Chem path Flashcards
Different urine investigations
Single sample
Dipstick testing
Microscopic examination
Proteinuria quantification (protein:creatinine ratio (PCR))
24hour collection Proteinuria quantification (superceded by PCR above) Creatinine clearance estimation Electrolyte estimation Stone forming elements
Urine microscopy: Crystals (stones) Red blood cells (stones, UTI) White blood cells (UTI, glomerulonephritis) Casts (glomerulonephritis) Bacteria (UTI)
ALP raised causes
physiological causes of high ALP.
Pregnancy – 3rd trimester (from placenta)
Childhood – growth spurt
very high ALP (> 5 x upper limit of normal).
Bone – Paget’s disease, osteomalacia
Liver – cholestasis, cirrhosis
moderately raised ALP (< 5 x upper limit of normal).
Bone – tumours, fractures, osteomyelitis
Liver – infiltrative disease, hepatitis
(osteoporosis ALP is normal)
Causes of high CK
Muscle damage Myopathy (e.g. Duchenne muscular dystrophy) MI Severe exercise Physiological (Afro-Caribbeans)
Types of fracture
- Falling on an outstretched hand causes a Colles fracture (the radius will then fracture backwards, away from the palm side)
- If you fall on a flexed wrist, it will cause a Smith fracture
- A Pott’s fracture is an ankle fracture that involves the tibia and fibula
Hypercalcemia DDx and Mx
Hyperparathyroidism (NB the PTH doesn’t have to be raised it just has to not be suppressed) (85% parathyroid adenoma)
Hypoadrenalism
Thiazide diuretics
Sarcoidosis (billateral hilar lymphadeopathy, PTH would be 0)
Benign Familial Hypercalcaemia
Excess Vit D (Sunbeds)
Thyrotoxicosis
Hypercalcaemia of malignancy (MM, mets and PTHrP lung ca) (PTH would be 0)
Mx: Hydration hydration hydration. Bisphos can help from mets eating the bone e.g. IV Pamidronate.
• 3-6 L of saline over 24 hours - The first litre should be given rapidly (over 1 hour) to rapidly rehydrate the pt. Unless liver failure in which case give dextrose to retain salt.
• Give Furosemide if elderly
Eventually, Minimally Invasive Parathyroidectomy if due to an adenoma.
What is a histopath feature of hyperparathyroidism?
Brown cell tumour in the bone (multinucleate giant cells- activated osteoclasts)
Metabolic Alkalosis and Acidosis causes
Alkalosis
o H+ loss (i.e. vomiting, pyloric stenosis)
o Hypokalaemia
o Ingestion of bicarbonate
Acidosis: Increased H+ production e.g. DKA Decreased H+ excretion (e.g. renal tubular acidosis) Bicarbonate loss (e.g. intestinal fistula)
Causes of hypokalaemia
GI Loss - Diarrhoea, vomiting Renal loss • Hyperaldosteronism • Excess cortisol (cushing's) • Increased sodium delivery to distal nephron (diseases that block the double or triple transporter) • Osmotic diuresis Redistribution into cells • Insulin • Beta-agonists • Alkalosis • NOTE: all of these are treatment for hyperkalaemia RARE causes • Renal tubular acidosis type 1 and 2 • Hypomagnesaemia
How to differentiate between the cushings’
The dexa tests. We give dexa and measure whether the adrenals still produce coritsol.
Adrenal tumours will suppress ACTH (only one with low ACTH)
Pituitary cushings will not be suppressed by low dose dexa but will be suppressed by high dose dexa.
Ectopic ACTH will not be suppressed by either and is also most commonly associated with hypokalaemia.
(This is because ectopic ACTH causes such high levels of cortisol that they start binding to aldosterone receptor s and a shit tonne of K+ is kicked out)
How to differentiate between acute and chronic kidney failure?
History
But if history can apply to both e.g. like our diabetic pt who presented with dehydration, the only proper way of distinguishing these differentials is with a renal biopsy
If it is ATN, the patient will need dialysis for 3 weeks but then they will recover (histology willl show tubules are all necrosed but the glomeruli are intact)
If it is diabetic glomerular kidney disease, they will be in end-stage renal failure and they will need lifelong dialysis
NB •In acute renal failure that is caused by dehydration, UREA will rise the most
•In chronic renal failure that is caused by a fall in GFR, CREATININE will rise the most
But definitively biopsy needed
What can rise in prostate cancer?
Acid phosphatase rises in prostate cancer
What is vitamin D level in primary hyperparathyroidism?
This is because PTH activates 1-alpha hydroxylase meaning that vitamin D is consumed (i.e. it is activated)
Marker of Glucose Control over the LAST 3 WEEKS
o FRUCTOSAMINE
o It is important to have good diabetic control during pregnancy
o You also cannot wait for 3 months to assess blood glucose control because the pregnancy only lasts 9 months
o It is also important to monitor blood glucose control because as the pregnancy progresses their control will deteriorate (because all the hormones in pregnancy are insulin-resistant)
o Soon, you will be able to use a FreeStyle Libre (a probe that you can put on your arm and swipe to get a reading)
Paget’s Disease
•There is an increase in activity of both osteoclasts and osteoblasts -> increase in ALP and osteocalcin
•A bowed tibia is a key feature of Paget’s disease (it will also be warm)
•They have a high risk of fracture
•Most people with Paget’s disease will be ASYMPTOMATIC
•TREATMENT: bisphosphonates (only if it is painful)
o This is because the bone that is formed with calcium bisphosphonate is not degradable by osteoclasts
Ix: Technetium Bisphosphonate Scan will highlight just one bone and nothing else (usually used for cancer mets)
Other signs
Both nerve and conductive deafness
If you have Paget’s disease of the ossicles (Malleus, Incus and Stapes) it will cause CONDUCTIVE deafness
o This means that bone conduction will be normal if you put the tuning fork on the mastoid process (they will not be able to hear it when you put it in front of their ear because the ossicles are Pagetic and cannot amplify the sound)
• Paget’s disease of the skull can compress the 7th cranial nerve and cause nerve deafness
What are PET scans used for
• Often used to look for abdominal metastases
• FDG (fluorodeoxyglucose) is sometimes used as a marker
o NOTE: the scan is labelled as an FDG PET Scan
• This is NOT specific
• Glucose is taken up by ANY active cell
• Cancer cells are more active so they will take up more FDG
What is a Gallium DOTATATE scan used for?
It can light up a neuro endocrine cell -> show an insulinoma
be an insulinoma
Gallium can be stuck onto a somatostatin analogue so that it goes to tissues that have somatostatin receptors (i.e. any neuroendocrine cell)
IMPORTANT: the spleen has a lot of receptors for somatostatin so it will always appear hot (so, localisation in the spleen is a telling feature of Gallium 68 scans using somatostatin analogues). The kidneys and adrenals will also appear hot.
What can you use for a phaeo?
MIBG is a precursor for adrenaline that is used for identifying phaeochromocytoma
NOTE: Gallium dotatate picks up any neuroendocrine tumour (includes phaeochromocytomas and insulinomas)
Why does ALP rise in obstructive jaundice?
