Drugs used in coronary artery disease

Describe how nitrates are used in management of angina

Angina happens when not enough blood gets through to the cardiac muscle. Nitrates dilate resistance vessels, including the coronary arteries supplying the heart, thus increasing the blood supply to the heart. The two main nitrates are glyceryl trinitrate (GTN) and isosorbide dinitrate. They are converted to nitric oxide via organic nitrate ester reductase, and the nitric oxide produced goes onto cause relaxation of vascular smooth muscle.

GTN and isosorbide mononitrate differ in terms of their pharmacokinetics. GTN has very high first-pass metabolism, meaning that if you try to give it orally, it will be broken down by the liver and you won't get much use out of the drug. Therefore, GTN is usually given by sublingual spray or transcutaneous patch, or by IV in severe cases. Isosorbide mononitrate has a lower first-pass clearance and can be given orally.

Another thing to keep in mind with nitrates is that they can lose their effectiveness quickly. If nitrates are used constantly over 24 hours, they lose their effect- a process called "tachyphylaxis." Therefore, if people are using transcutaneous GTN patches, the patches need to be taken off overnight.

Describe how antiplatelet agents, beta adrenoreceptor blockers, thrombolytics and anticoagulants are used in the context of ischaemic heart disease

This lecture basically covered emergency situations ("acute coronary syndromes"), including unstable angina, non-ST elevation acute myocardial infarction, and ST-elevation acute myocardial infarction (STEMI). (ST-elevation refers to a feature of the ECG tracing.)

Antiplatelet agents

Antiplatelet agents are drugs that block various actions of platelets. I've covered them here. Aspirin and clopidogrel (an ADP receptor antagonist) are good for inhibiting platelet aggregation on coronary plaques.

Beta-adrenoceptor blockers

Beta-blockers, as discussed here, reduce the contractility and rate of the heart. In turn, this reduces the heart's demand for oxygen so that it can make do with less oxygen than before. In acute coronary syndromes, beta-blockers help to limit the size of the infarct and reduce pain.

Thrombolytics

Thrombolytics (a.k.a. profibrinolytics) are good when urgent thrombolysis is needed (i.e. you need to get rid of a blood clot NOW, not prevent them from happening in the future). I have discussed them here.

Anticoagulants

Anticoagulants are good for preventing clots from happening in the future. One of the main ones that is used is low molecular weight heparin, which can prevent thrombotic and embolic complications of heart attacks. I have discussed these here.

Drug Management of Heart Failure

Describe the physiology of Na, K and H2O renal excretion, including the renin-angiotensin-aldosterone system

• Renal Physiology: Reabsorption part 1
• Renal Physiology: Reabsorption part 2

Describe the drug strategies to enhance Na and H2O excretion (ACE inhibitors, aldosterone antagonists)

ACE inhibitors, such as enalapril and captopril, work by inhibiting angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II. Since angiotensin II normally works on the arterioles to cause constriction and on the adrenal cortex to increase the release of aldosterone, inhibiting ACE causes vasodilation (and an increase in blood flow to the kidneys) and an increase in salt and water excretion (via the actions of aldosterone).

Angiotensin II and aldosterone can also be blocked directly. AT1 receptor blockers block the actions of angiotensin II (since AT1 receptors, confusingly enough, are the receptors for angiotensin II). These drugs tend to end with the suffix -sartan, such as irbesartan. Aldosterone antagonists such as spironolactone not only increase salt and water excretion, but also inhibit the myocardial remodelling that occurs during heart failure.

Describe the clinically important beta adrenoreceptor blockers

Beta-1 blockers can also be used to treat heart failure, as they can block cardiac modelling and also decrease the myocardial contractility (which in turn decreases the blood pressure). Furthermore, they can also slow the heart down, allowing more time for the ventricles to fill with blood (which is important in cases of diastolic heart failure). Most beta-blockers end with -olol, and include metoprolol and bisoprolol. Adverse effects of beta-1 blockers are mainly related to off-target activation of beta-2 receptors, and include bronchospasm (which is why beta-blockers tend to be avoided in people with asthma). There are also side-effects from having too much of a good thing, such as excessive slowing of the heart.

Describe the clinically important diuretics

I'll discuss diuretics in a later post, but essentially diuretics act on certain transporters in the tubule to decrease reabsorption and/or increase secretion of salts and water so that you pee more. The main types of diuretics include loop diuretics (e.g. frusemide), thiazides (e.g. hydrochlorothiazide), and aldosterone antagonists (e.g. spironolactone).

Describe how digoxin acts as antiarrhythmic agent and to increase cardiac contractility

Digoxin is an antiarrhythmic that is also used for heart failure. It works by blocking Na+/K+ pumps, thus reducing the gradients of sodium and potassium. Because it blocks the pumping out of sodium, it also has a downstream effect on Na+/Ca2+ exchangers, which bring in sodium to let calcium leave the cell. Because the Na+/Ca2+ exchangers are being affected, there is more intracellular calcium, which leads to more efficient contraction of myocytes and increased cardiac contractility.

Digoxin also has indirect effects on the heart via the vagus nerve. Digoxin stimulates the vagus nerve, causing an increase in parasympathetic stimulation and decreased heart rate. Therefore, digoxin is also good for treating supraventricular tachyarrhythmias (only the supraventricular ones as the ventricles don't get parasympathetic stimulation).

Even though digoxin can reduce heart rate, at toxic doses it can actually increase heart rate. Since digoxin blocks the Na+/K+ pump, there is a smaller potassium gradient and so less potassium leaves the cell during repolarisation. Therefore, the membrane becomes less polarised (i.e. less negative), making it easier to reach threshold during the next heartbeat.

Digoxin toxicity may also present with other symptoms, such as serious arrhythmias, nausea, confusion, and visual problems. Nausea and confusion are most commonly seen in elderly patients. Since digoxin relies a lot on the kidneys for excretion (~70% excretion via the kidneys), it is especially toxic in people with renal impairment. Digoxin is also especially toxic in people who are hypokalaemic, as potassium would ordinarily compete with digoxin for binding to the Na+/K+ ATPase.

Describe how nitrates may be used in heart disease

The actual mechanism of action of nitrates wasn't really discussed in this lecture, other than that they are vasodilators that can help in emergency situations by reducing afterload.

Renal Anatomy

I wasn't sure what to blog about next, so I wrote down all of the fields that we're studying (microbiology, anatomy, physiology, etc.) and let a random number generator pick for me. It picked the number corresponding to Anatomy, so I guess that's what I'll be blogging about now! (Also, I bombed a large proportion of the anatomy questions in the set of formative renal questions that we were given, so I guess I need the extra study...)

Describe the position and functional anatomy of the kidneys and ureters.

The kidneys are located in the abdomen, roughly between T12 and L3. The right kidney is slightly lower than the left kidney because it has been pushed down by the liver. The hilum of each kidney (where the blood vessels etc. join the kidney) is located at around L1-L2. Each kidney is surrounded by a layer of perirenal (or perinephric) fat, which is surrounded by a layer of renal fascia (a.k.a. Gerota's fascia), and then by a layer of pararenal (paranephric) fat.

Demonstrate the topographical relationships of the kidneys and ureters to other abdominal structures.

The kidneys are located laterally to the psoas muscle, and the ureters run along the front of the psoas. As the ureters enter the pelvis, they cross the bifurcation of the iliac arteries.

Describe the blood supply and innervation of the kidneys and ureters.

Blood supply

The kidneys receive blood from the renal arteries. Since both renal arteries arise from the aorta, and the aorta is on the left side of the body, the left renal artery is shorter than the right renal artery. The opposite is true for renal veins: the left renal vein is longer than the right renal vein. The left renal vein also receives blood from the gonads and adrenals (via the left gonadal vein and the left suprarenal vein respectively).

The ureters receive their blood supply from whatever structures are running close to them. The upper part of the ureters tend to receive blood from the renal artery, the middle part of the ureters tend to receive blood from the gonadal arteries and/or the aorta, and the lower part of the ureters tend to receive blood from the vesical arteries.

Innervation

The kidneys receive sympathetic innervation from T10 and T11 nerves (a.k.a. the lesser splanchnic nerves) and parasympathetic innervation from the vagus nerve. Sensory fibres follow the sympathetic fibres back to T10/T11, so kidney pain tends to be felt over those dermatomes. One important point is that nerves are not very important for renal function in general, but for renal blood flow. Aspects of renal function (how much salt and water to absorb, for example) tend to be controlled by hormones.

The ureters receive sympathetic innervation from T12 and L1, and parasympathetic innervation from the vagus and hypogastric (from S234) nerves. Just like with the kidneys, the sensory fibres follow the sympathetic fibres, so pain in the ureters is felt over T12 and L1.

Describe histology (microscopic anatomy) of the renal cortex and medulla including the renal corpuscle, proximal convoluted tubule, Loop of Henle, distal convoluted tubules, and juxtaglomerular apparatus and collecting tubules.

The outer region of the kidney is called the cortex, and is where the renal corpuscles and convoluted tubules are located. (Don't worry, I'll describe what they are and what they do in a bit.) The area deep to the cortex is the medulla, and contains the Loops of Henle and collecting tubules. There is, however, a bit of overlap between these two areas: the columns of the renal medulla contain the structures of the renal cortex, and the medullary rays of the cortex contain structures of the renal medulla.

Renal corpuscle

The renal corpuscle is made out of the glomerulus (a "knot" made out of arteries) and Bowman's space (the first part of the tubular system where urine is formed). Under the microscope, renal corpuscles basically look like a cluster of cells surrounded by a white ring (the Bowman's capsule). The renal corpuscle is the main site where filtration occurs (i.e. the blood gets filtered so that pretty much everything, except for large proteins, is pushed into the Bowman's capsule and the tubular system).

Proximal convoluted tubule

The proximal convoluted tubule is the first lot of tubules. The reabsorption of pretty much all glucose and amino acids occurs here, along with reabsorption of many other substances. Proximal convoluted cells are tall, columnar, and have a brush border to increase their surface area for reabsorption. Since the Na+/K+ pump is critically important for maintaining concentration gradients for reabsorption, proximal convoluted tubule cells have plenty of mitochondria to keep them topped up and ready to go.

