Sodium and Water (4) - The difference

OK, in the last post, I alluded to the difference between maintaining the body's water balance and maintaining the body's sodium balance. It's quite an important distinction, and it's clinically relevant too.

If you increase or decrease the total body water independently of its sodium content, then it follows that the sodium concentration will be altered. Think about it: if I have 100 mmol of sodium in one litre, but I then add 200 mls of water, I've changed the sodium concentration from 100 mmol/L to 83 mmol/L [100/1.2]. But changing the sodium concentration hasn't meant that I've changed the sodium content (amount) - which has remained the same, at 100 mmol, no matter how much water I've added.

Therefore, as a general rule, changes in sodium concentration reflect disturbed water homeostasis. The problem will lie with one of the regulators of water balance, then: water intake or AVP.

Now look what happens if I take a human body and force it to retain sodium. You might think that the sodium concentration would again be affected, but remember that sodium is highly osmotically active: it more or less drags an equal amount of water with it. Therefore, reabsorbing (or failing to excrete) sodium will not change the body's sodium concentration. Rather, it will cause there to be a rise in the total amount (content) of sodium and water in the body.

Therefore, as a general rule, changes in sodium content cause hyper- or hypovolaemia. Clinically, this manifests as oedema or dehydration/shock respectively. The problem lies with one of the regulators of sodium balance, usually the renin-angiotensin-aldosterone system.

Before this gets too theoretical, let's look at a few clinical examples.

1. Cardiac failure - in this state, the sodium concentration is often low, and the patient is oedematous. From this, we can infer that (1) water is being retained in excess of sodium, causing hyponatraemia, and (2) the body contains too much of both sodium and water, causing oedema. Sure enough, treatment involves water and salt restriction, and diuretics to promote water and salt loss.
2. Diarrhoea - the sodium level here can be low, normal or high depending on whether sodium is lost in excess of water or vice versa. For the sake of argument, let's say that in this patient the sodium is low. Regardless of the sodium level, however, the patient is certainly dehydrated. Therefore, unlike in cardiac failure, the treatment of hyponatraemic diarrhoea will include giving (not restricting) sodium and water (e.g. via intravenous normal saline).

In the next post, we'll discuss an approach to hyponatraemia.

Sodium and Water (3) - Sodium Balance

In the previous post, we discussed how the body regulates its free water content. Now we turn to sodium regulation.

We can lose a minimum of about 100 mmol per day. Therefore, this is the amount that we need to ingest on a daily basis. You lose some sodium in your sweat, and some sodium in your faeces, but these are largely unregulated losses. The place where the body does its sodium bookkeeping is in the kidneys.

Of the filtered load of sodium, about 98% is reabsorbed:

1. Two thirds is reabsorbed in the proximal convoluted tubule.
2. One quarter is reabsorbed in the thick ascending loop of Henle (via the Na⁺/K⁺/2Cl^- cotransporter)
3. About 5% is reabsorbed at the distal convoluted tubule (by the thiazide -sensitive Na⁺/Cl^- cotransporter.

These channels aren't particularly regulated from a sodium perspective. Rather it is at the last stage that the body finally turns its attention to the fate of sodium.


4. The remaining sodium reabsorption occurs at the distal proximal tubule, and in the cortical and medullary collecting tubules. This stage is sensitive to hormonal manipulation.

And what are these sodium-controlling hormones? The most famous is aldosterone, which causes the principal cells in this area to reabsorb sodium (in exchange for potassium). Incidentally, it also performs as similar swap in the gut, although this is a less important phenomenon.

A slightly less well-known hormone is atrial natriuretic peptide, which is secreted in response to atrial stretch. It promotes sodium loss directly (by inhibiting distal tubular sodium reabsorption) and indirectly (by decreasing renin, one of the controlling hormones for aldosterone release).

In a similar class is brain natriuretic peptide, which is secreted in response to ventricular stretch and has similar properties to its atrial counterpart. (Note, it doesn't come from our brains, despite the name!)