The zone around the bile duct in the portal triad has a lot of ALP, hence why ALP rises the most in diseases that cause obstructive jaundice
What is the pathophysiology of nodular cirrhosis?
oThe patient is likely to have a long alcohol history (with other signs such as Dupuytren’s contracture)
oThen they suddenly become ill because of the alcoholic hepatitis
oWith support and reducing inflammation with steroids, they will recover
oA lot of the hepatocytes die but a few will survive and attempt to regenerate
oWhen cells regenerate, they do NOT grow nicely into hexagons
oThe grow into nodules
oThis means that the blood from the portal triad has to go around the nodules before arriving at the central vein
oIf the patient gets another bout of alcoholic hepatitis, they will develop even more nodules
oThis will eventually result in nodular cirrhosis
oIn this case, the blood has an even tougher route around the nodules to get to the central vein
oThis leads to a rise in pressure (portal hypertension)
oThis will lead to varices at sites of porto-systemic anastomosis
In cirrhoSiS, AST rises the most
What do the different areas of osteopenia on a DEXA scan tell you?
Spinal fractures -> Cushing’s
Wrist fractures -> primary hyperparathyroidism
Hip and back -> excess steroid exposure, hyperthyroidism, post-menopausal osteoporosis
This is the MOST COMMON cause of septic monoarthritis in 18-30 year old patients
Neisseria Gonorrhoea
Diplococci Gram Negative
Secondary hyperparathyrdoisism
Excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels), with resultant hyperplasia of these glands. This disorder is primarily seen in patients with chronic kidney failure
Chronic kidney failure is the most common cause of secondary hyperparathyroidism. Failing kidneys do not convert enough vitamin D to its active form, and they do not adequately excrete phosphate. When this happens, insoluble calcium phosphate forms in the body and removes calcium from the circulation. Both processes lead to hypocalcemia and hence secondary hyperparathyroidism.
Secondary hyperparathyroidism can also result from malabsorption (chronic pancreatitis, small bowel disease, malabsorption-dependent bariatric surgery) in that the fat-soluble vitamin D can not get reabsorbed i.e. VITAMIN D DEFICIENCY. This leads to hypercalcemia and a subsequent decrease in parathyroid hormone secretion in an attempt to decrease the serum calcium levels. A few other causes can stem from inadequate dietary intake of calcium, a vitamin D deficiency, or steatorrhea
How does Addison’s effect the electrolyte levels?
Addisons -> adrenal insufficiency -> aldosterone not produced -> K+ isn’t excreted and Na+ isn’t reabsorbed -> Hyperkalaemia, Hyponatraemia
In patients with Addison’s disease, calcium rises slightly
This is likely to suppression PTH a small amount
Diabetes Inspidus
Learn thsi
What does CETP do?
In the plasma:
Moves cholesterol from HDL → VLDL
Moves triglycerides from VLDL → HDL
Cholesterol conditions mutations
- Familial hypercholesterolaemia (type II).
Caused by autosomal dominant gene mutations in:
LDL receptor (more LDL stays in the blood)
ApoB
PCSK9 (more LDL stays in the blood) - Polygenic hypercholesterolaemia.
NPC1L1 – this is transports cholesterol across the intestine
HMGCR (HMG CoA Reductase)
CYP7A1 - Familial hyperalphalipoproteinaemia
Increase in HDL caused by deficiency of CETP
This is associated with longevity
4.Phytosterolaemia
Increased plasma concentrations of plant sterols due to mutations in ABC G5 and ABC G8
NOTE: this condition is associated with premature atherosclerosis
Triglyceride disorders’ mutations
Familial Type I
Caused by deficiency of lipoprotein lipase and ApoC II
NOTE: LPL degrades chylomicrons, ApoC II @ LPL
Familial Type IV
Characterised by increased synthesis of triglycerides
Familial Type V
Characterised by deficiency of ApoA V
NOTE: these hypertriglyceridaemias show different patterns when the plasma is left overnight to separate
Lipid condition mutations
Familial combined hyperlipidaemia
Some people in the family have high cholesterol and others have high triglycerides
Familial dysbetalipoproteinaemia (type III)
Due to aberrant form of ApoE (E2/2)
NOTE: normal form is ApoE (3/3)
A diagnostic clinical feature of yellowing of the palmar crease (palmar striae)
Hypolipideamia mutations
Aβ-lipoproteinaemia • Autosomal recessive • Extremely low levels of cholesterol • Due to deficiency of MTP Hypoβ-lipoproteinaemia • Autosomal dominant • Low LDL • Caused by mutations in ApoB Tangier disease • Low HDL • Caused by mutation of ABC A1 Hypoα-lipoproteinaemia • Sometimes caused by mutation of ApoA1
Describe some lipid lowering drugs and why do they exist
Play a large role in atherosclerosis:
LDL becomes oxidised once it has got through the vascular endothelium
Once oxidised it is taken up by macrophages
Within the macrophages, the LDLs become esterified and you develop foam cells
- Statins – reduce LDLs, increase HDLs, slight increase in triglycerides
- Fibrates – lower triglycerides, little effects on LDL/HDL
- Ezetimibe – reduces cholesterol absorption (blocks NPC1L1)
- Colestyramine – resin that binds to bile acids and reduces their absorption
Novel forms of lipid-lowering drugs.
Lomitapide – MTP blocker
REGN727 – anti-PCSK9 monoclonal antibody
Mipomersen – anti-sense ApoB oligonucleotide
Which condition classically causes a mixed respiratory alkalosis and metabolic acidosis?
Aspirin overdose. It stimulates ventilation and reduces renal excretion of H+
How to measure liver function?
- Prothrombin time is the most representative marker of liver function. Normal 12-14s.
o General rule: if the PT in seconds is higher than the number of hours since the overdose, the patient should be transferred to a liver unit for a transplant - Albumin is also a good marker (because it is representative of the liver’s synthetic function) but PT is better
ALT and AST are enzymes that tell you that there is damage rather than telling you how your liver is actually functioning
When is ALP high in liver path?
Biliary obstructuon
Alcoholic Hepatitis histology and its differentials
Hepatocytes contain a lot of fat (balloon cells) and mallory hyaline. Eventually you will get brown patches which is the fat cells and hyaline blocking and trapping bile. There are also some inflammatory cells (neutrophil polymorphs) If anyone drinks too much alcohol, they will get fat deposits in their liver, however, these will go away if they stop drinking alcohol. But If alcohol abuse persists, you may develop alcoholic hepatitis (neutrophils will infiltrate the liver) When hepatocytes get damaged by alcohol hepatitis, you see balloon cells containing mallory hyaline and collagen deposits around the hepatocyte (stains blue). • This may NOT be reversible Tldr: DEFINING Histological Features 1. Liver cell damage 2. Inflammation 3. Fibrosis Associated Histological Features 1. Fatty change 2. Megamitochondria
DDx:
Non-alcoholic steatohepatitis (NASH)
• This looks exactly like alcoholic hepatitis
• It is the most common cause of liver disease in the Western world
o Alcoholic hepatitis
o Malnourishment (Kwashiorkor)
Chronic hepatitis histology
If you stop drinking, the liver will regenerate
However, the regeneration does NOT happen in a nice and organised manner
This will produce lots of little nodules that have a fibrous cuff (micronodules)
The disorganised nature of the regeneration means that the blood finds it difficult to flow through the liver, leading to a rise in portal pressure (splenomegaly, ascites and varices) and eventual intrahepatic shunting
Features of chronic liver disease
o Palmar erythema o Spider naevi o Gynaecomastia • Due to failure of the liver to break down oestradiol o Dupuytren's contracture
Describe how urobilinogen is formed. What is the significance of absent urobilinogen in the urine?