Loop of Henle

The loops of Henle have two parts: a thin descending limb and a thick descending limb. The thin descending limb is more permeable to water than salt, whereas the ascending limb is impermeable to water but permeable to salt. The appearance of the Loops of Henle depends on whether you have a cross-section or a longitudinal section of the loop: cross-sections look like little circles, whereas the longitudinal sections look like long white stripes that are lined by cells. (I think. Histology isn't my strong point.)

Distal convoluted tubules and collecting duct

The distal convoluted tubule and collecting duct cells are similar to those of the proximal convoluted tubule, except that cells in the distal convoluted tubule and collecting duct tend to be cuboidal and less metabolically active than those in the proximal convoluted tubule. Both the distal convoluted tubule and the collecting duct are under hormonal control to change the amount of salts and/or water reabsorbed.

Another point of interest is the juxtaglomerular apparatus. The juxtaglomerular apparatus of the distal tubule interacts with the afferent arteriole by secreting hormones etc. to maintain filtration rate (see here).

Describe the histology of the ureter.

Ureters, like many other bodily tubes, have a mucosa, muscularis layers, and an adventitia. (However, unlike many other bodily tubes, they likely do not have a submucosa.) There are two muscularis layers: one is circular, and one is longitudinal. Together, the muscularis layers work to propel urine towards the bladder.

Describe the anatomy of the urinary bladder, its base and ureteric openings and its relationship to the overlying peritoneum.

The bladder is shaped kind of like an upside-down triangular pyramid. The urethra connects to the bladder at the inferior "point." The umbilical ligament, which is a remnant of an embryonic structure called the urachus, joins at the apex, which is the anterior superior "point." The ureters join at the posterolateral points and continue to pass through the wall of the bladder.

One point of interest is the bladder trigone, which is formed from the intermediate mesoderm of the urogenital septum. This is in contrast to the rest of the bladder, which is formed from the anterior part of an embryonic structure called the cloaca. The bladder trigone makes up part of the posterior wall of the bladder. The ureters open into the bladder at the upper lateral corners of the bladder trigone.

Describe the blood supply and innervation of the urinary bladder.

The bladder receives its blood supply from the superior and inferior vesical arteries. The superior vesical artery comes from the patent part of the umbilical artery, which in turn comes from the anterior division of the internal iliac artery. The inferior vesical artery comes directly from the internal iliac artery.

Like the ureters, the bladder receives sympathetic stimulation from T12 and L1. However, its parasympathetic innervation is only from the hypogastric plexus (S234). Both sympathetic and parasympathetic nerves activate muscles, but they activate different muscles: sympathetic stimulation causes the external urethral sphincter to tighten (and stop you from peeing), while parasympathetic stimulation causes the detrusor muscle (i.e. the bladder muscle) to contract, thus making you pee. Sensory information is a bit mixed: pain fibres follow the sympathetic nerves back to T12 and L1, whereas stretch fibres follow the parasympathetic nerves back to S234.

An important reflex to discuss here is the micturition reflex. When the bladder wall is stretched, this information is conveyed back to S234, triggering reflex contraction of the detrusor muscle. When this happens, we feel the urge to pee. However, we can override this reflex through various centres in our brain and through contracting the external urethral sphincter.

Discuss the anatomical reasoning behind differences in referred pain from upper and lower urinary tract infections.

As mentioned, different parts of the urinary tract convey sensory fibres to different parts of the spinal cord. In the kidney, sensory fibres go back to T10/T11, in the ureter they go back to T12/L1, and in the bladder the fibres detecting pain (not stretch) go back to T12/L1. When we feel pain in the urinary tract, we tend to feel it over the dermatomes associated with those sensory nerves: e.g. pain in the kidney is felt over the T10/T11 dermatomes. (However, to my understanding, bladder stones might be felt lower down, like in the S1/S2 dermatomes.)

Describe the anatomy of the urethra; explain the anatomy of its different parts in males and females in relation to continence and catheterisation.

The male urethra is quite long and is divided into three parts (prostatic, intermediate / membranous, and spongy), whereas the female urethra is relatively short and isn't divided into parts. (Some textbooks may consider the pre-prostatic, or intramural, part of the urethra to be a fourth part of the urethra.) Because the female urethra is much shorter, it is easier to catheterise than the male urethra. However, the female urethra is more prone to urinary tract infections than the male urethra. Furthermore, women are more prone to incontinence (though this is also partly because they do crazy stuff like give birth).

An important structure within the male urethra is the verumontanum, also known as the seminal colliculus. The verumontanum is a thickening within the prostatic urethra. It has three orifices: one called the prostatic utricle, and two for the openings of the ejaculatory ducts. The verumontanum is an important marker to look for when removing the prostate via the urethra.

Describe the skeletal and ligamentous components of the pelvis.
Discuss the sexual differences in pelvic skeletal anatomy.
Describe the anatomy and functional importance of the pelvic diaphragm.
Describe the topographical arrangement of anatomical structures within the pelvis.

The pelvis wasn't exactly covered in any of the lectures that we just had (despite pelvic stuff being in the learning outcomes), so I guess it's 2nd year undergrad me to the rescue!

• Pelvis part 1
• Pelvis part 2

Tumours of the Bladder and Kidneys

List the major types of neoplasms of the kidney

Kidney tumours can be either benign (e.g. renal papillary adenoma) or malignant (e.g. renal cell carcinoma). In this post, I'll only be covering renal cell carcinoma because it was the only one talked about in depth in the lectures (probably because it's by far and away the most common). Clear cell renal cell carcinomas are the most common type of renal cell carcinomas.

Outline the aetiology, risk factors for development and pathogenesis of kidney neoplasms

Risk factors of renal cell carcinoma are pretty much the same as risk factors for many other illnesses: smoking, hypertension, obesity, genetic factors, and exposure to certain toxic chemicals. It is most commonly seen in men aged 50-70.

One genetic cause of renal cell carcinoma is Von Hippel-Lindau disease, which is a genetic disorder in which the VHL tumour suppressor gene on chromosome 3 is mutated. There are also sporadic forms of the disease in which one of the VHL genes has been lost (due to some kind of deletion of the short arm of chromosome 3), and then the other gene becomes mutated. Inactivation of VHL results in an increase in IGF-1, which is a growth factor that can upregulate hypoxia-inducible factors and ultimately vascular endothelial growth factor (VEGF).

List, in brief, the morphological and histological features of kidney neoplasms

Renal cell carcinoma arises from the epithelial cells of the proximal convoluted tubule. The cells look clear under the microscope and yellow macroscopically (i.e. to the naked eye), as the cells are filled with carbohydrates and lipids.

Outline the clinical presentations of kidney neoplasms

Renal cell carcinoma is usually pretty silent and is often simply picked up when patients are scanned for some other reason. Alternatively, patients might not get noticed at all until their disease has become severe. In patients who do show symptoms, the classic signs include haematuria, abdominal mass, and flank pain, though there may also be other symptoms. For instance, if the carcinoma spreads into the inferior vena cava and obstructs the left gonadal vein, it can result in scrotal varices. There may also be paraneoplastic syndromes from inappropriate secretion of hormones: hypercalcaemia from parathyroid hormone-related protein (PTHrP), erythrocytosis from EPO, hypertension from renin, and even Cushing's syndrome from ectopic ACTH.

Renal cell carcinoma is relatively resistant to traditional chemotherapy and radiotherapy, so surgery is often used as treatment. Immunomodulatory and anti-VEGF treatments may also be tried.

Provide an overview of staging of kidney neoplasms

Staging of renal cell carcinoma is generally done using the TNM system. The T stands for "tumour" and refers to a tumour that has not spread beyond the original site. The N stands for "nodes" and refers to a tumour that has spread to lymph nodes. Finally, the M stands for "metastatic" and refers to a tumour that has spread around the body.

List the major types of lower urinary tract neoplastic disease

The main types of bladder tumours are urothelial carcinoma (a.k.a. transitional cell carcinoma) and squamous cell carcinoma. Urothelial carcinoma is by far the most common in Australia, though squamous cell carcinoma is more common in areas where schistosomiasis (a parasite disease) is endemic.

Outline the aetiology, risk factors for development and pathogenesis of lower urinary tract neoplastic disease
List, in brief, the morphological and histological features of lower urinary tract neoplastic disease

Smoking and certain carcinogenic substances are the main risk factors for bladder cancers. They are most commonly seen in older men.

Urothelial carcinoma may have one of two types of precursor lesions: flat or papillary. Flat precursor lesions include urothelial carcinoma in situ, whereas papillary precursor lesions include papillary urothelial carcinoma. The flat precursors are more often seen in p53-dependent tumours, which tend to be more aggressive than p53-independent tumours, which often have papillary precursors. (p53 is a tumour suppressor gene that is important in the development of many cancers.)

Urothelial carcinoma is multifocal (meaning it can affect multiple sites) and recurrent (meaning that it comes back). There are two main theories as to why this is so: field effect theory and implantation theory. The field effect theory states that whatever caused the first cancer might have affected nearby sites, whereas the implantation theory states that cells from the first tumour could have broken off and implanted somewhere else. In reality, it could be a mixture of the two.

Treatment of urothelial carcinoma is basically a mix of surgery, radiation, and/or chemotherapy, depending on the situation.

Outline the clinical presentations of lower urinary tract neoplastic disease

Bladder cancer often presents with painless haematuria. Remember: painless haematuria is malignancy unless proven otherwise.

Provide an overview of staging of lower urinary tract neoplastic disease

Just like renal cell carcinoma, urothelial carcinoma also uses TNM staging. The T stage can be further divided up depending on where the tumour is. At the T1 stage, the tumour is in the lamina propria. T2 means that the tumour is in the muscularis propria, T3 in the perivesical fat, and T4 in adjacent organs. N refers to invasion of nodes, whereas M refers to metastasis.

Urinary tract congnital anomalies, cystic disease, urolithiasis, and obstructive disease

List the major types of congenital malformations affecting the kidney
Describe the anatomical and renal functional defects of the major types of congenital malformations affecting the kidney

The major types of congenital malformations affecting the kidney are agenesis of the kidney, kidney hypoplasia, ectopic kidneys, and horseshoe kidneys.

