synthesis
186
What are different types of primary mixed lipidaemia?
- Familial combined hyperlipidaemia
- Familial dysβlipoproteinaemia
- Familial hepatic lipase deficiency
187
What are different types of hypolipidaemia?
- Aβ-lipoproteinaemia
- MTP deficiency
- Hypoβ-lipoproteinaemia
- Truncated apoB protein
- Tangier disease
- HDL deficiency
- Hypoα-lipoproteinaemia
- apoA-I mutations (sometimes)
188
What is the order of lipoproteins in terms of density?
- Chylomicron < FFA < VLDL < IDL < LDL < HDL
189
What is PCSK9
- Binds LDLR and promotes its degradation
- Loss of function mutation of PCSK9 --> low LDL
levels
- Novel form of LDL-lowering therapy is AntiPCSK9 MAb
190
What is the management of lipoprotein (a)?
- Nicotinic acid
191
What is the management of hyperlipidaemia?
- First line is always conservative – dietary modification and exercise [although dietary intake of cholesterol correlates poorly with actual triglyceride levels]
- Statin therapy
- HMG-CoA reductase inhibitor
- Reduces intrinsic synthesis of
cholesterol in the liver
- Side effects – myopathy/rhabdomyolysis, fatigue
- Other agents more rarely used include Ezetimibe
192
What is the management of obesity?
- Conservative measures
- Medical
- No medication has been safely proven to provide sustained weight loss
- Orlistat (A gut lipase inhibitor) is used however side effects of
profound flatus and diarrhoea are often too cumbersome for
patients to tolerate
- Rimonabant (a cannabinoid antagonist) was trialled and discontinued from use as there was an increased risk of adverse events in the form of suicide
- Surgical
- Bariatric surgery is indicated in patients with a BMI >40 or >35 with a comorbidity associated with obesity
- Includes gastric band, gastric sleeve and gastric bypass (roux en y or mini)
- Bypass also has the added improvement of improving diabetic control in type 2 diabetics.
- To be considered requires extensive screening and must commit to long term follow up usually.
193
Describe UK screening via Guthrie blood spot test
- 1969 – Phenylketonuria
- 1970 – Congenital hypothyroidism
- 2004 – Cystic Fibrosis
- 2006 – Sickle cell disease
- 2009 – Medium Chain AcylCoA dehydrogenase Deficiency
- The newborn screening programme measures chemicals in the blood spot, it doesn’t involve
any genetics. An abnormal chemical level doesn’t always mean that there is a genetic
disorder
194
What are the outcomes and screening tests of phenylketonuria?
- Phenylalanine hydroxylase deficiency
| - Screening test: Phenylalanine levels
195
What are the outcomes and screening tests of congenital hypothyroidism?
- Dysgenesis/Agenesis of the thyroid gland
| - TSH levels
196
What are the outcomes and screening tests of cystic fibrosis?
- Mutation in CFTR - viscous secretions → ductal blockages
| - Immune reactive trypsin. If positive → DNA mutation detection
197
What is specificity?
- the probability (in %) that someone without the disease will correctly test negative
- TN/(TN+FP)
198
What is sensitivity
- the probability that someone with the disease will correctly test positive
- TP/(TP+FN)
199
What is PPV?
- the probability that someone who tests positive actually has the disease
- TP/(TP+FP)
200
What is NPV?
- the probability that someone who tests negative actually doesn’t have the disease
- TN/(TN+FN)
201
What are examples of metabolic disorders due to accumulation of toxins?
- Organic acidaemias
- Includes propionic acidaemia etc…
- Urea cycle disorders
- 9 in total, includes ornithine transcarbamylase deficiency
- Aminoacidopathies
- Includes PKU and maplesyrup urine disease
202
What are features of metabolic disorders due to accumulation of toxins?