Bilirubin released into the bowels will be converted by bacteria in the colon, into urobilinogen and stercobilinogen
Some urobilinogen will be absorbed and transported via the enterohepatic circulation to the liver
Some of this urobilinogen will then be excreted in the urine
The presence of urobilinogen in the urine is NORMAL
The absence of urobilinogen in the urine is suggestive of biliary obstruction
Where does pancreas tend to metastasise to?
Liver liver baby
Urea cycle disorders
CHARACTERISED BY HIGH AMMONIA (>200uM) The urea cycle is responsible for taking ammonia and producing urea. There are SEVEN enzymes in this pathway and there are documented disorders in each of them and there also some other diseases that are classed in this subgroup. Features: o Vomiting without diarrhoea o Respiratory alkalosis o Hyperammonaemia o Neurological encephalopathy o Avoidance or change in diet All are AR apart from ornithine transcarbamylase deficiency (OTC)
Ix: The body is incapable of excreting a very high level of ammonia, so, instead, the body will attach an ammonium group to glutamate to make glutamine
= plasma GLUTAMINE in hyperammoniaemic conditions will be high
You can also meausre urine orotic acid
Mx:
o Remove ammonia (using sodium benzoate or sodium phenylacetate or dialysis)
o Reduce ammonia production (low protein diet)
Hyperammonaemia with Metabolic ACIDOSIS and High Anion Gap.. what is the disorder?
ORGANIC ACIDAEMIAS (aka the worst one to have)
High urea, ketones
Metabolic acidosis
Treat with low protein diet, acylcarnitine and haemofiltration
Often have funny smells due to the organic acids
Presentation in neonates: Feeding difficulty, unusual odour, myoclonic jerks, trunkal hypotonia
Chronic Intermittent Form
• Recurrent episodes of ketoacidotis coma
• Cerebral abnormalities
• Reye Syndrome (triggered by aspirin)
Hypoketotic hypoglycaemic disorder?
Mitochondrial Fatty Acid Oxidation Defect
• If you are hypoglycaemic, you should be making ketones as an alternative energy source
• If you are unable to make ketones, it suggests that you are unable to break down fatty acids
• Also causes hepatomegaly and cardiomyopathy
Screened with blood acylcarnitine
Ix: urine organic acids
Mx: regular carbohydrate (TWO BEST DISEASES)
Metabolic disorder that also causes conjugated bilirubinaemia in the neonatal period that isn’t picked up in the neonatal period might present later with…
bilateral cataracts (The high concentrations of Gal-1-phosphate ends up becoming a substrate for aldolase which is found in the lens of your eye )!
Due to galactosaemia
3 known disorders of galactose metabolism
Galactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency is the MOST SEVERE and MOST COMMON form
Raised Gal-1-PUT leads to liver and kidney disease
Neonatal presentation: D&V, conj bili, hepatomegaly, hypoglycaemia, Sepsis (because galactose-1-phosphate inhibits immune responses)
Investigations • Urine reducing substances (high levels of galactose) • Red cell Gal-1-PUT Treatment • Avoid galactose (e.g. milk)
WHy do glycogen storage type 1 have hypoglycaemia? + Inheritiance
AUTOSOMAL RECESSIVE
Whenever you break down glucose, you make glucose-1-phosphate or glucose-6-phosphate and then the phosphate groups have to be removed (because they are high energy groups meaning that the molecule CANNOT get across the membrane with the phosphate attached)
Without a phosphatase, the G6P and G1P cannot be exported
This results in your muscles and your liver building up loads of glycogen which cannot be liberated and so you become hypoglycaemic. (Also increases risk of hepatoblastoma)
Clinical Features • Hepatomegaly • Nephromegaly • Hypoglycaemia • Lactic acidosis • Neutropaenia Development delay, hepatoblastoma risk is high
TWO BEST DISEASES- treat with regular CHO
Features of mitochondrial disorders in general
- Heteroplasmy of mitochondrial DNA means that once you reach a certain load of mitochondrial DNA you will start to develop symptoms
- Mitochondrial DNA is maternally inherited
- Nuclear DNA plays a huge role in mitochondrial function (e.g. getting parts of the oxidative phosphorylation pathway into the mitochondria)
- Mitochondrial disorders can present in any organ, at any age with any form of inheritance
- Defective ATP production leads to multisystem disease especially affecting organs with a high energy requirement (e.g. brain, muscle, kidney, retina, endocrine organs)
Mitochondrial metabolism disorders
Investigations:
Involve the CNS, muscle and heart
High lactate (should be low after fasting in normal peple) and CK Muscle biopsy diagnostic (Red Ragged Fibres)
Examples of diseases:
MELAS - LActic acid Stroke
Kearns SayrE - EYE
Barth Syndrome - harth
Barth syndrome – HEART & NEUTROPHILS: cardiomyopathy, neutropaenia and myopathy starting at birth
MELAS – LACTIC, STROKE: encephalopathy, lactic acidosis and stroke-like episodes
Kearns-Sayre syndrome – EYES: chronic progressive external ophthalmoplegia, retinopathy, deafness and ataxia; CSF protein is elevated
NEC
Inflammation of the bowel wall progressing to necrosis and perforation
Characterised by bloody stools, abdominal distension and intramural air (pneumatosis intestinalis)
Renal development milestones
- Nephrons develop at Week 6
- Start producing urine at Week 10
- Have fully competent nephrons at Week 36
- functional maturity of glomerular function at 2 yrs
Differences between baby and adult kidneys
SHORT, SHORT & UNRESPONSIVE -> Sodium, potassium and water requirements are higher
- Short proximal tubule so lower reabsorptive capability > Reduce reabsorption of bicarbonate leading to a propensity to acidosis. Reduced ability to reabsorb glucose -> glycosuria occurs at a lower glucose level
- Loop of Henle and distal collecting ducts are short and juxtaglomerular leading to reduced concentrating ability (maximum urine osmolality of 700 mmol/kg)
- Distal tubule is relatively unresponsive to aldosterone leading to persistent sodium loss and reduced potassium excretion (sodium loss of 1.8 mmol/kg/day, and upper limit of normal K+ of 6 mmol/L in neonates)
How do babbers lose weight in first week?
Pulmonary resistance drops and you get release of ANP leading to redistribution of fluid
This can lead to up to 10% weight loss within the first week of life
Roughly 40 mL/kg loss in preterm infants
Which drugs can cause electrolyte balance in kiddos?