Agenesis

Agenesis involves the absence of one or both kidneys. Bilateral renal agenesis, also known as Potter's syndrome, is incompatible with life, as not only does it result in oligohydramnios (decreased urine output), it also results in hypoplastic lungs (small lungs that haven't formed properly). Fetuses with Potter's disease tend to have very "squashed" faces. Unilateral agenesis, on the other hand, is usually asymptomatic, partly because the remaining kidney may undergo compensatory hypertrophy. Patients with unilateral renal agenesis may also be other abnormalities of the genitourinary tract.

Hypoplasia

Hypoplastic kidneys have developed normally, but are small. Usually only one kidney is affected.

Ectopic kidneys

Ectopic kidneys are kidneys that aren't where they're supposed to be (between around T12 and L3). Usually ectopic kidneys are found in the pelvis due to failure to ascend, but rarely you might get a kidney that has managed to ascend all the way into the thorax. Most ectopic kidneys are either normal sized or slightly smaller.

Horseshoe kidneys

Horseshoe kidneys are formed from fusion of the upper or lower poles of the kidneys. They are usually located quite low down as their ascension is obstructed by the inferior mesenteric artery. Usually horseshoe kidneys have numerous renal arteries supplying them.

Outline the major types of cystic disease of the kidney in terms of aetiology, pathogenesis, clinical features and complications

Cystic diseases are, well, diseases in which there are cysts. There are a range of cystic kidney diseases, but in this post we will only focus on some of the main ones.

Simple renal cysts

Simple, or localised, renal cysts are incredibly common, especially in patients over the age of 50. However, simple cysts are usually asymptomatic. There is a risk of rupture, causing haematuria, pain, and so on, but usually the biggest problem with simple renal cysts is that a malignant tumour might be mistaken as a simple renal cyst. There are some clues, however, that might help in differentiating a malignancy from a simple cyst: multiple septa, thickened cyst walls, and solid areas within or around cysts are all clues to malignancy.

Cystic renal dysplasia

Cystic renal dysplasia is malformation of the kidney (or kidneys- it can be either unilateral or bilateral) with cysts of various sizes. It is a common cause of abdominal mass in infants. Under the microscope, kidneys look abnormal and have many immature structures.

Polycystic kidney disease

Polycystic kidney disease is characterised by fluid-filled cysts in the kidney. It comes in two flavours: autosomal dominant (ADPKD) and autosomal recessive (ARPKD).

ADPKD is the most common type of polycystic kidney disease. The three main genes identified are PKD-1, PKD-2, and PKD-3. Cyst formation begins in utero but progresses very slowly, so patients usually don't present until they are in their 30s or even in their 50s. Due to the formation of cysts, the kidneys can become quite large and the cysts can compress surrounding renal tissue. The resulting damage can cause symptoms such as pain and haematuria.

ARPKD is rare and involves the PKHD1 gene. The kidneys appear smooth and have small cysts. ARPKD, unlike ADPKD, presents quite early on (in childhood or even in infancy).

Classify the different forms of urinary tract obstruction according to aetiology, pathogenesis, morphology, clinical features and complications.
Explain how urinary tract obstruction can lead to kidney injury

Obstructive uropathy is a fancy term that refers to obstruction anywhere in the urinary tract. There are many causes of obstructive uropathy, but they tend to lead to dilation of the renal pelvis and calyces and eventual enlargement of the kidney. The bladder may also have a thick wall. Hydronephrosis may occur as a result of obstructive uropathy. In hydronephrosis, the urine backs up, causing distension and dilation of the renal pelvis and calyces. Eventually, this can lead to atrophy of the kidney, because while kidneys can dish out urine like it's nobody's business, they can't take it.

Urolithiasis, or kidney stones, is a common cause of obstructive uropathy. There are many types of kidney stones, all formed by various solutes precipitating out of solution. Dehydration, hypercalciuria, and several other conditions can all conspire to increase the risk of kidney stones. Certain bacteria (Proteus and Klebsiella) may even be responsible for stones that are made out of struvite (magnesium ammonium phosphate). Such stones are quite large and are sometimes known as "staghorn calculi" because they are shaped somewhat like the horns of a stag.

Kidney stones might be painless if they are small, but if they are larger, they can cause pain and other symptoms related to obstructive uropathy. If they cause damage, they may also result in haematuria and/or infection. If the kidney stones are large, one type of pain that might be experienced is "renal colic," which is an excruciating pain that radiates from the flank to the groin. Renal colic might also be accompanied with other symptoms, from haematuria to vomiting. I have discussed treatment of kidney stones here.

Vascular and Tubulointerstitial Diseases of the Kidney

This lecture actually did have some more learning outcomes, but I think I might actually just stick to using the diseases as headings.

Vascular Diseases

Vascular diseases of the kidney, as the name implies, are diseases that affect the vasculature of the kidney.

Hypertensive nephrosclerosis

Hypertensive nephrosclerosis is scarring (sclerosis) of the kidney (nephro-) due to hypertension. Hypertensive nephrosclerosis can be either benign or malignant. Benign nephrosclerosis is due to chronic hypertension, defined as a blood pressure greater than 140/90, whereas malignant nephrosclerosis is due to accelerated hypertension (i.e. a rapid spike in blood pressure) or malignant hypertension, defined as a blood pressure greater than 180/110 with acute end-organ damage.

Benign hypertensive nephrosclerosis is the third most common cause of chronic renal failure. Over time, the small arteries and arterioles become thickened and there is damage to the glomeruli and tubules. Benign hypertensive nephrosclerosis may be asymptomatic with proteinuria, but over time it may progress to chronic renal failure. Malignant hypertensive nephrosclerosis is a medical emergency in which the damage is quite severe, and may present as acute renal failure. Under the microscope, there is fibrinoid necrosis of arterioles and hyperplastic arteriolosclerosis.

Renal artery stenosis

Renal artery stenosis is narrowing (stenosis) of the renal artery, which can lead to secondary hypertension. (As you can see, there can be a bit of interplay between the kidneys and hypertension: renal artery stenosis can lead to hypertension, which can lead to hypertensive nephrosclerosis.) Renal artery stenosis is usually due to atherosclerosis in elderly patients, but it can also be due to fibromuscular dysplasia in young women. (Fibromuscular dysplasia involves segmental thickening of arteries, which looks kind of like a string of beads on angiography. So far, the cause of this is unknown.)

One of the problems with renal artery stenosis is that it decreases blood flow to the kidneys, activating the RAAS, which increases vasoconstriction. The vasoconstriction triggered by the RAAS exacerbates the problem, forming a vicious cycle.

Tubulointerstitial Diseases

Tubulointerstitial diseases are diseases that affect the tubules and the interstitium of the kidney. (I love it when names are logical!)

Acute tubular necrosis

Acute tubular necrosis is one of the most common causes of renal failure. Acute tubular necrosis is necrosis of the kidney tubules (again, I'm loving these logical names), which may be due to ischaemia or toxins. There are three main phases of acute tubular necrosis: initiation, maintenance, and recovery. In the initiation phase, there is mild oliguria and a mild increase in serum creatinine. In the maintenance phase, oliguria and the increase in serum creatinine continue. There may also be uraemia. Finally, in the recovery phase, there is a large amount of diuresis (peeing). Because you're losing a lot of fluid pretty rapidly, you're also losing a lot of electrolytes at the same time, which can pose other problems.

Tubulointerstitial nephritis

Tubulointerstitial nephritis is inflammation of the tubules of the kidney. Tubulointerstitial nephritis may be either acute or chronic, with the chronic form being irreversible. There are many causes of tubulointerstitial nephritis but the main one to be aware of is drugs, particularly NSAIDs, proton pump inhibitors, and antibiotics. Unfortunately, drug-related tubulointerstitial nephritis is somewhat hard to predict: we don't really know who will get it and at what dose. It is thought that drugs act as a hapten in order to trigger an immune response (see here for information on what a hapten is).

It is important to distinguish between acute tubulointerstitial nephritis and acute pyelonephritis, as the two conditions may present similarly. (Apparently we will be learning about acute pyelonephritis next week, so stay tuned!) While acute tubulointerstitial nephritis is often drug-related and can be treated by simply removing the drug (and perhaps also giving some steroids), acute pyelonephritis is usually due to an ascending UTI that can be treated with antibiotics.

Chronic pyelonephritis

Chronic pyelonephritis is chronic inflammation of the kidney. It is usually due to either reflex nephropathy (reflux of urine back into the kidney) or obstructive nephropathy (some obstruction to urinary outflow). The kidney surface can have very deep, irregular scars, and under the microscope the inflammation can be so severe that the tubules look almost like the follicles of the thyroid gland. (This is also known as "tubular thyroidisation.")

Myeloma kidney

Myeloma kidney is a result of plasma cell myeloma (a.k.a. multiple myeloma). As the name suggests, plasma cell myeloma is a malignant proliferation of plasma cells (i.e. antibody-producing B cells). Plasma cell myelomas secrete large amounts of the same antibody, and sometimes these antibodies might be abnormal. For instance, the antibodies that are secreted might only consist of light chains. There are a range of complications that can result from myeloma kidney, but for now we'll only focus on two: myeloma cast nephropathy and amyloidosis.

Myeloma cast nephropathy occurs when abnormal light chains precipitate out of solution, forming casts. These casts can clog up the tubules, resulting in acute renal failure. Under immunofluorescence, these light chains will consist of only kappa chains or only lambda light chains (remember, in myeloma, large amounts of the same antibody are being made).

Amyloidosis is characterised by a build-up of amyloid, which consists of abnormally-folded extracellular proteins that resist degradation. Amyloid can be visualised with the Congo red stain. Under the Congo red stain, they stain salmon-pink, and if seen under polarised light while stained, they appear apple-green. In myeloma kidney, amyloidosis occurs due to the light chains in myeloma, and thus this type of amyloid is called AL-amyloid. Amyloid can deposit in a range of places in the kidney, causing a lot of problems.

Glomerulonephritis

Yes, I'm skipping ahead to another pathology lecture. Yes, I know that I've written more about pathology than about any other field this year. Unfortunately, pathology is the area that I've been struggling with the most, so it's the area I'm writing about the most, and unless anyone comments asking for me to cover a different topic, I'm just going to keep ploughing ahead.

This lecture was long, but it only had one learning outcome: "Classify glomerulonephritis with reference to aetiology, pathogenesis, clinical presentation, key morphological findings and natural history." I will be using my own headings for this post instead.