- Organic acidaemias
- High urea, ketones
- Metabolic acidosis
- Treat with low protein diet, acylcarnitine and
haemofiltration
- Often have funny smells due to the organic
acids
- Urea cycle disorders
- High ammonia (>200uM) leading to
encephalopathy and developmental delay
- Respiratory alkalosis
- Vomiting?diarrhoea
- Treat with low protein diet (stops urea
formation)
- Aminoacidopathies
- High phenylalanine, blue eyes and fair hair/skin
- Retardation
- MSUD apparently causes sweaty feet…
203
What are examples of metabolic disorders to due reduced energy stores?
- Glycogen storage disorders
- Includes Von Gierke’s
- Galactossaemia
- Fatty acid oxidation disorders
- Includes MCADD
204
What are key features of metabolic disorders to due reduced energy stores?
- Glycogen storage disorders
- Hypoglycaemia and lactic acidosis
- Hepatomegaly, developmental delay
- Hepatoblastoma risk high
- Treat with regular CHO
- Galactossaemia
- Increased Gal-1-phosphate levels cause
cataracts
- Hypoglycaemia, neonatal conjugated jaundice
- Test urine reducing agents
- Treat with low lactose/galactose diet
- Fatty acid oxidation disorders
- Hypoglycaemia, cardiomyopathy, rhabdomyolysis
- Low ketones
- Screened with blood acylcarnitine
- Test urine organic acids
- Treat with regular carbohydrate
205
What are metabolic disorders of large molecule synthesis?
- Peroxisomal disorders
- Cannot catabolise very long fatty acids or make
bile acids
- Glycosylation disorders
206
What are key features of metabolic disorders of large molecule synthesis?
- Peroxisomal disorders
- Poor feeds, seixures
- Retinopathy
- Hepatomegaly and mixed hyperbiliribinaemia
- Glycosolation disorders
- Measure serum transferrins
- Lead to retardation and nipple inversion
207
What are metabolic disorders with defects in large molecule metabolism?
- Lysosomal disorders
| - Include Tay Sachs disease
208
What are key features of metabolic disorders with defects in large molecule metabolism?
- Very slow progressing
- Neuroregression, hepatosplenomegaly
- Cardiomyopathy
- Test urine mucooligopolysaccharides and WBC
enzyme levels
209
What are examples of mitochondrial metabolic disorders?
- Various: MELAS, Kearn’s, Sayre, POEMS
210
What are key features of mitochondrial metabolic disorders?
- Involve the CNS, muscle and heart
- High lactate and CK
- Muscle biopsy diagnostic
211
What are common problems in low birth weight?
- Respiratory distress syndrome
- Retinopathy of prematurity
- Intraventricular haemorrhage
- Patent ductus arteriosus
- Necrotizing enterocolitis – inflammation of bowel wall – necrosis and perforation
212
When does functional maturity of GFR happen?
- By 2 years old
213
What are consequences of low GFR for surface area in children?
- slow excretion of a solute load
| - limited amount of Na+ available for H+ exchange
214
Why is there less rebasorption in a child than in an adult?
- Due to shorter proximal tubule
| - Although usually adequate for small filtered load
215
Why is there a reduced concentrating ability of urine in children?
- shorter loops of Henle and distal collecting ducts
216
What is the maximum urine osmolality in children?
- 700 mmol/kg
217
Why is there persistent sodium loss in children?
- Distal tubule resistant to aldosterone
218
Why is there high water loss in children?
- High surface area to bodyweight ratio
- Skin blood flow is increased
- Higher metabolic/respiratory rate than adults
- Skin is less of a good barrier due to being immature
219
When in infancy is hypernatraemia more common?
- First 2 weeks of life
| - Although can be a marker of dehydration or over-concentrated milk formula
220
Why would hyponatraemia occur in first 4/5 weeks of life?
- Excess total body water usually due to excessive intake.
| - Rarely may be SIADH secondary to infection (pneumonia/meningitis) or intraventricular haemorrhage
221
Why would hyponatraemia occur in after first 4/5 weeks of life
- Sodium loss due to immature tubular function in patients on diuresis
222
What are other causes of hyponatraemia in children?
- Factitious (i.e. Na+ normal but appears low) e.g. hyperglycaemia
- Congenital Adrenal Hyperplasia
- Addisonian presentation
- Usually identified on Guthrie spot
223
What are causes of neonatal jaundice?