Bicarbonate for acidosis (contains high Na+) (as well as intraventricular haemorrhage both cause) Hypernatraemia
Antibiotics (usually sodium salts)
Caffeine/theophylline (for apnoea) – increases renal Na+ loss -> Hyponatraemia
Indomethacin (for PDA) – causes oliguria
NOTE: growth can also cause electrolyte disturbance
What can cause hyponatraemia in kiddos?
Congenital adrenal hyperplasia
Most commonly caused by 21-hydroxylase deficiency
Leads to reduce cortisol and aldosterone production and shunting of 17-OH progesterone and 17-OH pregnenelone which goes towards androgen synthesis
As a result: Hyponatraemia/hyperkalaemia; Hypoglycaemia; Ambiguous genitalia in female neonates; Growth acceleration
(AS WELL AS CAFFEINE)
What levels of bilirubin are considered pahological?
More than 20 µmol/L
what is OOP?
Oestopenia of prematurity Calcium is usually normal Phosphate < 1 mmol/L ALP > 1200 U/L (10 x adult ULN) Mx: Phosphate/calcium supplements 1-alpha calcidol (NB the reverse is true for term babies- they actually have high phosphate because the gut is good at reabsorbing it and calcium falls after birth)
Genetic Causes of rickets
Pseudo-vitamin D deficiency I (defective renal hydroxylation) Pseudo-vitamin D deficiency II (receptor defect) Familial hypophosphataemias (low tubular maximum reabsorption of phosphate, raised urine phosphoethanolamine) NOTE: top two conditions are treated with 1,25-OH Vitamin D
What is a phorphyria?
Deficiencies in enzymes in the haem synthesis pathway either manifesting as acute neuro-visceral attacks or acute/chronic cutaneous syndromes.
Haem
It is made in the mitochondria by ALA (which is toxic). ALA leaves the mitochondria where it is converted into porphyrinogen- which is colourless (by the help of PBG and HMB synthase).
Porphyrinogens are then oxidised into porphyrins (colourful)- this occurs in places where there is oxgen i.e. circulation
Porphyrins are then activated by UV Light. Those
List the phophyrias
Acute:
Acute Intermittent (AD)
Acute with skin lesions (AD) (HCP and VP)
Plumboporphryia
Chronic:
CEP
EPP
PCT
Acute Intermittent Porphyria
HMB Synthase deficiency (AD) causes an accumulation in precursors PBG and ALA. Usually ~50% enzyme efficiency.
ALA is toxic so a rise in these symptoms causes neuro -visceral attacks:
- Abdo pain and consitpation
- Seizure and Psych distrubances
- N&V
NO cutaneous symptoms
Triggers: ALA synthase inducers (e.g. barbiturates, steroids, ethanol, anticonvulsants - all of these are cytochrome P450 inducers)
Ix: Urinary ALA and PBG. Decreased HMB synthase activity in erythrocytes.
Mx: Avoid attacks, Adequate nutritional intake, Avoid precipitant drugs, Prompt treatment of infection/illness
- IV carbohydrate - inhibit ALA synthase
- IV haem arginate - This will make it seem like there is an abundance of haem in the body and, therefore, turn off haem synthesis through the negative feedback system
Acute Porphyria with skin lesions
Hereditary coproporphyria- coproporphyrinogen oxidase
Variegate porphyria - protoporphyrinogen oxidase def
Both of these enzymes are potent inhibitors of HMB Synthase therefore you get raised PBG and ALA in urine as well
BUT they have skin manifestations and both have raised PORPHYRIN in the faeces.
NOTE: both diseases will have detectable levels of the porphyrinogens in the stool because the defect is towards the end of the pathway and, hence, the molecules are not as soluble
Hereditary Coproporphyria
o Autosomal DOMINANT o Acute neurovisceral attacks o Skin lesions • Blistering • Skin fragility Classically on the backs of the hands after sun exposure
Variegate Porphyria
o Autosomal DOMINANT
o Acute attacks
o Skin lesions
Non acute prophyrias
CEP - Congenital Erythropoietic Porphyria
EPP - Erythropoietic Protoporphyria
PCT - Porphyria cutanea tarda (MOST COMMON)
CEP - Uroporphyrinogen III synthase
PCT -Uroporphyrinogen decarboxylase
EPP - Ferrochetelase
PCT - MOST COMMON - Vesicles on sun exposed sites
Urine/plasma uroporphyrins + coproporphyrins are increased. Ferritin is often increased.
o Avoid precipitants (e.g. alcohol, hepatic compromise) and phlebotomy
EPP - NON BLISTERING photosensitivity with oedema. Only erythroid cells are affected, so you need to measure RBC protoporphyrin. Avoid Sun. Associated with MDS.
CEP - Assoicated ith MDS.
During acute porphyria the most useufl sample to send is?
urine
What does ALA synthase deficiency cause?
- This does NOT cause any porphyrias
- Causes X-linked sideroblastic anaemia
- However, an ALA synthase gain-of-function mutation will result in an increased throughput through the pathway
- This will result in a build up of protoporphyrin IX which overwhelms the ability of ferrochetalase to convert it to haem, resulting in an accumulation of protoporphyrin IX (similar to erythropoietic protoporphyria)
Plumbopophryia?
PBG Synthase deficiency aka Acute Porphyria
The lack of PBG synthase (also known as ALA dehydratase) leads to ALA dehydratase deficiency porphyria
• This leads to an accumulation of ALA
• It is an extremely RARE form of porphyria
• This leads to neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)
Abdominal pain is most improtant feature!
Thyroid axis
• TSH controls uptake of iodide to the thyroid (blocked by perchlorate)
• Iodide goes through the membrane via Na+/K+ ATPase
• Iodide is then converted into iodine by thyroid peroxidase
• The iodine is then taken up by thyroglobulin and then converted into thyroxine through a number of processes
• The iodination of tyrosine residues in thyroglobulin leads to the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT)
• Once the thyroxine (T4) is produced, it is stored within the thyroid gland
• When it needs to be released, it is secreted into the capillary lumen
• In the periphery, T4 will be converted to T3.
T4 will feed back to the hypothalamus AND pituitary, which will produce less TSH.
How is the thyroid hormone transported in the blood?