Clinical Presentations of Renal Disease

There are four (or five, depending on how you count them) main presentations of renal disease: acute renal failure, chronic renal failure, nephritic syndrome, and nephrotic syndrome. There is also rapidly-progressing glomerulonephritis, which is a subset of nephritic syndrome. Renal diseases are very common: around 40% of adults over 75 will have indicators of chronic kidney disease, and this number is even higher in Indigenous populations.

Acute renal failure

Acute renal failure is characterised by azotaemia, which is a rapid rise in serum urea and/or creatinine (a marker of renal function). There may also be uraemia, which is essentially just symptomatic azotaemia (symptoms include lethargy, decreased appetite, shortness of breath, peripheral neuropathy, and oedema). Other symptoms include oliguria (reduced urine output), or maybe even anuria (no urine output). Symptoms arise over days to weeks and may completely resolve (though there is a chance of progressing to chronic renal failure).

Causes of renal failure can be classified into three categories: pre-renal, renal, and post-renal. Pre-renal causes encompass basically anything that affects the blood supply to the kidneys. Renal failure encompasses intrinsic kidney diseases, and post-renal causes encompass anything that affects urine outflow.

Chronic renal failure

Chronic renal failure is basically the same as acute renal failure, but it is over a longer period of time (months to years). Furthermore, chronic renal failure is irreversible and will eventually progress to end-stage renal failure, defined as a glomerular filtration rate of less than 5% of normal. Treatment of chronic renal failure aims to delay progression.

Nephritic syndrome

Nephritic syndrome is a set of symptoms that includes azotaemia/uraemia, oliguria, macroscopic haematuria (blood in the urine that you can see), mild/moderate proteinuria, and hypertension. It is usually caused by glomerulonephritis (disease that affects the glomerulus). Rapidly-progressive glomerulonephritis (RPGN) is a subset of nephritic syndrome in which the rise in serum urea and creatinine is very rapid. RPGN is usually due to a subset of glomerulonephritis called crescentic glomerulonephritis.

Nephrotic syndrome

Nephrotic syndrome is a set of symptoms that includes proteinuria (>3.5g/24h), hypoalbuminaemia, peripheral oedema, hyperlipidaemia, and lipiduria. Nephrotic syndrome, like nephritic syndrome, is usually due to glomerulonephritis. If glomerulonephritis increases the permeability of glomerular capillaries, proteins can leak out into the urine, resulting in proteinuria. Since protein is leaving the body through the urine, there is low protein in the serum, leading to hypoalbuminaemia and a reduced serum oncotic pressure, which in turn can lead to peripheral oedema. At the same time, there is increased hepatic lipid synthesis, leading to hyperlipidaemia and eventually lipiduria.

Glomerulonephritis

I've mentioned glomerulonephritis before, but what is it exactly? Well, glomerulonephritis refers to a range of diseases that affect the glomeruli of the kidneys. Most of these diseases are mediated by the formation of immune complexes or structural issues. Diagnostic tools for glomerulonephritis include light microscopy, immunofluorescence, and electron microscopy. Glomerulonephritis can be iether primary or secondary: primary glomerulonephritis has no identifiable cause, whereas secondary glomerulonephritis is due to a recognisable cause (e.g. drugs, infections, etc.).

Glomerulonephritis can present in different ways, depending on the specific disease. Some types of glomerulonephritis have a presentation resembling nephrotic syndrome, whereas others have a presentation resembling nephritic syndrome. In this post, I'll be starting with the most "nephrotic" types of glomerulonephritis and working my way towards the most "nephritic" types of glomerulonephritis.

Minimal change disease

Minimal change disease is a type of glomerulonephritis that mainly affects children and presents with nephrotic syndrome. It is a disease mediated by structural changes, in particular of the podocytes surrounding glomerular capillaries. As you can guess by the name, there are minimal changes in the diagnostic tests. Light microscopy and immunofluorescence both look normal: you have to use electron microscopy to see the difference. Normal podocytes have "slit diaphragms" between the foot processes, and these "slit diaphragms" have the negative charge that repels proteins and stops them from getting into the urine. In minimal change disease, foot processes are effaced and fused together, meaning that the slit diaphragms and the repulsive negative charge are lost, allowing proteins to leak into the urine, resulting in nephrotic syndrome.

Prognosis of minimal change disease is very good in children, as it responds well to steroids in this population. The response in adults, however, is less predictable.

Membranous nephropathy

Membranous nephropathy mainly affects adults and results in nephrotic syndrome. It is mediated by immune complexes that deposit in the subepithelial space (i.e. under the podocytes but outside the basement membrane... I think). Basement membrane "spikes" (thickening of the basement membrane) appear between the deposits of immune complexes. Immunofluorescence shows granular IgG and C3.

Unlike with other forms of glomerulonephritis, primary membranous nephropathy now has an identifiable cause. Primary membranous nephropathy is due to autoantibodies to the podocyte phospholipase A2 receptor. Secondary membranous nephropathy can be all the usual suspects: drugs, infections, autoimmune diseases, etc.

Prognosis of membranous nephropathy is quite variable. 40% of patients will go into pontaneous remission. However, 40% of patients will progress to chronic renal failure. The remaining 20% of patients will have stable disease.

Focal segmental glomerulosclerosis (FSGS)

Focal segmental glomerulosclerosis (FSGS) is focal, meaning that less than 50% of all glomeruli are affected, and segmental, meaning that less than 50% of an individual glomerulus is affected. (Just for comparison: diffuse means that more than 50% of all glomeruli are affected, whereas global means that more than 50% of individual glomeruli are affected). FSGS is the most common cause of nephrotic syndrome in adults and is due to structural abnormalities in the podocytes.

As the "sclerosis" part of the name suggests, there is scarring involved in FSGS. Scarring can be seen under both light and electron microscopy. FSGS is not immune-mediated, but due to scarring, larger antibodies such as IgM may be trapped and can be identified under immunofluorescence. Sometimes, complement molecules such as C3 may be also be activated by the trapping of IgM.

Prognosis of FSGS is not the worst, but it's not the best either. Around 30% of patients respond to steroids, but the rest progress to chronic renal failure.

IgA nephropathy (a.k.a. Berger's disease)

IgA nephropathy is the most common cause of glomerulonephritis worldwide and usually affects young adults. It is immune-complex mediated and presents with nephritic syndrome (note: this is the first type of glomerulonephritis I've spoken about so far that presents with nephritic, rather than nephrotic, syndrome). Under light microscopy, there is mesangial matrix expansion and hypercellularity, and under electron microscopy, the immune-complexes can be seen. Immunofluorescence reveals granular IgA (hence why this disease is called IgA nephropathy).

Prognosis of IgA nephropathy follows the "Rule of Thirds": around 1/3 resolve spontaneously, 1/3 have stable disease, and 1/3 progress to FSGS and/or chronic renal failure.

Post-infectious glomerulonephritis (a.k.a. acute proliferative glomerulonephritis or post-streptococcal glomerulonephritis)

Post-infectious glomerulonephritis usually affects children around 1-4 weeks after a bout of cellulitis or pharyngitis. It is immune-complex mediated and is often a response to streptococcal pyrogenic exotoxin B, which is why this disease is sometimes called post-streptococcal glomerulonephritis. (Note, however, that Streptococcus species are not the only species that can cause this disease.) Post-infectious glomerulonephritis presents with nephritic syndrome. Microscopy reveals inflammation and immune-complex deposits, whereas immunofluorescence reveals granular IgG and C3.

There is no such thing as primary post-infectious glomerulonephritis: it is always secondary to infection (hence the "post-infectious" in the name). As mentioned before, it is usually due to Streptococcus, but not always. Prognosis is very good in children, with nearly all children recovering with only conservative treatment. However, prognosis is not so good in adults: around 40% of adults with post-infectious glomerulonephritis progress to chronic renal failure.

Crescentic glomerulonephritis

As mentioned earlier, crescentic glomerulonephritis is a subset of glomerulonephritis that can present with rapidly progressive glomerulonephritis (a subset of nephritic syndrome). Crescentic glomerulonephritis is not a diagnosis- it is simply a histological pattern with an underlying cause that needs to be identified.

The "crescents" in crescentic glomerulonephritis are formed by a proliferation of parietal epithelial cells, which are epithelial cells lining Bowman's capsule. The crescents can fill up Bowman's space and block it, leading to chronic renal failure within weeks to months. There are three main categories of crescentic glomerulonephritis. Type I crescentic glomerulonephritis is characterised by anti-glomerular basement membrane (anti-GBM) autoantibodies, type II is immune complex mediated, and type III is "pauci-immune" (which I think means that there is minimal evidence of hypersensitivity).

Type I crescentic glomerulonephritis

Type I crescentic glomerulonephritis, or anti-GBM disease, involves autoantibodies against the α3 chain of the Type IV collagen in the glomerular basement membrane. These autoantibodies may cross-react with the basement membranes of other tissues, notably in the lung, resulting in a syndrome called pulmonary-renal syndrome. Pulmonary-renal syndrome is also known as Goodpasture syndrome.

Type II crescentic glomerulonephritis

Type II crescentic glomerulonephritis is immune-complex mediated and includes several types of glomerulonephritis that I've already written about above, including post-infectious glomerulonephritis and IgA nephropathy.

Type III crescentic glomerulonephritis

Type III crescentic glomerulonephritis, or pauci-immune glomerulonephritis, involves an antibody called ANCA. ANCA stands for anti-neutrophil cytoplasmic antibody, and as the name suggests, it acts against cytoplasmic enzymes in neutrophils. Type III crescentic glomerulonephritis is associated with small-vessel vasculitis, including Wegener's granulomatosis (a.k.a. granulomatosis with polyangiitis, or GPA), and Churg-Strauss syndrome (a.k.a. eosinophilic granulomatosis with polyangiitis, or EGPA). GPA involves necrotising granulomatous inflammation of the respiratory tract and kidney. EGPA is similar, but there may also be asthma and eosinophil-rich granulomas.