- Jaundice within the 1st 24 hours of life (acute haemolysis or sepsis)
- Jaundice after 2 weeks of life (hepatobiliary failure)
- Conjugated hyperbilrubinaemia at any stage of infancy
224
What is a porphyria?
- 7 disorders caused by deficiency in enzymes involved in haem biosynthesis, leading to a build up of toxic haem precursors
225
What is acute intermittent porphyria? (AIP)
- Autosomal dominant inheritance
| - HMB (Hydroxymethylbilane) synthase deficiency
226
What are the symptoms of acute intermittent porphyria?
- (neuro-visceral only) - abdo pain, seizures, psych disturbances, nausea & vomiting, tachycardia, hypertension, sensory loss, muscle weakness, constipation, urinary incontinence. NO cutaneous manifestations due to absence of porphyrinogens
227
How is acute intermittent porphyria diagnosed?
- ALA + PBG in urine ("Port wine urine")
228
What are precipitating factors of AIP?
- ALA synthase inducers (steroids, ethanol, barbiturates)
- Stress (infection, surgery)
- Reduced caloric intake and endocrine factors (e.g. premenstrual)
229
What is the treatment of AIP?
- avoid precipitating factors, analgesia, IV carbohydrate/ haem arginate
230
What are acute porphyrias with skin lesions?
- Hereditary coproporphyria (HCP) and Variegate porphyria (VP)
- Autosomal dominant
- Raised porphyrins in faeces or urine
231
What are symptoms of acute porphyrias with skin lesions?
- neurovisceral + skin lesions
232
What are non-acute porphyrias with skin lesions?
- Congenital Erythopoietic porphyria (CEP)
- Erythropoietic protoporphyria (EPP)
- Porphyria Cutanea Tarda (PCT)
233
What are clinical features of EPP?
- Photosensitivity, burning, itching oedema following sun exposure
234
What is PCT?
- Inherited/ acquired
| - Uroporphyrinogen decarboxylase deficiency
235
What are symptoms of PCT?
- (cutaneous) – Vesicles (crusting, pigmented, superficial scarring) on sun exposed sites
236
How is PCT diagnosed?
- ↑ urinary uroporphyrins + coproporphyrins + ↑ ferritin
237
How is PCT treated?
- avoid precipitants (alcohol, hepatic compromise), phlebotomy
238
What condition is characterised by high TSH and low T4?
- Hypothyroidism
239
What condition is characterised by high TSH and normal T4?
- Treated hypothyroidism or subclinical hypothyroidism (look for associated hypercholesterolaemia)
240
What condition is characterised by high TSH and high T4?
- TSH secreting tumour or thyroid hormone resistance
241
What condition is characterised by low TSH and high T3 or T4?
- Hyperthyroidism
242
What condition is charactersied by low TSH and normal T3 or T4?
- Subclinical hyperthyroidism
| - This may progress to primary hypothyroidism, especially if the patient is anti-TPO antibody positive
243
What condition is characterised by low TSH and low T4?
- Central hypothyroidism (hypothalamic/pituitary disorder)
244
What condition is characterised by ↑(later ↓)TSH ↓T3 and ↓ T4?
- Sick euthyroidism (with any severe illness).
| - The body tries to shut down metabolism as the thyroid gland has reduced output
245
What condition is characteriseed by ↔TSH, abnormal T4 ?
- ? assay interference, changes in TBG, amiodarone
246
What are causes of high uptake hyperthyroidism?
- Graves disease: 40 - 60%, F>M (9:1), autoantibodies ++, high uptake on isotope scan (with Tc99)
- Toxic multinodular goitre: 30 - 50%, high uptake
- Toxic adenoma: 5%, ‘hot nodule’ on isotope scan (1 area of uptake)
247
What are causes of low uptake hyperthyroidism?
- Subacute De Quervains thyroiditis: self-limiting post viral painful goiter. Initially hyperthyroid, then hypothyroid
- Postpartum thyroiditis (like De Quervain’s but postpartum)
248
What are causes of autoimmune hypothyroidism?