• Once secreted from the thyroid cells, the majority of it is bound to protein
• A very small proportion is active thyroxine (fT4)
• Only 0.03% of thyroxine in the circulation is active
• Most of it is bound to thyroxine binding globulin (TBG)
o NOTE: if you are lacking albumin, you TBG levels will go down
• Thyroxine can also bind to thyroxine-binding pre-albumin (TBPA) and albumin
• Once the thyroxine goes to the tissues, it can be converted to T3
Hypothyroidism aetiology
Most hypothyroidism is PRIMARY i.e. a problem with the thyroid gland itself
- Drugs e.g. lithium, amiodarone
- Autoimmune (Hashimoto’s- plasma cell infiltration, elderly)
- Iodine deficiency
- Post radiation (~within a year)
- Post graves (radioactive iodine, surgery, natural history or thionamines)
- Congenital (thyroid agenesis or dysgenesis)
- Atrophic Gland
- Secondary hypothyroidism, pituitary disease (TSH no utility)
- Peripheral thyroid hormone resistance
- Sick Euthyroid (extreme severe illness can cause the t4/t3 to dip and TSH can be normal or can rise slightly(- they DO NOT have symptoms
Hypothyroid features
o Cold and dry hands, feels cold
o Hyponatraemia
o Normocytic anaemia unless pernicious anaemia
o Myxoedema, goitre
Other normal ones
How does pregnancy effect the thyroid?
o Thyroid hormone levels change during pregnancy
o hCG has a similar structure to TSH - so if you have too much hCG, it can make the thyroid gland produce too much thyroxine
o The rise in hCG in the first trimester of pregnancy makes your free T4 levels increase slightly
o This is a normal physiological process, so the ‘normal ranges’ of TSH and T4 in pregnancy are slightly different
o TBG levels increase dramatically in pregnancy because it is under the control of oestrogen
o Later on in pregnancy, hCG levels will drop and, consequently, T4 levels will also go down and the TSH levels will rise slightly
Subclinical Hypothyrodism
o The T4 level is NORMAL but TSH is HIGH
o However, the pituitary gland senses that level of T4 and thinks that the thyroid hormone is NOT producing enough thyroxine so it produces more TSH
o Sometimes referred to as compensated hypothyroidism
o If TPO antibodies are positive, it suggests that the patient may go on to develop thyroid disease
o Subclinical hypothyroidism is UNLIKELY to be the cause of their presenting symptoms
o Hypothyroidism is associated with hypercholesterolaemia, so this may be the only benefit of treating subclinical hypothyroidism
Hypothyroid management
Do an ECG - if underlying cardiovascular disease and you give them thyroxine, their myocardial contractility will increase and they may be at risk of ischaemia. If so start low dose and build up
T4 (levothyroxine) - 50-125-200 mcg/day titrated to a normal TSH
Excessive thyroxine can cause osteopaenia and AF
(there is NO evidence base for giving T3 rather than T4)
Hyperthyroid causes
Grave’s > Toxic multinodular > Toxic single adenoma (hot nodule on isotope technetium scan, rest show pan increased uptake)
Low uptake causes: subacute thyroiditis (de quervian’s- post viral painful goiter, hyper -> Hypo), post partum thyroiditis (hyper -> hypo)
Thyroid storm
An acute presentation of shock, pyrexia, confusion, vomiting. Treat with HDU/ITU, require cooling, high dose antithyroid meds, corticosteroids, circulatory support.
Rare causes:
Factitious Thyroxine
Silent thyroiditis - (initially hyperthyroid with just a painful lumps as symptoms, then thyroid stops working entirely and become permanently hypothyroid. It is likely that theyll be in the latter stage by the time you pick them -> high TSH low T3/t4)
• TSH-induced
• Thyroid cancer induced
• Trophoblastic tumour and Struma ovarii
• Due to excessive hCG production
Hyperthyroid mx
- Symptomatic: Beta-blocker if pulse > 100 bpm, topical steroids for dermatopathy, eye drops.
- Thionamides:
Carbimazole (Titrate to normal T3, S/E rash and agranulocytosis. Blocks TPO so Iodide is not > iodine) or Propylthiouracil - Radioiodine (if M fails, but there is a risk of permanent hypothryoidism or thyroid storm, CI in pregnant or breast feeding women S/E tracheal compression or opthalmopathy. Can make Graves Eye disease worse!)
- Surgery
SCANS TO DO:
o Other autoimmune conditions (e.g. coeliac disease, Addison’s disease)
o ECG
o Bone mineral density (osteopenia)
Indications of thyroidectomy
Surgical Hemi/total 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
Pts must be euthyroid prior tosurgery
o Total thyroidectomy patients will require thyroid replacement
o Potassium perchlorate can be given to hyperthyroid patients before surgery to block the uptake of iodide by the thyroid cells
Thyroid neoplasia
- Papillary
>60% of cases, 30-40y, Thyroxine (to ↓TSH).
Painless mass in neck or presents with cervical LN mets
Psammoma bodies, optically clear nucleoli (orphan annie eyes) and intranuclear lesions on histology
very good prognosis.
Mx: Total thyroidectomy+/- radioiodine (to remove any remaining cells). Then we give high dose thyroxine to lower TSH so that no other cells are stimulated. Measure serum TBG to see if cancer has come back - Follicular
25%, Middle age, well differentiated but spreads early via blood to lung liver and bone
Surgery + RI + thyroxine - Medullary
Neuroendocrine Tumour
5% originates in parafollicular “C” cells – linked to MEN2 in young patients.
Produce calcitonin and can be deposited as amyloid (Congo red). Calcitonin and CEA are tumour markers
4 Lymphoma
5% MALT origin. Risk factor: chronic Hashimotos (as lots of lymphocytes that proliferate), good prognosis
- Anaplastic
Rare. Elderly. Poor response to any treatment. Death due to local invasion.
SIADH causes
Most common cause of hyponatraemia
CNS pathology (subdural haematoma, subarachnoid haemorrhage, trauma, cavernous sinus thrombosis)
Lung pathology (anything, legionella pneumophila)
Drugs (SSRIs, TCAs, opiates, PPIs, carbamazepine)
Tumours
Surgery (ADH rises post op)
Hyponatraemia treatment
- HypOvol Hyponat - Volume replacement with 0.9% saline (will replenish the circulating fluid volume + switch off ADH stimulus) Need to be sure pt is hypovol because giving 0.9% saline to a euvolaemic patient can worsen the hyponatraemia
- Other Hyponatraemia - Fluid restriction & Treat underlying cause
- Severe Hyponatraemia (Reduced GCS, Seizures) Seek expert help (treat with 3% hypertonic saline) Not more than 8-10 mmol/L in the first 24 hrs due to osmotic demyelination (central pontine myelinolysis)
SIADH: Demeclocycline (Reduces responsiveness of collecting tubule cells to ADH, Monitor U&Es (risk of nephrotoxicity)) & Tolvaptan (V2 receptor antagonist)
o NOTE: this is expensive and associated with rapid rises in serum sodium
• Alternative: fluid restriction + salt tablets + frusemide
Hypovlolaemia hyponatraemia signs
Most reliable sign: Low urine sodium (suggests that you are trying to retain fluid- you reabsorb water and salt but the salt is not reabsorbed fast enough to correct the hyponatraemia)
NOTE: this may be high in patients on diuretics
Tachycardia Postural hypotension Dry mucous membranes Reduced skin turgor Confusion Reduced urine output
Hypovolaemia hyponatraemia vs euvol hyponatraemia investigations
Hypovolhyponatramie - LOW urine sodium
Euvol Hyponatramiea - SIADH will have high urine osmolality and as a result low plasma osmolality.
Hypernatraemia pathogenesis and causes
Defined as serum sodium concentration > 145 mmol/L
Caused by unreplaced water loss
o GI losses (COMMON)
o Sweat losses
o Renal losses: osmotic diuresis, diabetes insipidus
This tends to only be seen in patients who do not tend to drink when they are dehydrated (e.g. elderly, children)
Diabetes Insipidus (pathogenesis, types, investigations, mx)
Inability to concentrate your urine (nothing to do with DM)
It can be ‘central’ i.e. due to not producing any ADH (idiopathic - 30%, tumour, surgery or trauma related).