Haemolytic Anaemia and Haemoglobinopathies

Types of haemolytic anaemia

Haemolytic anaemia occurs when red blood cells only have a short lifespan. Haemolytic anaemia is often associated with increased bilirubin (a product of the breakdown of haem), increased lactate dehydrogenase (an enzyme found within red blood cells), and reduced haptoglobins (a protein that normally binds to haemoglobin following cell death, but can get used up when large numbers of cells are dying). A blood film may also show spherocytes (round cells) and schistocytes (fragmented cells). There may also be an increase in immature red blood cells as the body attempts to create more cells to counteract the anaemia.

Intravascular and extravascular

Red blood cell death can occur either in the macrophages of the reticuloendothelial system (i.e. liver, spleen, etc.) or in the blood vessels. If cell death occurs in the reticuloendothelial system (i.e. if it is extravascular), the globin is broken down to its amino acids, the iron is released and recycled, and the haem is metabolised to bilirubin (which may result in jaundice). There may also be increased lactate dehydrogenase. If cell death occurs in the blood vessels (i.e. if it is intravascular), the haemoglobin is released in the plasma and can find its way into the urine, resulting in dark plasma and brown urine.

Inherited and acquired: membrane, enzyme, environment

Haemolytic anaemia can be due to an inherited condition, such as a defect in the red blood cell membrane, enzyme production, or globin chains. Haemolytic anaemia may also be due to an acquired condition, such as an immune disorder, liver disease, or infections.

Membrane defects

The red blood cell membrane must be stable yet able to deform in order to squeeze through small blood vessels. If there is a defect in the membrane, the cell may be more prone to breaking.

Hereditary spherocytosis

Hereditary spherocytosis is the most common inherited haemolytic anaemia. It is an autosomal dominant disorder in a structural membrane protein. It usually affects peripheral proteins such as spectrin and actrin, but it can affect integral proteins such as Band 3 as well. In hereditary spherocytosis, the red blood cells lose their membrane as they pass through the spleen, causing them to become rigid and spherical. Ultimately, the red blood cells are destroyed. Hereditary spherocytosis can have variable severity, not only between patients but within the same patient (anaemia might normally be compensated for, but all that goes out the window once the patient gets an infection).

Hereditary spherocytosis may be associated with splenomegaly (since the spleen needs to work overtime to get rid of the damaged cells) and gallstones (from the high levels of bilirubin). On a blood film, there may be increased reticulocytes (as the body is trying to increase RBC production) and/or spherical cells. The EMA test, which is a flow cytometry test looking at levels of Band 3, can also be used for diagnosis. Treatment involves giving folic acid to help with making new blood cells, and may also involve getting rid of an enlarged spleen or the gallbladder.

Hereditary elliptocytosis

Hereditary elliptocytosis, just like hereditary spherocytosis, is an autosomal dominant disorder. However, hereditary elliptocytosis is milder and is mainly associated with mutations in spectrin. As the elliptocytes are less prone to destruction than spherocytes, most people with hereditary elliptocytosis are asymptomatic. Symptomatic hereditary elliptocytosis is also known as hereditary pyro-poikilocytosis.

Enzyme defects

Just like every other cell in the body, red blood cells need certain enzymes to carry out the processes that keep them healthy. When there are defects in these enzymes, the red blood cells may be more prone to damage and haemolysis.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that converts glucose-6-phosphate to 6-phosphogluconate, while at the same time reducing NADP+ to NADPH. NADPH can then act as a reducing agent in other reactions, such as synthesis reactions. Therefore, people with a G6PD deficiency are more prone to oxidant stress, particularly when exposed to triggers such as certain drugs, hypoxia, infection, or even certain foods such as fava beans. Oxidised haemoglobin gives the appearance of a white cap on the red blood cell, and when this oxidised haemoglobin is removed, "bite" cells can result.

G6PD deficiency is an X-linked recessive disorder, meaning that males are more prone to this disorder. There is no cure for G6PD deficiency. Treatment mainly involves avoidance of triggers of oxidant haemolysis as when the patient is not in an oxidant crisis, their blood count is normal. If it is absolutely necessary, transfusion might be considered, but it's important to remember that transfusion is a last case resort (remember, transfusing someone else's blood is basically just a transplant and comes with risks).

Pyruvate kinase deficiency

Pyruvate kinase is the last enzyme in the glycolysis pathway (see here if you want to punish yourself with a bunch of enzyme names). Without pyruvate kinase, not enough ATP is made, resulting in a rigid cell membrane (since red blood cell shape is controlled by ATP) and premature cell death. Red blood cells may appear "prickle-shaped" on a blood film. It is autosomal recessive and presentations can range from mild to severe. Pyruvate kinase deficiency can be diagnosed via a pyruvate kinase assay.

Immune haemolytic anaemia

Immune haemolytic anaemia is, as the name suggests, haemolytic anaemia triggered by an immune process. There are two main types of immune haemolytic anaemia: auto-immune (where antibodies are directed against own blood cells) and allo-immune (where antibodies are directed against blood cells from another person).

Auto-immune haemolytic anaemia is mostly idiopathic, but some conditions such as B-cell lymphoma can cause it. It can be diagnosed via the Direct Antiglobulin Test (DAT), which looks for antibodies against red blood cells. Auto-immune haemolytic anaemia can be treated by treating the cause (if known) or by immunosuppressive drugs (e.g. corticosteroids). Features of the blood film include spherocytes, polychromasia, and increased reticulocytes (as the body is trying to make more cells in order to compensate for the cell destruction).

Allo-immune haemolytic anaemia includes transfusion reactions and haemolytic disease of the newborn. Haemolytic disease of the newborn occurs when an Rh(D) negative mother is pregnant with an Rh(D) positive fetus. At birth, some of the blood from the fetus may mix with the blood from the mother, causing the mother to produce anti-D antibodies. If the mother becomes pregnant with another Rh(D) positive fetus, her newly-formed anti-D antibodies might attack the fetus' blood (since the new antibodies are IgG and IgG can cross the placenta). In order to prevent haemolytic disease of the newborn, Rh(D) negative mothers are given exogenous anti-D so that the Rh(D) antigen is cleared before the mother can make her own antibodies and memory cells against it.

Fragmentation haemolysis

Fragmentation haemolysis is an acquired cause of haemolytic anaemia. It is also known as "micro-angiopathic haemolytic anaemia." In fragmentation haemolysis, there is mechanical damage to the red blood cells due to exposure to an abnormal surface, such as damaged blood vessels or fibrin strands in the vasculature. Damage to the red blood cells results in the formation of schistocytes (fragmented cells).

Liver disease

Liver disease can also cause haemolytic anaemia. There wasn't too much detail on this during the lecture, other than that severe liver disease can alter the red blood cell membrane, resulting in spiky cells called acanthocytes. (Severe renal dysfunction results in similar-looking cells called echinocytes.)

Infections

Several different infections can cause damage to red blood cells, causing haemolytic anaemia. Two examples of infections that can lead to haemolytic anaemia include malaria (caused by Plasmodium protozoa) and Clostridium welchii. Severe bacterial sepsis with disseminated intravascular coagulation can also cause severe sepsis.

Explain the biology and clinical consequences of inherited disorders of haemoglobin

Globin chain defects, or haemoglobinopathies, can affect the structure and function of haemoglobin and can lead to microcytic (small) red cells. Haemoglobinopathies are inherited, rather than acquired. The main types of haemoglobinopathies are structural haemoglobinopathies (amino acid substitution leading to abnormal chain structure) and thalassaemias (reduced production of chains). Haemoglobinopathies can be variable in their presentation, because haemoglobin doesn't read textbooks. Sigh.

Structural haemoglobinopathies

Structural haemoglobinopathies, as mentioned earlier, are abnormal globin chains (usually beta-globin chains) due to amino acid substitution. There are three main structural haemoglobinopathies to know about. HbS is the structural haemoglobinopathy that results in sickle cell anaemia, in which the red cells are sickle-shaped and can occasionally get stuck, leading to pain and decreased blood flow to certain areas. HbE is a structural haemoglobinopathy commonly found in Thailand and HbC is a structural haemoglobinopathy commonly found in West Africa.

Thalassaemia

Thalassaemia is a condition in which there is reduced production of globin chains due to a mutation. The most common types are alpha- and beta-thalassaemia, which are characterised by reduced production in alpha- and beta-globin chains, respectively.

Alpha-thalassaemia, which involves mutations in the alpha-globin gene, is most common in southeast Asia. We have four alpha-globin genes (two from each parent), so the severity of alpha-thalassaemia depends on how many genes have been affected. If only two genes have been affected, the patient will have thalassaemia minor. If three genes have been affected, the patient will have Haemoglobin H disease. Finally, if all four genes are affected, the patient will have Hb Barts hydrops fetalis, which may result in death in utero (however this paper mentions a patient who was 31 in 2017).

Beta-thalassaemia is most common in the Mediterranean or in southeast Asia. It involves mutations in the beta-globin gene, resulting in reduced beta-chain production. Since fetal haemoglobin has alpha and gamma chains, and adult haemoglobin (with alpha/beta chains) doesn't fully take over until around 6 months of age, symptoms of homozygous beta-thalassaemia (a.k.a. thalassaemia major) may not present until 3-6 months of age. (Heterozygous beta-thalassaemia, or thalassaemia minor, may remain asymptomatic.) Thalassaemia major results in severe anaemia that requires regular transfusions. The only cure for thalassaemia major is a bone marrow transplant.

Folate, Vitamin B12, and Anaemia

Vitamin B12 metabolism

Vitamin B12 can be acquired from animal products (so vegans need to take care to get enough vitamin B12). We only need around 1μg of B12 per day, but our body can store 2-4mg, so we essentially have several years' worth of B12 supply. Therefore, a deficiency in B12 can take years to manifest.

Absorption of Vitamin B12 requires intrinsic factor, which is secreted by parietal cells in the stomach. However, Vitamin B12 doesn't bind to intrinsic factor until later. Instead, in the stomach, B12 binds to R-binder, which protects it from stomach acid. B12 is later released from R-binder by the action of pancreatic enzymes in the duodenum. Further down the duodenum and jejunum, B12 finally binds to intrinsic factor. In the ileum, B12 bound to intrinsic factor is absorbed into the body. Once in the body, active B12 is bound to transcobalamin II, and inactive B12 is bound to transcobalamin I. Active B12 and transcobalamin II levels can be measured by using the HoloTransCobalamin assay.