Between them, these three hormones regulate the amount of sodium in our bodies. They don't really regulate sodium concentration though - this is the job of the body's water balance system described in the previous post. It's important not to get this mixed up. If your patient comes back with a low serum sodium concentration, he may still have a high total body sodium content.

If this last point seems a bit oblique, don't worry: we'll spend a bit of time on it next.

Sodium and Water (2) - Water balance

To maintain a steady state, your intake of a substance must equal your loss of that substance, and water is no exception. So what are you obligatory water losses - those losses that you can't help but sustain?

First up, the kidney can only concentrate substances up to a maximum of 1200 mosmol/L. Since we produce about 600 msomol of substances per day, that means that you have to urinate out about 500 ml per day, no matter how inconvenient this is.

Next, we have evaporation from the skin, which totals a minimum of about 400 ml per day. If you're exercising, or out in the hot sun, this amount can increase to a staggering 5 L.

Then there's evaporation from our respiratory tracts. The air we breathe in has a lot less water vapour in it than it ends up with as it descends into our lungs - water evaporates from our moist mucosa to join it. Under normal conditions, the amount of water lost in this way is about 350 ml, but this number will increase rapidly if you are breathing heavily or rapidly.

Lastly, there is fluid loss in our stools, which as we all know aren't perfectly dry. The body is actually quite good at retaining fluid from our gastrointestinal tracts, and so we only lose an average of about 100 ml per day via defaecation.

OK, so under optimal conditions, this means that we lose about 1400 ml per day, although usually it's a bit more than this. Therefore, this is the minimum amount if fluid we need to take in to keep in balance.

Fortunately, we don't have to do the calculation consciously: our intake of water is regulated by the sensation of thirst. Osmoreceptors, located in the anterior hypothalamus, are stimulated by the rise in osmolarity that corresponds to water depletion. As a result, we drink more and the status quo is preserved.

On the other hand, what if we've taken too much water on board, and need to excrete the excess? The kidneys come to the rescue here: they are capable of excreting urine with an osmolality of just 50 mosmol/L and so can get rid of large volumes of water (without necessarily increasing the renal losses of other substances). The principle determinant of renal water excretion is arginine vasopressin (AVP, also known as antidiuretic hormone - ADH). This polypeptide hormone is secreted by the posterior hypothalamus and acts on the V2 receptors of the kidney (mainly in the collecting tubules and ducts). Binding of the hormone causes these cells to insert water channels (aquaporins) into their luminal membrane, thereby massively increasing the permeability of these cells to water. The water can then passively move from the 'urine' side back into the cells and hence back to the body.

Between them, thirst and AVP are the two main mechanisms that preserve a constant body osmolality.

Ineffective vs effective osmoles

Here's a challenge for you. In the previous post, I said that examples of ineffective osmolytes were urea and glucose. That's because these two substances, although osmotically active, could easily distribute themselves across the various body compartments and so wouldn't cause fluid shifts from one compartment to the other. Although this is true in health, what happens in the case of diabetes?

The answer, of course, is that glucose becomes an effective osmolyte, capable for causing fluid shifts from the intracellular to the extracellular compartments. This is because diabetics have a (relative or absolute) lack of insulin, which is required for glucose entry into many cell types. Thus, for all intents and purposes, glucose becomes more confined to the extracellular compartment in diabetes.

This has serious implications, since the resultant fluid shifts are a major part of the pathogenesis of both diabetic ketoacidosis and the hyperosmolar non-ketotic state, which you've probably heard about.

Sodium and Water (1) - Body compartments

The human body is approximately 50-60% water (on the higher end for men, on the lower end for women). This water is distributed in two major compartments - the intracellular fluid compartment and the extracellular fluid compartment, in a ratio of roughly 2:1.