It can be nephrogenic i.e. your kidneys are not sensitive to ADH e.g. lithium toxicity
Gestational or hypothalamic (due to injury of the region that controls thirst -> xs fluid intake)
Ix:
Exclude: hypokalaemia, diabetes mellitus, hypercalcaemia, plasma and urine osmolality (low), can have hypernatraemia water deprivation test - see if still dilute when you’re not drinking fluids to see if DI. Then give desmopressin and that can distinguish between nephrogenic and low ADH production.
Mx: Fluid replace with dextrose
How does diabetes affect the serum sodium?
- DM has a variable effect on serum sodium depending on the degree to which each of the following mechanisms predominate
- Hyperglycaemia will draw water out of cells leading to hyponatraemia
- However, osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia
Outline the renin angiotensin axis
Reduced perfusion or low sodium will stimulate the production of renin from the juxta-glomerular cells
This cleaves angiotensinogen to angiotensin I
This is then converted by ACE in the lungs to angiotensin II
Angiotensin II stimulates aldosterone production from the adrenals
Aldosterone stimulates sodium reabsorption and potassium excretion in the principal cells of the cortical collecting tubule through ROMK channels
NOTE: water will also be drawn in with the sodium so aldosterone should not greatly affect sodium concentration
Causes of hyperkalaemia
Reduced GFR (renal failure)
Reduced renin activity (Renal tubular acidosis type 4- triggered by trimeth, NSAIDs)
ACE inhibitors/ARBs
Addison’s disease
Aldosterone antagonists
Potassium release from cells (rhabdomyolysis, acidosis)
Management of hyperkalaemia
10 mL 10% calcium gluconate
50 mL 50% dextrose + 10 U insulin
Nebulised salbutamol
Treat the cause
Causes of hypokalaemia
GI loss
Renal loss
• Hyperaldosteronism, Cushing’s syndrome
• Increased sodium delivery to distal nephron
• Osmotic diuresis
Redistribution into cells
• Insulin
• Beta-agonists
• Alkalosis
Rare causes
• Renal tubular acidosis (type 1 and 2)
(TYPE 1 - impairment in hydrogen ion secretion in the distal tubule
TYPE 2 - bicarbonate wasting from proximal tubule)
• Hypomagnaesmia
• Conditions that increase the delivery of sodium to the distal nephron by blocking the triple transporter (Barterr Syndrome and loop diuretics) and double transporter (Na+/Cl-) (Gitelman syndrome and Thiazide diuretic)
Hypokalemia PC, Ix and Mx
Muscle weakness Arrhythmia Polyuria and polydipsia (due to DI) Ix: Aldosterone: renin ratio (primary hyperaldosteronism will show high aldosterone and low renin) Mx: 3-3.5 mmol/L Oral potassium chloride (2 x SandoK TDS for 48 hours) Re-check serum K+ concentration < 3 mmol/L IV potassium chloride infusion Maximum rate: 10 mmol/hr NOTE: rates > 20 mmol/hr irritate the superficial veins TREAT THE CAUSE
Calcium range and how is calcium stored in blood?
2.2-2.6
Free (ionised) – 50% - biologically active
Protein-bound – 40% - bound to albumin
Complexed – 10% - citrate/phosphate
2 forms of vitamin D
Vitamin D2 (ergocalciferol) – from plants Vitamin D3 (cholecalciferol) – produced when UV hits the skin and converts 7-dehydrocholesterol to cholecalciferol NB both are active
Main roles of vitamin D
Increased intestinal calcium absorption
Increased intestinal phosphate absorption
Critical for bone formation
Osteomalacia biochemical abnormalities
Low P, Low Ca, Low Vit D
High PTH, High ALP (not hugley raised, just raised)
(Remember LOOSER ZONE = OSTEOMALACIA)
Causes of vitamin D deficiency
Low sunlight
Ethnicity
Anticonvulsants – promote the breakdown of vitamin D
Phytic acid – food like chapatis have a high level of phytic acid which chelates vitamin D in the gut and reduces absorption
Other causes of osteoporosis
Low BMI Thyrotoxicosis Hyperprolactinaemia Cushing’s syndrome or exogenous steroids Prolonged recurrent illness (Acromegaly causes testosterone deficiency, which can lead to osteoporosis) Age-related decline in bone mass Early menopause Sedentary lifestyle Alcohol
Osteoporosis Mx
Weight-bearing exercise Stop smoking Reduce alcohol consumption Mx: M- Vitamin D Bisphosphonates Teriparatide (PTH derivative) Strontium (anabolic and anti-resorptive) HRT SERMs (e.g. raloxifene)
Sx of hypercalcaemia
Polyuria/polydipsia
Constipation
Confusion, seizures, coma
NOTE: these tend to occur when calcium level > 3 mmol/L
Causes of hyperparathyroidism
80% Parathyroid adenoma
Parathyroid hyperplasia (associated with MEN1)
<1% Parathyroid carcinoma
Hypercalcaemia causes
- Hyperparathyroidism (primary or tertiary- autonomous PTH secretion post renal transplant)
- Familial benign hypercalcaemia. (A mutation in the calcium-sensing receptor (CaSR) leads to an increase in the set-point for PTH release (leads to mild hypercalcaemia))
- Hypercalcaemia of malignancy
- Humoral hypercalcaemia of malignancy (e.g. small cell lung cancer) caused by PTHrP release
- Bone metastases (e.g. breast cancer) caused by local bone osteolysis (ALP RAISED)
- Haematological malignancy (e.g. myeloma) caused by cytokines
- Sarcoidosis (ALP can be raised if there is a space-occupying hepatic granuloma)
- Hyperthyroid (increases bone turnover too fast for osteoblasts to recover & causes osteoporosis and hypercalcaemia) (high ALP) or overtreatment of hypothyroidism.
- Hypoadrenalism (renal Ca2+ transport)
- Thiazide diuretics (renal Ca2+ transport)
- Excess vitamin D (e.g. sun beds)
Milk alkali syndrome
milk-alkali syndrome is characterised by high blood calcium and metabolic alkalosis caused by taking in too much calcium and absorbable alkali; common sources of calcium and alkali are dietary supplements taken to prevent osteoporosis and antacids.
What is the rate limiting step in Vitamin D activation?
1 alpha hydroxylase in kidney
31 year old presents with profound tiredness. Acutely unwell a few days. Vomiting.
Na 125 (low), K 6.5 (high), Glucose 2.9mM (low)
FT4<5nM low TSH >50 (high)
What is the diagnosis?