Vitamin B12 is mainly used in two reactions. The first main reaction involving B12 is the conversion of homocysteine to methionine, which is important in methylation in DNA, RNA, and proteins. The second main reaction involving B12 is the conversion of methylmalonyl CoA to succinyl CoA, which is important in breaking down fatty acids and amino acids to ATP (succinyl CoA can enter the citric acid cycle).

Folate metabolism

Folate (vitamin B9) can be found in fruits and leafy green vegetables. We require about 100μg per day. Unlike vitamin B12, we do not have years' worth of folate storage: instead, we only have around 3-4 months. Therefore, folate deficiencies crop up much more quickly than B12 deficiencies. Folate is absorbed in the upper GI tract.

Folate is an essential coenzyme in the production of DNA. Folate is reduced to tetrahydrofolate, which is involved in the synthesis of nucleotides. There is also some interplay between folate and vitamin B12, as vitamin B12 can help to recharge inactive folate.

Causes and consequences of deficiencies

Vitamin B12

Vitamin B12 deficiency can be due to inadequate intake (more likely in vegans as B12 is only found in animal products) or malabsorption. The main cause of B12 malabsorption, and the main cause of B12 deficiency in general, is pernicious anaemia. In pernicious anaemia, there are auto-antibodies either to intrinsic factor or to the parietal cells that produce intrinsic factor. Since there is reduced intrinsic factor, there is reduced absorption of B12. Pernicious anaemia is most common in females aged around 60 with a family history of auto-immune disease.

B12 deficiency has gradual onset and as such can be asymptomatic for a long time. However, over time, there can be mild jaundice due to ineffective erythropoiesis (red blood cells need B12 to form properly), or neurological symptoms due to degeneration of the spinal cord. These neurological symptoms may include tingling of the feet or difficulties in walking. B12 deficiency causes megaloblastic anaemia, which I will describe later.

B12 deficiency treatment is simple: simply give IM vitamin B12. Usually 1000μg is given three times per week for two weeks, and then one injection every 3 months until the deficiency is corrected (or for life if the deficiency cannot be corrected). It is also possible to give large doses of oral vitamin B12, but this is less reliable, particularly in patients with pernicious anaemia (if they can't produce enough intrinsic factor, most of that B12 won't be absorbed anyway).

Folate

Folate deficiency may be due to inadequate intake, poor absorption, increased folate requirements (e.g. during pregnancy), or excessive folate loss (as may happen in dialysis). Certain medications and excessive alcohol may also lead to folate deficiency.

As folate is important for DNA and RNA synthesis, it is also important for fetal growth and development (a time when lots of cell division and signalling is going on). Folate deficiency may cause the fetal neural tube to fail to close. Neural tube closure usually happens at around 21-27 days and, depending on the severity of the defect, can lead to a range of problems, from spina bifida (part of the spinal cord bulging out) to anencephaly (loss of most of the brain).

Just like with B12, treatment is fairly straightforward: simply provide folate supplementation. In this case, the amount is 5mg/day until the deficiency is corrected.

Megaloblastic anaemia

Megaloblastic anaemia is a type of macrocytic anaemia, meaning that the red blood cells are larger than normal. Red blood cells are also oval in shape. Neutrophils may be hypersegmented, meaning that their nuclei have a lot of lobes (they usually have 3, but can have 5 or more in a hypersegmented state). The bone marrow tends to be hypercellular: it has lots of cells because the body is trying to produce more red blood cells to counter the anaemia, but they can't develop properly due to the lack of B12 and/or folate. (I think.)

Megaloblastic anaemia results in abnormal erythroblasts in the bone marrow. Haemoglobinisation appears at a normal rate, but maturation of the nucleus is delayed due to impairment in DNA production. Therefore, you might see cells that are reasonably red (due to haemoglobinisation), but still have quite large nuclei (remember, red blood cells get smaller nuclei as they mature, so a large nucleus is a hallmark of an immature cell).

It is also important to note that megaloblastic anaemia is not the only type of anaemia that is macrocytic (has large blood cells). Liver disease, for instance, may also result in macrocytic anaemia. Also, in many cases of anaemia, the body tries to produce more red blood cells, and since the immature ones (e.g. reticulocytes) tend to be larger, the mean cell volume increases. Some of these other macrocytic anaemias may also have specific features. For instance, macrocytic anaemia in liver disease may have target cells (red blood cells that have a dark part in the pale centre) and/or acanthocytes (spiky cells).

Anaemia: General Concepts and Iron

Just going to skip a bit ahead because we have a tute on anaemia this afternoon :)

Definition of anaemia

Anaemia is when haemoglobin levels are lower than would be expected for that individual (based on characteristics such as age and sex). There is usually a reduction in red cell count and haematocrit. Anaemia is not a disease in its own right but rather a manifestation of some other underlying problem that needs to be diagnosed.

Clinical manifestations of anaemia: symptoms, signs and classification on MCV

Since haemoglobin carries oxygen, and we kind of need oxygen to make our cells work, the lack of haemoglobin seen in anaemia can lead to tiredness, shortness of breath, dizziness, and many other fun symptoms. Signs can include pallor (especially of mucous membranes) and tachycardia (the body tries to increase cardiac output to make up for the low oxygen in the blood). Specific types of anaemia may also have specific symptoms: for instance, jaundice might be seen in either haemolytic or megaloblastic anaemia.

Causes of anaemia: principles

The main causes of anaemia are reduced production of red blood cells and increased loss of red blood cells (perhaps due to bleeding or haemolysis of red blood cells). Remember, anaemia is not a disease in its own right and the underlying cause does need to be diagnosed.

Investigations usually start by doing a blood count to see how many cells there are and how big they are, and if any abnormalities are detected, from looking at a blood film. As well as looking at red blood cells, it might also be useful to look at the other types of cells. For instance, in aplastic anaemia, the bone marrow has failed, so there will be reduced production of all types of cells in the blood. On the other hand, in pure red cell aplasia, there will only be reduced production of red blood cells. Other causes of anaemia, such as myelodysplasia (bone marrow dysfunction), or secondary causes such as insufficient nutrition (especially with iron, B12, and folate), may also lead to their own pattern of cell abnormalities.

As mentioned earlier, specific types of anaemia may also have specific symptoms. These symptoms can be used to help narrow down the cause of anaemia. For instance, since red blood cells are broken down in the spleen, splenomegaly (a large spleen) may be seen in haemolytic anaemia.

Iron metabolism and iron deficiency

Iron is important for making haemoglobin, as each haem unit is associated with iron. We normally have around 4-5g of iron, and over half of that is found in red blood cells. Once iron is absorbed, it is bound to transferrin and transported to the bone marrow. Excess iron may be stored in liver macrophages as ferritin.

Iron deficiency is due to either reduced intake of iron or increased usage of iron. Reduced intake may be due to insufficient consumption (rare in the developed world) or poor absorption (perhaps due to a condition such as coeliac disease). Increased usage may be due to chronic blood loss (due to a bleeding ulcer or perhaps heavy periods) or increased usage in general (iron requirements increase quite a bit during pregnancy).

The main causes of iron deficiency vary according to age. In very young children (<5 years), inadequate iron in the diet is the main cause of deficiency. In children aged 5-15 years old, the increased usage due to growth is the main cause. For 15-40 year olds, the main causes vary according to sex: for women, menstruation and pregnancy are the main culprits, but since men don't menstruate or get pregnant, their main cause of deficiency is coeliac disease. Finally, in people over 40 years of age, the main cause of iron deficiency is gastrointestinal blood loss (presumably due to an ulcer or something similar).

Iron deficiency anaemia is a gradual process. It starts off with negative iron balance (i.e. more usage than intake). At this stage, there is no anaemia. In the next stage, in iron deficient erythropoiesis, the red blood cells that are being produced may have lower iron, but this is still not enough to cause anaemia. Eventually, if the iron imbalance is not corrected, full-blown iron deficient anaemia can result.

In iron deficient anaemia, most red cell indices (haemoglobin levels, haematocrit, mean cell volume, etc.) are low. The main exception is the red blood cell distribution width (RDW), which might be high. This is because older red blood cells that were created prior to the deficiency might be normal, whereas the newer red blood cells are abnormal. Abnormal iron deficient cells tend to be smaller (microcytic) and hypochromic (pale). Sometimes there might be mild thrombocytosis (increased platelets) and a reduced reticulocyte count (suggesting that not as many new blood cells are being made). Iron levels can be measured directly: iron tends to be low, transferrin tends to be increased (as the body is trying to make sure that it carries and transports as much iron that it can get its hands on), transferrin saturation is low, and ferritin is low.

Other clinical features that might be seen in iron deficient anaemia are atrophic glossitis (smooth tongue), angular chelitis (redness and fissures at the corner of the mouth), and koilonychia ("spoon nails"), but these visible features are uncommon.

To treat iron deficiency, the underlying cause should be treated. If the person is not taking in enough iron, they should adjust their diet to increase their iron intake. If they are bleeding from an ulcer, the ulcer should be treated. In the interim, patients can also be given iron replacement tablets or syrup (or maybe injections if severe) to top up their iron levels.

Iron overload

Iron overload is, well, an overload of iron. Serum iron, transferrin saturation, and ferritin are all increased. There may also be abnormal liver and endocrine function as excess iron can form damaging haemosiderin deposits. Patients with genetic haemochromatosis can undergo regular venesection (basically bloodletting, but more modern) to get rid of the excess iron. Patients who have iron overload due to having blood transfusions can undergo chelation therapy to get rid of the excess iron.

Anticoagulant, Antiplatelet, and Thrombolytic Drugs

This lecture actually has learning outcomes... or rather, a learning outcome: "Describe the pharmacology, use and monitoring of anticoagulant, antiplatelet and fibrinolytic agents." It looks like I'll be mainly making up my own headings. Le sigh.

This post will mainly cover drugs that are for preventing thrombosis (inappropriate clotting), rather than drugs that are for preventing excessive bleeding.

Warfarin

Warfarin is derived from coumarin, which in turn is derived from some plants. It inhibits vitamin K epoxide reductase, preventing inactive vitamin K from being recycled. As vitamin K is a cofactor in the processes leading to production of factors II, V, IX, and X, administration of warfarin leads to reduced formation of these factors over time. Because warfarin is affecting production of the clotting factors, rather than the factors themselves, warfarin takes a long time to kick in and lasts for a long time once it does (it has a half-life of around 1 day). Reversing warfarin (which can be done with vitamin K) can also be a lengthy process because re-forming the factors takes time. A haemorrhaging patient who is on warfarin may be given fresh frozen plasma instead which already has the clotting factors made.