The extracellular fluid is further divided into interstitial fluid and plasma, in a ratio of about 3:1. Together, therefore, the breakdown looks something like this:

There are barriers between these compartments. Between the intracellular and extracellular compartments is the cell wall, and between the interstitial and plasma compartments lies the blood vessel wall (at its thinnest, just a single layer of endothelial cells).

Water can move freely between these compartments without difficultly, but many other substances, some of them osmotically active, can't. Therefore, the amount of water in each compartment depends on the relative number of osmolytes in each compartment - water will always flow to the compartment with a higher osmolality. The major division is between the intracellular and extracellular portions:

• The major extracellular determinants of osmolality are sodium and its accompanying anions (chloride and bicarbonate, mostly).
• The major intracellular determinants of osmolality are potassium and organic phosphates (ATP, creatinine phosphate and phospholipids).

Hence, if the sodium concentration goes up in your extracellular fluid, water will tend to leave your cells and move to make up the difference there. Since water moves so quickly, the osmolalities of the extracellular and intracellular compartment are always equal. This does not mean that the (shared) osmolality is normal, though. In the sodium example above, the osmolality in both the intra- and extracellular comparments will be higher than normal (the normal range for osmolality is 275 - 290 milliosmoles / kg).

Lastly, a word about the so-called ineffective osmoles. Osmolytes that (like water but unlike sodium) can move easily between compartments tend to increase the osmolality of both compartments without ever inducing water to shift compartments. Glucose and urea are two examples of such osmolytes. If I injected your extracellular fluid with extra urea, the osmolality of the compartment would increase temporarily, but since urea can move with ease to the intracellular compartment too, it would wouldn't have the opportunity to cause fluid shifts. It would merely increase the osmolality of both compartments simultaneously and there would be no net movement of water from any compartment. This is not the case with sodium, for example, which is effectively stuck in the extracellular compartment. Injecting your extracellular fluid with sodium would cause a rise in the osmolality of only this compartment, and fluid would flow out of the intracellular compartment until the osmolalities of both compartments were equal again (though both would be higher than before).

You can estimate the osmolality of your body's fluids by the following equation (all concentrations in mmol/L):

osmolality = 2 ⨯ [Na⁺] + [urea] + [glucose]

If your glucose and BUN measurements are made in mg/dL (typical in the US), then the equation becomes:

osmolality = 2 ⨯ [Na⁺] + [glucose]/18 + [BUN]/2.8

More on Anaemia of Chronic Inflammation

Here's a good chance to revise your understanding of iron metabolism with a discovery that's hot off the press.

The body has no special method to get rid of iron. Any excess iron can only be lost by shedding cells that contain the element, such as red cells (in bleeding) and enterocytes (as part of faeces). Iron absorption therefore has to be closely scrutinized, and the chief regulator is a protein produced by the liver, called hepcidin. The 'export proteins' for iron are called ferroproteins, and were known to be present on cells participating in iron metabolism, including enterocytes (where iron is absorbed and some of it stored) and macrophages (which engulf aged red cells and recycle their iron).

Hepcidin binds to and destroys ferroproteins, with the net result that iron is trapped within its storage sites. Under conditions of iron deficiency, therefore, hepcidin is down-regulated, permitting the ferroproteins to rapidly move iron out of the stores to the rest of the body. Conversely, cytokines (like IL-6) produced during inflammation up-regulate hepcidin, sequestering the iron away from microbes (real or imaginary) that the body assumes are causing the inflammatory response. This is one mechanism producing the familiar anaemia of chronic inflammation (ACI).

OK, that's the background; now the new bit. It has long been known that, although characteristic of either condition, the microcytosis of iron deficiency is usually far worse than that of ACI. In fact, in about 70% of ACI cases, there isn't even a microcytosis! This is puzzling, though, since in either case the microcytosis is caused by a deficiency of iron to the developing red cells - there isn't enough iron in the body in the former, and the iron is inaccessible in the latter. Furthermore, the microcytosis might be supposed to be more severe in ACI, since in this condition iron's transport protein, transferrin, is also down-regulated. Yet the opposite pattern occurs. Why?