Schmidt Syndrome
Primary hypothyroidism
Addison’s Disease
Hyponatraemia + hyperkalaemia suggests that there is a deficiency of mineralocorticoid
Similarly, hypoglycaemia suggests that there is a deficiency of glucocorticoid
This is also known as polyglandular autoimmune syndrome type II
o This patient has antibodies against their thyroid gland and their adrenal glands
Synacthen test how do you do it
Measure cortisol and ACTH at the start of the test
Administer 250 µg synthetic ACTH by IM injection
Check cortisol at 30 and 60 mins
Healthy people should produce > 550 nM of cortisol within 30 mins
Phaeo treatment
Urgent alpha blockade (with phenoxybenzamine or phentolamine or doxazocin)
Some fluids may be given before alpha blockade as it can cause a dramatic drop in blood pressure
A beta-blocker should be given after the alpha-blocker to prevent reflex tachycardia
Patients should receive high-dose alpha and beta-blockade before surgery as the action of surgery can cause the release of catecholamines from the adrenals
Syndromes associated with phaeo
Von Hippel Lindau
NF1
Men2
The order of the cushing’s test and how you do it
- Midnight cortisol
- Low-dose dexamethasone suppression test *
if cortisol isn’t suppressed, you assume its a pituitary (85% chance) and do a sinus sample to confirm. - Inferior petrosal sinus sampling (we don’t’ do high dose anymore as (20% of ectopics are also suppressed by high dose dexa) and MRI (can pick up incidentalolmas) and confuse the diagnosis)
*The patient’s baseline ACTH and cortisol is measured at the start
Then they are given 0.5 mg dexamethasone every 6 hours for 48 hours. This should suppress cortisol to < 50 nM . (high dose is 2mg)
If there is failure of suppression of cortisol, the patient should be sent for inferior petrosal sinus sampling
Cushings (PC, Ix, Mx)
PC: Moon face, buffalo hump, hirsuitism, obesity, HTN, PROXIMAL MYOPATHY
Ix:
High Na, Low K (this is because mineralocorticoid receptors are not specific and are activated by cortisol) High Glucose, Aldosterone and Renin is low in cushings syndrome
1. Midnight (if the midnight cortisol is low then it is definitely not cushings)
2. Low dose dexa (this rules out pseudo cushings syndrome)
> inferior petronasal sinus sampling
Mx: Treat underlying disease surgical removal
Addison’s
Primary adrenal insufficiency
PC: postural hypotension, bronze skin, HYPOGLYCAEMIA, lethargy depression
Causes: Autoimmune destruction, infection destruction (TB),
Ix: high na low K, ACTH will be high due to -ve feedback. Renin is high due to -ve feedback. Calcium slightly (PTH is slightly suppressed)
Short synacthen test doesn’t produce cortisol (serum cortisol <497 nanomols/L (<18 micrograms/dL)).
Mx: Replacement of hormones (hydrocortisone and fludrocortisone)
Cx: addisonnians crisis (low BP, D&V) - you would give hydrocortisol, fluid and eventually dextrose (make sure not to worsen hyponatraemia)
NB After short synacthen you can do Long synacthen test. The idea behind it is that you stimulate the adrenals for a longer period of time and so if the addisons is due to atrophied adrenals due to pituitary failure these will respond after persistent acth stimulation. Adrenals that are diseased won’t respond.
Conn’s syndrome
Uncontrolled HTN, High Na low K+,
Ix: Aldo Renin ratio would be high, due to adrenal tumour
Fludrocortisone suppression test is the most definitive (we give fludrocortisone for 4 days and see if aldosterone has been suppressed sufficiently, if not then it is definitively PA)
Adrenal venous sampling - If the aldosterone/cortisol ratio on one side is significantly higher (>2 times higher) than the simultaneous peripheral venous ratio, with a ratio no higher than peripheral on the other side, the study is considered to show lateralisation, indicating that unilateral adrenalectomy should cure or significantly improve the hypertension.
mx is spironolactone other aldo antagonists if bilateral
Blood supply to the adrenals
• The adrenal gland has an extensive arterial supply with 57 small arteries
• However, there is only 1 vein
• To get a blood sample to test adrenal output, you will need to put a cannula through the IVC and into the adrenal vein
• Each adrenal gland drains via a different route:
o LEFT - into the left renal vein
o RIGHT - directly into the IVC
Why is this important? Adrenal vein sampling
Von Hippel Lindau Syndrome
- Phaeochromocytomas
- Renal cell carcinoma
- Renal cysts
- Retinal/CNS haemangioblastomas
MEN 2
- Parathyroid tumours
- Medullary thyroid cancer
- Phaeochromocytomas
- NOTE: MEN2b is associated with a Marfanoid appearance and neuromas of the GI tract
Causes of a high anion gap
Ketosis
Lactic acidosis
Methanol
Ethylene glycol poisoning
How does the mechanism of unconciousness different betweeen alkloses and acidoses
In alkalosis: As pH increases, plasma proteins start to stick to calcium more than usual
Total plasma calcium levels will remain normal but there will be less free ionised calcium (active form)
This leads to tetany (which can make patients hyperventilate even more)
TLDR -> Alkalosis causes hyperventilation due to tetany which can result in alkalotic patients presenting unconscious compared to acidoses where it is because brain enzymes can’t function at low pHs.
Result of a metformin overdose
Lactic acidosis
Lactate is produced by anaerobic glycolysis in the muscles
This goes to the liver and is converted back to glucose which will then return to the muscle
Metformin inhibits hepatic gluconeogenesis (the conversion of lactic acid to glucose in the liver) thereby resulting in lactic acidosis
NOTE: excess lactic acid is normally excreted by the kidneys, but in renal failure the kidneys cannot handle the excess lactic acid
How would you manage 60 year old man who presents unconscious A&E with a history of polyu and polyd. Na 160, K6, U 50, pH 7.3, Glucose 60
hyperosmolar hyperglycaemic state (HHS)
• If you give them lots of fluid and try and normalise the numbers too quickly, they will get cerebral oedema and die so they need to be treated cautiously and slowly
• You should use 0.9% saline because this will enable a slower reduction in plasma sodium concentration
(HHS) is a complication of diabetes mellitus in which high blood sugar results in high osmolarity without significant ketoacidosis.
NB DKA typically develops in younger patients, <45, who have little or no endogenous insulin production, whereas HHS usually occurs in much older non-insulin-dependent patients (who are often greater than 60 years old).
Enzymes that are raised post MI
• AST will increase following an acute MI because AST is found within the myocytes
o AST goes up about 3 days after an MI and remains for around 14 days (3-14 days)
o Enzymes that increase following MI
• Troponins
• CK (MB)
• AST
• LDH
Rhabdomyolysis- which enzymes are raised and why? How do we treat this?
• Rhabdomyolysis can lead to acute kidney injury (because myoglobin is very nephrotoxic)
o If patients have a very high CK because of muscle breakdown, it can lead to renal failure
o To prevent this from happening, you give them IV bicarbonate which allows them to pee out all the extra CK
ALT:AST ratio tells us what in different diseases?
- ALT will be higher than AST in patients with viral hepatitis
- AST will be higher than ALT (2:1) in patients with chronic alcoholic cirrhosis. cirrhoSIS - AST
What enzyme rises in prostate cancer?
Acid phosphatase
What is the level of vitamin D in primary hyperparathyrdoisim?
