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24hour collection Proteinuria quantification (superceded by PCR above) Creatinine clearance estimation Electrolyte estimation Stone forming elements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