Many factors affect the activity of warfarin. Levels of vitamin K affect how well warfarin works, as does hepatic disease (can increase activity as there is already impaired synthesis of coagulation factors) and pregnancy (can decrease activity). Also, just like pretty much every other drug, warfarin can interact with other drugs. The main test used to monitor warfarin is the INR (see here).

Heparin

Heparin is a highly sulfated glycosaminoglycan derived from pig or cow mucosa that mimics the effect of human heparan sulfate. It has a highly variable molecular weight (since it varies between animals) but the active part (a repeating pentasaccharide) is pretty much the same no matter where you get the heparin from. Heparin has a strong negative charge and can bind to and increase the activity of antithrombin III which, as you can guess from the name, inhibits thrombin as well as other coagulation proteins (namely IX, X, and XI). After the heparin-antithrombin complex has done its job, the heparin is released and an inactive antithrombin complex is left behind. Over time, it is possible to run out of antithrombin, resulting in desensitisation to heparin.

Heparin works much more quickly than warfarin but is not available orally. It can be monitored by APTT and reversed by protamine sulfate if necessary. There are also low molecular weight versions of heparin in which the inactive parts of the protein have been removed. Low molecular weight heparin is more potent but cannot be reversed. There are also pentasaccharide versions that only have the repeating pentasaccharide part. The pentasaccharides are even more potent but they also cannot be reversed.

New/Direct Oral Anticoagulants (NOACs/DOACs)

Some of the newer oral anticoagulants directly inhibit thrombin (IIa) and/or factor Xa. Many of the thrombin inhibitors, such as dabigatran, end with -gatran, and many of the Xa inhibitors, such as rivaroxaban, end with -xaban. Since they bind directly to thrombin, they don't rely on the patient's antithrombin levels to work. Unfortunately, factor Xa inhibitors are currently (as of March 2019) irreversible in Australia as recombinant Xa, which would serve as an antidote, is not yet approved here (it is approved in the US though).

Profibrinolytics

Profibrinolytics activate plasminogen to plasmin, which in turn breaks down blood clots. There are three main profibrinolytics. Streptokinase and urokinase are derived from bacteria and are inexpensive, but because they are antigenic they can only be used once (well, streptokinase is antigenic at least, I'm not 100% sure about urokinase). Alteplase is human-derived so does not have the problem of antigenicity, but is very expensive. Profibrinolytics can be given to rapidly break down an existing blood clot if necessary (whereas the anticoagulants I've discussed so far are mainly for prevention of future blood clots).

Anti-platelet agents

Aspirin

Aspirin irreversibly inhibits cyclooxygenase, reducing the production of thromboxane A2 (which activates platelets). It can also inhibit production of prostacyclin (which would normally inhibit platelets) in endothelial cells, but this pathway is less sensitive to aspirin. Therefore, aspirin tips the balance towards reduced platelet activation. (I've also discussed this towards the end of this earlier post.) Note that since aspirin irreversibly inhibits cyclooxygenase, the effect on platelets is also irreversible.

Fibrinogen receptor inhibitors

Fibrinogen receptor inhibitors, as the name suggests, blocks fibrinogen receptors (a.k.a. glycoprotein IIb/IIIa). These drugs therefore block fibrinogen binding to the platelets, preventing them from aggregating. Fibrinogen receptor inhibitors are only effective if injected acutely.

Thienopyridines (ADP receptor antagonists)

Thienopyridines, or P₂Y₁₂ antagonists, or ADP receptor antagonists (so many names!) can inhibit amplification of the platelet response by blocking ADP receptors. (Remember, ADP helps in activation of platelets.) Many of these drugs are metabolised in the liver and are thus prone to drug-drug interactions with other drugs metabolised in the liver.

Others

Other drugs that I haven't mentioned, but seemed kind of important, included vorapaxar (inhibits a thrombin receptor called PAR-1) and PDE inhibitors such as dipyridamole and cilostazol (inhibit destruction of the signalling molecules cAMP and cGMP, so that they can go on to inhibit platelet activation).

Disorders of Haemostasis

This lecture didn't come pre-packaged with learning outcomes (rather the Unit Guidebook has learning outcomes for the entire week, which isn't really helpful for this post) so I'm going to have to actually make up my own headings. Yaaaaaaaaayyyyyyyyyy.

Bleeding Disorders

Thrombocytopaenia

Thrombocytopaenia is a fancy word for "low platelet count." Usually we have around 150-400 * 10^9 platelets, but since we have a lot of redundancy, we usually don't show symptoms until platelets have dropped below 50 * 10^9 or so. When platelet levels are around 20-50 * 10^9, patients may bruise easily and bleed a lot following surgery. When platelet levels are 10-20 * 10^9, patients may have frequent nosebleeds and pinprick rashes called petechiae. If platelet levels are below 10 * 10^9, patients may experience serious bleeds. However, it is also important to note that low platelet count isn't always associated with increased bleeding. Sometimes platelets are low due to increased thrombosis throughout the body.

Thrombocytopaenia can be congenital, but is usually acquired. It may be acquired from certain drugs or from problems with the bone marrow that may arise during life (e.g. leukaemia). Hypersplenism can lead to thrombocytopaenia as the spleen stores platelets, so a larger spleen means that more platelets are stored and there are fewer circulating platelets. Another possible cause of thrombocytopaenia is Immune Thrombocytopaenic Purpura (ITP), an idiopathic condition in which there is increased destruction of platelets and inhibited megakaryocyte production (which in turn leads to reduced platelet production).

Platelet defects or deficiencies such as thrombocytopaenia usually lead to a pattern of bleeding called "mucocutaneous bleeding," in which petechiae are common but haematomas are not. There is usually immediate bleeding after procedures.

Haemophilia

Haemophilia is a congenital deficiency in clotting factors. In Haemophilia A, there is a deficiency of Factor VIII, whereas in haemophilia B, there is a deficiency of Factor IX. It is X-linked recessive, so it affects more males than females. Haemophilia can be diagnosed by looking at APTT (as both Factor VIII and Factor IX are in the intrinsic pathway, which is tested by APTT) and by directly measuring clotting factor concentrations. Haemophilia can be treated with recombinant FVIII or IX, which may be given routinely and/or prior to procedures. Most patients with haemophilia should have a card that contains useful details such as the severity and usual treatment.

Clotting factor deficiencies such as haemophilia usually lead to a pattern of bleeding called "deep tissue bleeding," in which haematomas are common (in cases of severe deficiency or following injury) but petechiae are not. There may be immediate bleeding after procedures, or it may be delayed.

Von-Willebrand's Disease

Von-Willebrand's Disease (vWD) is a deficiency of von-Willebrand Factor (vWF), which as discussed here is important for platelet adhesion to blood vessels. Therefore, vWD may present with the mucocutaneous bleeding seen in platelet deficiencies. vWF is also a carrier protein for factor VIII, so patients with vWD may also experience the deep tissue bleeding seen in clotting factor deficiencies. vWD is autosomal dominant, so it affects both sexes equally. It is also worse in people who are homozygous for the gene than in people who are heterozygotes.

There are three main types of vWD. In type 1 vWD, there is a decrease in quantity of vWF. In type 2 vWD, there is a decrease in function of vWF. Type 3 vWD is rare and is a severe deficiency of vWF seen in those who are homozygous for vWD. vWD can be diagnosed with a "von-Willebrand screen," which looks for vWF antigen, vWF function, and factor VIII levels.

Prior to procedures, patients with vWD can be given DDAVP (a.k.a. desmopressin), which releases any stored vWF in platelets and endothelium. The idea here is to maximise the amount of vWF present in the blood during the procedure. Tranexamic acid may be given for the first few days after the procedure in order to stabilise the fibrin clot. Patients who are severely vWF deficient or do not respond to DDAVP can be given biostate, which is essentially just Factor VIII and vWF from donor plasma.

Vitamin K Deficiency

Vitamin K deficiency is basically what it says on the box- a deficiency in vitamin K. As noted here, vitamin K is a cofactor in the carboxylation of clotting factor precursors, namely II (thrombin), VII, IX, and X. Deficiency in vitamin K leads to prolonged PT, either normal or prolonged APTT, and normal fibrinogen.  Eat yo' leafy green veggies, kids (that's where a lot of dietary vitamin K comes from!).

Babies have very little vitamin K as it doesn't cross the placenta and there is very little in breast milk. Therefore, babies receive IM vitamin K at birth. (Unless, of course, they're born to extreme anti-vax parents who think that the vitamin K injection is a vaccine just because it's delivered by injection. Wonder what they think of the oral rotavirus vaccine.)

Liver Disease

As many clotting factors are made in the liver, liver disease leads to decreased production of clotting factors as well as decreased clearance of already-activated clotting factors. Liver disease also leads to decreased absorption of vitamin K. Therefore, many patients with liver disease will have increased PT and APTT, as well as decreased fibrinogen and platelets.

Massive Transfusion

"Massive transfusions" are transfusions of more than 50% of blood volume in 12-24 hours. This can be problematic as blood transfusions tend to be mostly packed cells and not much in the way of clotting factors and platelets. Over time, clotting factors and platelets may become diluted, leading to prolonged INR and APTT, as well as low fibrinogen and platelets. In order to combat the problems of massive transfusion, many institutions will make sure to transfuse some fresh frozen plasma in between transfusions of packed cells.

Disseminated Intravascular Coagulation (DIC)

In DIC, there is bleeding due to coagulation elsewhere in the body. In sepsis, severe trauma, and several other nasty conditions, there may be massive thrombin generation and widespread coagulation, which uses up clotting factors and platelets. Patients with DIC will have a severely prolonged INR and a severely prolonged APTT, as well as low fibrinogen and platelets. They may also have raised D-dimers (breakdown products of thrombi).