A recent study by Zhang et al. located ferroproteins on erythroid precursors, a fact that came as a surprise to us all, since these cells would be the one cell type you would least expect to export iron - they're busy stuffing themselves full of iron-containing haemoglobin proteins! It therefore appears that the body sometimes needs to make use of this iron elsewhere in the body, in myoglobin, cytochromes, etc. But now think of the implication: during conditions of iron deficiency, hepcidin levels plummet, allowing the ferroproteins to release iron from the erythroid precursors to be used by the rest of the body. On the other hand, during inflammation, hepcidin production is ramped up, and the iron is trapped within the erythroid precursors, where it can presumably be used to continue red cell production.

At a stroke this solves the puzzle of why the erythrocytes are so much worse off, iron-wise, in iron deficiency, compared to ACI.

Source: Keel, Sioban B., Abkowitz, Janis L.

The Microcytic Red Cell and the Anemia of Inflammation
N Engl J Med 2009 361: 1904-1906

What is the commonest cause of primary hyperparathyroidism?

Primary hyperthyroidism is due to pathologically excessive and autonomous secretion of PTH by the parathyroid glands. The key concept is that the excess secretion is autonomous - it doesn't care what the serum calcium levels are, and consequently the serum calcium ends up getting rather high. (Contrast this with secondary hyperparathyroidism, where the increased PTH secretion is appropriate in the context of a low serum calcium.)

Theoretically, excess parathyroid hormone could come from a place outside of the parathyroid glands (for instance, ectopic secretion by a tumour), but in practice this fundamentally never occurs. This is helpful, as it narrows our search down to one or more of these glands, which sit embedded in the much larger thyroid gland. There, the possibilities are:

• an adenoma (a benign neoplasm)
• a carcinoma (a malignant neoplasm)
• diffuse hyperplasia (a general, non-neoplastic increase in the size of all four glands)

And the winner is...

A parathyroid adenoma, which accounts of about 85% of all cases. Congratulations to it!

Do the two ovaries alternate which one of them ovulates?

Women have two ovaries, of course, and yet under normal circumstances only one ovum (egg) is released into the abdominal cavity each month. How is this coordinated?

A woman's ova must mature first before they are ready to be released. From birth to puberty, each ovum is surrounded by a single layer of granulosa cells and is termed a primordial follicle. This is more or less how a woman finds her ovaries just before puberty - filled with tens of thousands of primordial follicles.

Each month, some of these follicles are coaxed into further development by the action of two hormones produced in the pituitary gland: luteinizing hormone (LH) and follicle stimulating hormone (FSH). But here's the crucial point: only some of the primordial follicles - typically between six and twelve - develop further each month. These follicles are spread out across both ovaries.

Then, after about a week of stimulation (but before ovulation), one of the follicles begins to outgrow all the others. The others, sensing a winner, give up their chance at immortality and simply involute, leaving the only remaining one to eventually release its ovum. Which ovary (left or right) the winner comes from appears to be largely random - the ovaries aren't so well coordinated as to alternate sides or anything. For instance, the right ovum might produce the ova for three months in a row before the left gets a chance, or vice versa. It's like tossing a coin.

There are two related questions that are begging for an answer here. Firstly, if only one ovum is released each month, why do the other five to eleven of the primary follicles even bother to enter the race? A clue lies in the fact that as follicles develop, they begin to secrete oestrogen and progesterone. Apparently the body needs more than one cell per month in order to generate enough of these hormones - although it obviously needs only a single ovum for fertilisation purposes.