• In primary hyperparathyroidism, the vitamin D level is LOW
o This is because PTH activates 1-alpha hydroxylase meaning that vitamin D is consumed (i.e. it is activated)
When do we need dialysis?
HIGH CK IS NOT AN INIDICATION Acidosis Electrolytes - Hyperkalaemia Intoxication e.g. ethylene glycol, salicyclates Overload/ pulmonary oedema Uraemic encephalopathy
What are MIBI scans used for?
MIBI is used by the parathyroid glands and by the myocardium e.g. in MI the infarcted areas wil not take up MIBI
FRAX score
Risk of fracture
Which valves is S viridans more likely to infect and why?
o Normally, the S. viridans will pass through the right side of the heart and be filtered out by the lungs
o However, if you experience repeated S. viridans bacteraemia, it may settle on a DAMAGED valve
o The tricuspid and pulmonary are part of low pressure systems so the valves are less likely to experience any trauma
o However, the aortic and mitral are part of high pressure systems and are more likely to be damaged
o If there is NO damage at all, you are only going to get endocarditis if it is an aggressive bacterium such as S. aureus
• Staphylococcus aureus is very aggressive so it will land on the first valve it sees (usually tricuspid) and cause life-threatening septicaemia
“30 year old man complains of polyuria and polydipsia . His fasting blood glucose is 4.7. Na 157 (high), K 4.2 (normal), Ca 2.35 (N), phosphate 1.2 (N), PTH 4.2 (N).
Diabetes Inspidus
Types of Creatine Kinase
o CK-MM - skeletal muscles
o CK-MB - cardiac muscle
o CK-BB - brain - activity is minimal even in severe brain damage (very small quantities)
o NOTE: CK-MM is responsible for almost the entire normal plasma activity
What is the first enzyme to be released post MI?
Myoglobin is a cystolic enzyme as its the first to be released
It isn’t very specific
When does troponin rise post MI?
• Troponins are present within the contractile apparatus of the cardiac muscle
• There is also a free cytosolic pool of troponins
• Initially, troponins from the free cytosolic pool will be released
• Later on, as the contractile bundles break down, there will be increased release of troponins
• Troponins
o Rise at 4-6 hours post MI
o Peaks at 12-24 hours
o Remains elevated for 3-10 days
o Therefore, it should be measured at 6 hours and again at 12 hours after the onset of chest pain
Diagnostic criteria for MI?
o Either of the following: • Typical rise and gradual fall in troponin or more rapid rise and fall in CK-MB with at least one of the following: • Ischaemic symptoms • Pathological Q waves on ECG • ECG changes indicative of ischaemia • Coronary artery intervention • Pathological findings of an acute MI
Cardiac failure markers
• Natriuretic peptides
o ANP (atria)
o BNP (ventricles)
• BNP can be measured to assess ventricular function
• BNP can be used to exclude heart failure in a clinical setting
Why does ethylene glycol poisoning cause acidosis and AKI?
It gets converted to oxalic acid which precipitates with calcium to form calcium oxalate stones
Single Injection Plasma markers - how and when do we use this?
51Cr-EDTA
99Tc-DTPA
Iohexol
The injection is administered followed by measurement of urine collection using a Geiger counter or blood samples can be taken to look for a progressive reduction in radioactivity
NOTE: this is only used under specific circumstances (e.g. when accurate estimation of GFR is necessary before chemotherapy
Inulin
Neutral, freely filtered fructose polymer that is technically the perfect marker
However, measurement of inulin concentrations is difficult and it requires a steady-state infusion
So, it is only used as a research tool
AKI definition
AKI is defined as a rise in serum creatining over 26.5 in 48h or to 1.5x baseline in 48h (3x is severe). It can also be defined as a urine output of less than 0.5mls/kg/hr but prostate and bladder pathology can acutey cause this too
What factors make creatinine a good/bad marker for clearance?
Produced by Muscle cells Good as: Freely filtered Produced at a constant rate NOTE: it is actively secreted into the urine by tubular cells But dependent on: Muscularity Age Sex Ethnicity
What equations are used to turn urine creatinine -> EGFR
Cockcroft-Gault – estimates creatinine clearance by taking into account weight, age and sex (may overestimate when GFR < 30 ml/min)
MDRD – estimates GFR from creatinine clearance and takes into account age sex, serum creatinine and ethnicity (may underestimate in overweight and young people)
CKD-EPI – improvement of MDRD and currently recommended
Why is Cystatin C a good marker of endogensou egfr?
NOTE: it is constitutively produced by all nucleated cells, is generated at a constant rate and freely filtered. It is almost completely reabsorbed and catabolised by tubular cells
Stages of AKI
Stage 1: increase in serum creatinine by 1.5-1.9 times baseline
Stage 2: increase in serum creatinine by 2-2.9 times baseline
Stage 3: increase in serum creatinine by >=3 times baseline
Post renal AKI pathophysiology
GFR is dependent on a hydraulic pressure gradient
Obstruction results in increased tubular pressure
This results in an immediate decline in GFR
Glomerular ischaemia
Tubular damage
Long-term interstitial scarring
MAI Mx
Mycobacterium avium intracellulare • Clarithromycin/azithromycin • Rifampicin • Ethambutol • With or without streptomycin/amikacin
Rapid-growing NTM
• Based on susceptibility testing
• Usually macrolide based
LFTs of ischaemic hepatitis
There are three things that can elevate AST and ALT into the thousands and they are: toxic hepatitis, ischaemic damage, and viral hepatitis.
Drug induced cholestasis
Choelstatic LFTs (Raised ALP, GGT)
REMEMBER: half-life of albumin is 20 days so in very acute liver failure the albumin may appear normal
• A USS was performed and there was NO bile duct obstruction
• A diagnosis of drug-induced cholestasis
o AUGMENTIN is the most common drug that causes drug-induced cholestasis (UTI)
When would you use cincalet?
Secondary hyperparathyroidism [in patients with end-stage renal disease on dialysis
Hypercalcaemia in parathyroid carcinoma,
Primary hyperparathyroidism [in patients where parathyroidectomy is inappropriate
It directly suppresses PTH
- What might be seen on urine microscopy in a patient with ATN?
Epithelial Cell casts
What durgs can cause pre renal AKI?
Calcineurin inhibotrs (tarolimus, cyclosporin)
ACEi
NSAIDs
Renal Acidosis causes and consequences
Muscle and protein degradation
Osteopaenia due to mobilisation of bone calcium
Cardiac dysfunction
Oral sodium bicarbonate
Medications that cause hyperkalaemia
ACE inhibitors
Spironolactone
Potassium-sparing diuretics
Renal Bone Disease Pthophysiology
Damaged kidneys are unable to excrete phosphate and activate vitamin D
Phosphate retention stimulates the production of FGF23 and Klotho
This lowers the levels of activated vitamin D
To try and get rid of the excess phosphate, the body will produce more PTH
Furthermore, to try and increase levels of vitamin D, the body will produce more PTH (i.e. there are two stimuli for PTH release)
High levels of phosphate in the blood will complex with calcium leading to a reduction in the level of free calcium
High levels of PTH will result in the bone becoming resistant to PTH