Thrombosis

Deep Vein Thrombosis (DVT)

• Vascular Disorders

Pulmonary Embolism (PE)

Sometimes blood clots, such as those seen in DVT, may break off and lodge elsewhere in the body. As venous clots travel through progressively larger veins before getting back to the right atrium, the first small veins that the clot will meet are usually in the lungs. A clot that has moved around the body is called an embolus, or a venous thromboembolism (VTE) if it came from the veins. A pulmonary embolism may cause chest pain and shortness of breath, so it has to be differentiated from other conditions that could cause these symptoms. Not all pulmonary emboli are symptomatic, but non-symptomatic PEs may have a fatal recurrence as the original blood clot may still be around and prone to breaking off again.

Factor V Leiden

Before I get onto talking about Factor V Leiden, I'm just going to give a quick mention to various anti-clotting mechanisms that our body has. Firstly, there is antithrombin, which can inhibit thrombin (duh) as well as some other agents of the clotting cascade (mainly IX, X, and XI). Secondly, there are proteins C and S, which are vitamin-K dependent and inactivate factors V and VIII.

Factor V Leiden, as you can probably guess by the name, affects Factor V. It is a point mutation that makes Factor V resistant to protein C, so that protein C can no longer inactivate it. Patients with Factor V Leiden are therefore more susceptible to blood clots and venous thromboemboli, but only around 5% of heterozygotes for Factor V Leiden will ever experience a VTE.

Prothrombin Gene Mutation

A prothrombin gene mutation is- you guessed it!- a mutation in the gene coding for prothrombin. Prothrombin is the precursor for thrombin. Prothrombin gene mutations tend to be gain-of-function, increasing the amount of prothrombin and the risk of thrombosis.

Antibiotics for Gram-Positive Infections

Review and outline the four broad mechanisms by which bacteria can be resistant to antibiotics.
Explain the mechanism of resistance of MRSA to beta-lactam antibiotics.

• Introduction to Antibiotics
• Antibiotic Resistance

Explain why 80% or more of S. aureus strains are resistant to penicillin.

Roughly 80% of strains of S. aureus are able to produce penicillinases (enzymes that break down penicillin), resulting in them being resistant to penicillin.

Name 2 penicillins and two cephalosporins that are resistant to staphylococcal beta lactamase.

• Penicillins: Dicloxacillin, flucloxacillin, methicillin, nafcillin
• Cephalosporins: Ceftazidime, cefepime. Other good ones against penicillinases include cephalexin and cephalothin.

Discuss the use of and mechanism of beta-lactamase inhibitors and name an oral and parenteral drug combination in which these are used.

Beta-lactamase inhibitors can be given in combination with beta-lactam antibiotics in order to prevent bacterial beta-lactamases from breaking down the antibiotic. Examples of oral drug combinations are amoxicillin + clavulanic acid and trimethoprim + sulphamethoxazole. An example of a parenteral drug combination is piperacillin + tazobactam.

Name 4 oral antibiotics, each from a different class, which may have activity against MRSA.

• Cephalosporins: Ceftaroline (the only beta-lactam that works against MRSA)
• Macrolides: Erythromycin
• Lincosamides: Clindamycin
• Sulfonamides: Trimethoprim + sulfamethoxazole (co-trimoxazole)
• Fluoroquinolones: Ciprofloxacin

Name an IV antibiotic used to treat serious MRSA infections.

Vancomycin (a glycopeptide). Some oral antibiotics, such as rifampicin, can also be given via IV for serious infections.

Name an infection where formal MIC testing is done on the causative organism and discuss why.

Formal MIC testing is often done on Viridans streptococci as they have highly variable degrees of susceptibility to penicillin.

Explain why a 10 day course of antibiotics is used in the treatment of streptococcal pharyngitis. Name two drugs used for this purpose.

Penicillin is usually used to treat streptococcal pharyngitis, but azithromycin can be used if the patient is allergic. Antibiotics are usually given for 10 days in order to protect against development of rheumatic fever (see here for more information about rheumatic fever).

Cardiovascular Anatomy 1 and 2

A lot of the content in this lecture was basic stuff I've covered many times before. Half the reason I'm writing this post is because I want to productively procrastinate over having to write anything more difficult. Yay.

Identify the major anatomical features of each chamber of the heart and explain their functional significance.
Describe the position of the atrioventricular, pulmonary and aortic valves and describe their function in the prevention of reflux of blood during the cardiac cycle.
Describe the origin, course and main branches of the left and right coronary arteries and discuss the functional consequences of their obstruction in conditions such as ischaemic heart disease.

• Heart and Mediastinum
• Coronary Artery Disease

Outline the embryological development of the heart.

(NOTE: I don't think this was actually covered in the lecture, so this post is going to have wayyyyyyyy more detail than you actually need for this course.)

• Development of the Heart

List cardiac structures that are susceptible to congenital defects.

I'm not sure if this was even covered in lecture either, but this post has a bit about congenital defects:

• Dysrhythmias and Congenital Heart Defects

Describe the differences between foetal and neonatal circulation.

• Development of the Heart

Describe the histology of the heart wall and myocardium.

• Muscles I and II (tl;dr cardiac muscle is stripy and branched- I think that's literally all we need to know for this lecture)
• Tubes (relevant for blood vessels)

Lipid-lowering therapies

This post is one of my first in a while to not be about pathology! This one is about pharmacology instead :)

Know basic principles of lipid metabolism and how this can lead to biochemical derangement and disease

• Lipid and Lipoproteins: Structure, Function, and Metabolism

Understand the relationship between cholesterol level and cardiovascular disease risk

Pretty much the main takeaway from this lecture is that levels of LDL cholesterol is positively associated with increased cardiovascular disease risk. Therefore, it is important to try and manage cholesterol levels so that levels of "good" cholesterol (HDL) prevail over levels of all the "bad" cholesterol (pretty much all of the other types of cholesterol).

Understand the options of drug and non-drug treatments for hyperlipidaemia

Drug treatments

There are various drugs that can lower lipid levels. I will discuss this a bit further down in this post.

Non-drug treatments

There are several non-drug lifestyle treatments that can help with hyperlipidaemia. In short: cessation of smoking, exercise, and a healthy diet are all factors that can help in treating hyperlipidaemia. The Mediterranean diet (see here) is generally considered to be one of the best for overall cardiovascular health. For patients who specifically need to lower cholesterol, a low saturated fat diet may be helpful, and for patients who specifically need to lower triglycerides, simply losing weight may be helpful. (However, please note that I am not a dietician, so do take my words with a pinch of salt ;) )

Know the main classes of lipid lowering drugs

Statins

Statins are the first-line therapy for lowering LDL and reducing the risk of cardiovascular disease. They decrease the synthesis of cholesterol by inhibiting the enzyme HMG-CoA reductase. They can also increase SREBPs (transcription factors that regulate LDL receptors), increasing LDL receptor production, which in turn increases removal of cholesterol from the blood. Common side effects of statins include an increase in diabetes risk and some hepatic side effects (0.5-3% of patients have an increase in an enzyme called transaminase, which to my understanding is a marker of liver damage). Myositis is another side-effect of statins. There has also been concern about memory loss associated with statin use, but only 60 cases of this have been reported since 1997.

Another important thing to know about statins is that while a small dose of statins can reduce LDL levels by a decent amount, increasing the dose has a much smaller effect. Therefore, in some cases, it might be better to add a second drug (e.g. ezetimibe, which I'll talk about next) rather than increase the dose of the statin.

Ezetimibe

Ezetimibe is the second-line therapy for lowering LDL and reducing cardiovascular disease risk. Ezetimibe inhibits NPC1L1 receptors on enterocytes, preventing uptake of cholesterol. It is generally well-tolerated but may have some side-effects such as diarrhoea and fatigue. It is sometimes used as a good alternative to statins in patients with myositis, or used in addition to statins to reach the target LDL level.

PCSK9 inhibitors

PCSK9 inhibitors are relatively new. PCSK9 can bind to LDL particles that have bound to LDL receptors, triggering breakdown of the receptor as well as the LDL. What this means is that the LDL receptor is not recycled and taken to the surface, meaning that the cell cannot remove as much LDL from the circulation. Patients with gain-of-function mutations in the PCSK9 gene may be at a greater risk of familial hypercholesterolaemia (high levels of cholesterol in the blood). Currently-approved PCSK9 inhibitors include alirocumab and evolocumab, which are antibodies against PCSK9. Since they are antibodies, they need to be given by injection every few weeks. Side effects from PCSK9 inhibitors appear to be relatively mild, such as nasopharyngitis and reactions at the injection site.

Mipomersen

Mipomersen is an antisense oligonucleotide against the mRNA of apoB. Therefore, it can stop production of apoB. However, it seems to have a high rate of injection site reactions (~90%) and may increase hepatic fat and transaminase levels.

Lomitapide

Lomitapide is an inhibitor of microsomal transfer protein (MTP) (an enzyme that packages cholesteryl ester and triglycerides together to form chylomicrons). Hence, lomitapide prevents the formation of lipoproteins that contain apoB. Unfortunately, it seems to have a high rate of GI side effects (~93%).

Fibrates

Fibrates activate PPARα, increase beta-oxidation of fatty acids, and down-regulates ApoCIII. As ApoCIII inhibits lipoprotein lipase (contrast with ApoCII which activates lipoprotein lipase), downregulation of ApoCIII allows lipoprotein lipase to become more active and break down lipoproteins.

n3 Polyunsaturated Fatty Acids

n3 polyunsaturated fatty acids (a.k.a. omega-3 fatty acids), such as those found in fish, may help to reduce cardiovascular disease. The actual mechanism is quite complex, but it may help reduce synthesis of lipoproteins. In particular, they seem to reduce levels of basically all non-HDL cholesterols, with the exception of LDL, which they increase.

Niacin

Niacin downregulates hepatic DGAT, reducing the synthesis of triglycerides. However, it has not been seen to improve outcomes in people with cardiovascular disease, and has very limited indications now.

GLP1
DPP-4 inhibitors

• Pathophysiology of Glucose Metabolism and its Treatment

While these drugs can be used to manage glucose levels, they are also being trialled to see if they will help with cardiovascular disease as they appear to also affect lipid levels.

Thiazolidinediones

Thiazolidinediones are PPARγ agonists that act on adipose tissue, muscle, and liver. They can stimulate uptake of lipids and reduce fatty acid supply to the liver and muscles. They can also increase glucose uptake and decrease glucose production, so they are often used to treat diabetes. (Cardiovascular disease outcomes, however, are still uncertain.)