Secondly, what causes the other follicles to give up the race? As the follicles mature, they set up a positive feedback cycle whereby the oestrogen they produce sensitizes the cells to more FSH and LH, which further promotes their development and oestrogen secretion, which sensitizes ... (you get the picture). This process of exponential growth is therefore explosively quick, and so any follicle that edges ahead of the rest of the pack (even if through sheer randomness) quickly outstrips any rivals. It is postulated that this 'dominant follicle' soon secretes so much oestrogen that FSH and LH secretion by the pituitary is suppressed (high levels of oestrogen almost always do this). Starved of stimulation, the paucity of FSH and LH causes the other follicles to involute, whilst the largest follicle is still sufficiently sensitive to the lower levels of FSH and LH to continue its development.

Why astronomers use red light to read by

You may recall that our retinas are packed with two types of photon-detectors: rods and cones. Under conditions of sufficient light, we almost only use our cones. Since these come in three flavours, each responding maximally to a different range of light frequencies, we get to see in colour during the day. Furthermore, since they are densely packed right where the images focus (at the fovea), and since they are cleverly wired up, the visual acuity that we get with our cones is really good. This type of vision - under well-lit conditions - is known as photopic vision.

When light levels drop, however, we have to switch to low light, scotopic vision, which uses our rods. There's only one 'flavour' of these cells, and so our vision at night is monochromatic. Also, because these cells are 1000 times more sensitive to light than the cone cells are, they permit us to see in the dark. However, they are distributed largely at the peripheries of the retina, and so the image they collect is rather distorted. Furthermore, many rods all club together to send a message to the brain (via the bipolar cells, if you remember your retinal anatomy) and although this increases the chance of a bipolar cell responding to dim light, it also means that localisation is less precise. Together, these two facts conspire to ensure that our visual acuity at night is rather poor.

Enter the astronomer. She comes with an unreasonable demand: she needs scoptopic vision to make out faint stars by night (her cones wouldn't detect anything at these low levels), but she also occasionally needs her high acuity photopic vision to consult her star charts, or to write notes. For this she needs to add enough light to her page for her cones to kick in.

This may sound like a nice plan, but unfortunately to get her rods to see optimally in the dark requires about 30 minutes. Consider walking off the street at noon into a dark theatre: you are functionally blind for a good few seconds, and your retina only gradually adapts to the dark thereafter. Clearly switching frequently between enough-light-to-read-by and dark-enough-to-see-stars is impractical unless one has many hours to kill. So what to do?

Fortunately, there is a partial solution. Shine most shades of light at levels bright enough to excite your cones and you will knock out your rods for several minutes (e.g. walking into the theatre from a bright street). However, your rods are fortunately rather insensitive to pure red light when they are dark-adapted. In fact, they are 50 to 100-fold less sensitive than the flavour of cones that happens to detect red light. What this means is that if you use red light that isn't too bright, you can excite your cones enough to read by, without blowing your rods. In other words, you can then switch quickly between scotopic and photopic vision without having to wait for your eyes to adjust to the change in light levels.

The spleen's jobs

The spleen is an odd-shaped organ that lies hidden away behind our ribs, posteriorly, on our left sides. It's functions are threefold:

1. Red blood cell 'quality control' - the arterioles of the spleen mostly empty into a series of splenic cords. These lack an endothelial lining, and consist chiefly of a loose array of reticulin (a type of collagen) lined by macrophages and fibroblasts. To get back into the circulation, hopeful blood cells must squeeze themselves into the splenic sinuses that all ultimately empty into the splenic vein (and hence the general circulation). Old and damaged red blood cells aren't able to do this, and so they are doomed to remain in the cords where they are phagocytosed by the macrophages.
2. Immunity - the spleen is in many ways analogous to a a lymph node, in that blood-borne pathogens are amply exposed to macrophages and dendritic cells, which in turn present them to T and B cell aggregations within the spleen. The spleen seems particularly good at preventing infections by encapsulated organisms such as Streptococcus pneumoniae, Haemophilus influenzae and Neiserria meningitidis.
3. Extramedullary haemopoiesis - the spleen usually stops making our blood cells after about 7 months of gestation, but it has the ability to be reactivated if our bone marrows can't produce enough blood cells for whatever reason. (e.g. myelofibrosis, where the marrow is obliterated.)