- Primary atrophic hypoT: diffuse lymphocytic infiltration & atrophy. No goiter so small thyroid. No known antibodies detected yet
- Hashimotos thyroiditis: Plasma cell infiltration & goitre. Elderly females. May be initial ‘Hashitoxicosis’. ++ Autoantibody titres (anti TPO/TG)
249
What are causes of other types of hypothyroidism?
- Iodine deficiency (common worldwide)
- Post thyroidectomy/radioiodine
- Drug induced – antithyroid drugs, lithium, amiodarone
250
What is the treatment of hyperthyroidism split into?
- Medical
- Radio-iodine
- Surgical
251
What is the medical management of hyperthyroidism?
- Symptom relief – Beta blockers, topical steroids for dermopathy, eye drops for patients with symptomatic eye disease in graves.
- Antithyroid medications
- Carbimazole most commonly used
- Two approaches – Titration to normal T3 or block and replace [cause hypothyroidism then give levothyroxine – uncommon as high risk of side effects]
- Side effects – Agranulocytosis (rare), rashes (common)
252
How is radio-iodine used to manage hyperthyroidism?
- Good efficacy for primary treatment, sometimes used after medical therapy has failed
- Risk of permanent hypothyroidism
- Contraindicated in pregnancy and lactating women
253
What are indications for surgical thyroidectomy?
- Women intending to become pregnant in the next 6/12
- Local compression secondary to thyroid goitre (oesophageal/tracheal)
- Cosmetic
- Suspected cancer
- Co-existing hyperparathyroidism
- Refractory to medical therapy
- N.b. Prior to surgery patients MUST be euthyroid prior to surgery
- Total thyroidectomy patients will require thyroid replacement
254
What is a thyroid storm?
- An acute state that presents as shock, with pyrexia, confusion, vomiting.
- Must be treated with HDU/ITU support, usually require cooling, high dose anti-thyroid medications, corticosteroids and circulatory and respiratory
support.
255
How is hypothyroidism treated?
- Thyroid replacement therapy
256
What are different types of thyroid neoplasia?
- Papillary
- Follicular
- Medullary
- Lymphoma
- Anaplastic
257
What is papillary thyroid neoplasia?
- >60% of cases, 30-40y, surgery +/- radioiodine, Thyroxine (to ↓TSH). May see psammoma bodies on histology, these patients have a very good prognosis.
258
What is follicular thyroid neoplasia?
- 25%, Middle age, well differentiated but spreads early, Surgery + RI + thyroxine
259
What is medullary thyroid neoplasia?
- 5% originates in parafollicular “C” cells – linked to MEN2. Produce calcitonin
260
What is lymphoma thyroid neoplasia?
- 5% MALT origin. Risk factor: chronic Hashimotos (as lots of lymphocytes that proliferate), good prognosis
261
What is anaplastic thyroid neoplasia?
- Rare. Elderly. Poor response to any treatment.
262
What is Multiple Endocrine Neoplasia?
- These are a group of 3 inherited disorders (autosomal dominant), whereby there is a predisposition to develop cancers of the endocrine system
263
What is MEN1?
- (3Ps): Pituitary, Pancreatic (e.g. insulinoma), Parathyroid (hyperparathyroidism)
264
What is MEN2a?
- (2Ps, 1M): Parathyroid, Phaeochromocytoma, Medullary thyroid
265
What is MEN2b?
- (1P, 2Ms): Phaeochromocytoma, Medullary thyroid, Mucocutaneous neuromas (& Marfanoid)
266
What does deficiency in Vitamin A cause?
- Colour blindness
267
What does excess Vitamin A cause?
- Exfoliation
| - Hepatitis
268
What does deficiency in Vitamin D cause?
- Osteomalacia/rickets
269
What does excess Vitamin D cause?
- Hypercalcaemia
270
What does deficiency in Vitamin E?
- Anaemia
- Neuropathy
- Malignancy
- IHD
271
How are Vit ADE tested?
- Serum
272
What does Vit K deficiency cause?
- Defective clotting
273
How is Vit K tested?
- PTT