These three functions are helpful to keep in mind when it comes to remembering the causes for splenomegaly. We'll cover that in the next post.

The Cell Cycle

There is a constant rate of cellular attrition in our bodies: some cells wear out, some are ordered to die by apoptosis, some are damaged by trauma or microorganisms, and still others are actively killed by our immune cells as a result of their becoming infected or cancerous. To replace this constant loss, most of our cells must clone themselves to make up the deficit.

The orderly process by which they accomplish this is known as the cell cycle. It is divided into four distinct phases, which revolve around a fact of necessity: if a cell has to divide in two, it has to duplicate its DNA first. If this were not the case, the amount of genetic material in each cell would halve after each division, leaving the resulting cells without their central instruction manual.

The phases are labelled in the chart below: G1, S, G2 and M, and we'll get to them individually in just a second. Once all four phases have been completed, the cell divides in half, thus creating two identical clones instead of the original single cell. The length of the entire cell cycle varies quite a lot from cell type to cell type, but a typical figure might be about 24 hours.

After a cell has been created by division, the first thing it does is get back to doing whatever it is supposed to be doing! Think of it as cellular "me time". (The mitotic process that produced it is metabolically costly, and many routine cellular processes had to be put on hold for its duration.) However, the cell also has one eye on the future: it synthesises certain key enzymes neccessary for the next step. This stage is known as G1 (in which the 'G' stands for 'gap').

The next phase is labelled S, for 'synthesis'. As suggested by this name, this is the time during which the cell's DNA is replicated. Another copy of it is made, so that each chromosome is now made up of two sister chromatids.

After the S phase comes another 'gap' stage, called G2. Once again, the cell can resume normal cellular activities. As with the first gap though, the cell also uses the time to synthesise things of use in the next phase. (Its organelles replicate, and the cell volume swells.) Together, these first three stages can be lumped under the title, interphase.

The last phase is usually the briefest, and it's called the M phase ('M' stands for 'mitosis'). This stage is bewilderingly complex (and the subject of many an exam question!) and so we'll have to cover it in detail on some other occasion. Suffice it to say, the cell now obliges by dividing down the middle, making sure that each cell has a full complement of DNA and organelles.

Not all cells have the be active in the cell cycle (think, for instance of neurones, which don't divide). Those which aren't interested in dividing are said to be in G0.

The making of thyroid hormones

I had initially planned to do a two-part post on everything-you-need-to-know-about-thyroid-physiology, but I seem to have posted the second bit first.  Oh well, here's the first bit:

The thyroid is unique amongst our endocrine glands in that it stores large amounts of hormone extracellularly (as opposed to small amounts intracellularly).  It structural units are called thyroid follicles, which are spheres formed by a single layer of epithelial cells.  Within these spheres is a substance called thyroid colloid, which is composed largely of thyroglobulin.  Thyroglobulin is the how the thyroid hormones are stored.  You can see a cross section through several of the follicles below; note the single layer of epithelial cells encircling the central (pink) colloid.

(The image is from this blog.)  As you can also see from the image, the follicles are surrounded by a stroma (connective supporting tissue) rich in blood vessels.  This makes sense, as the organ we're talking about is an endocrine gland - it's gotta be pumping hormones into the bloodstream when required to do so.

Iodine from our diets is taken up from the bloodstream by the follicular epithelial cells and then spat out into the inside of the follicle.  Concurrently, the follicular cells also secrete thyroglobulin into the follicle's lumen.  The iodine then combines with the bits of thyroglobulin that contain the amino acid tyrosine. The results are tri-iodothyronine (T₃) and tetra-iodothyronine (T₄) - in other words, the thyroid hormones.

These hormones remain bound to thyroglobulin in an inactive form, however.  When the hormones are needed (i.e. when thyroid stimulating hormone is secreted), the thyroglobulin-hormone complex is endocytosed and fused with a lysosome, which is a sort of general purpose package of destructive chemicals.  The hydrolytic enzymes in the lysosome cleave the hormones from the thyroglobulin, and the free hormones can diffuse into the bloodstream.

And from here, the story is taken up by the first post...

How do thyroid hormones work?

The thyroid gland produces two hormones for export: tri-idothyronine (T3, thyroxine) and tetra-iodothyronine (T4).  About 95% of the exported thyroid hormones are in the form of T4, but this situation is complicated by two factors.  Firstly, T3 is 3-4 times as potent as T4, and secondly, the bulk of T3 is formed from T4 by peripheral tissues.  These facts conspire to balance the workload of T3 and T4 somewhat, despite the lopsided nature of their initial secretion.

Like steroid hormones (but unlike most peptide or protein hormones), T3 and T4 must enter the cell to effect any changes.  This they do either by simple diffusion or else by a specific transport mechanism. 

Once inside the cell, they bind to thyroid hormone receptors, of which there are two types (α and β).  The hormone-plus-receptor complex then binds to specific DNA sequences in the promoter area of various genes (these specific regions are sometimes referred to as thyroid response elements).  The effect of this is to either upregulate or downregulate the transcription of these genes, and this is how thyroid hormones create their effects.

Quite a number of genes must be activated (or repressed) for thyroid hormones to have their wide-ranging effects.  Amongst other things, thyroid hormones act on:

• the heart - increasing the rate and force of contraction
• the brain - promoting normal brain development and function
• the bones - promoting normal skeletal growth and development, and accelerating bone turnover
• the muscles - increasing protein breakdown
• the gut - increasing carbohydrate absorption
• the adipose tissue - increasing lipolysis (breakdown of their stored fat)

as well as, generally, increasing the metabolic rate of tissues, thereby increasing oxygen consumption and heat production.

Why do you get a tachycardia in anaemia?

Anaemia is defined as a decreased concentration of haemoglobin, and this is relevant because haemoglobin is virtually the only way for oxygen to be taken up and transported in the blood.  Anaemia therefore threatens to cause hypoxia (decreased oxygen tension) at the tissues.  How should the body respond?

First and foremost, it should try to alleviate the cause, by doing things like stopping any bleeding, and increasing red blood cell production.  But let's say these things aren't sufficient, or aren't done quickly enough.  What compensatory measures can be put in place?

Well one thing that can be done is to shunt blood to the tissues that most need it.  This means that the important organs get more blood than usual, even if the haemoglobin concentration (and thus oxygen content) of this blood is decreased.  Indeed, the body does make use of this trick, and that's one reason why the sclerae of an anaemic patient are so pale.  It isn't just that there is a decreased (red) haemoglobin concentration; it's also that there is simply less blood being pumped there, as more is being diverted to other areas. 

Another compensatory mechanism is to increase the cardiac output, principally by increasing the heart rate.  In this way, more oxygen per second is transported to the tissues, which helps to make up for there being less oxygen per unit of volume in the blood.

Does that make sense?  Perhaps an analogy will help.  Think of fish swimming down a river, with you having to catch a certain amount of fish per hour.  A problem strikes: this year has been a poor one for the fish, and there are fewer than usual fish per kilolitre of water.  What can you do?  The tachycardia option would be the equivalent of making the fish swim faster down the stream, so that you can keep your quota-per-hour to normal.  (The shunting option would be represented by closing down certain rival streams to divert enough fish per hour towards you.)

Incidentally, this increased cardiac output often produces a soft ejection systolic murmur, as a result of the increased speed and volume of blood passing by the aortic valve. 

(Oh, what other one thing could you do?  You could try to make sure that haemoglobin gave up its oxygen load more easily - by doing any of these things, thereby "shifting the curve to the right".)

How many blood cells are produced daily by the bone marrow?

Although in children most of the blood cells are produced by the long bones, by the time adulthood beckons, they are largely produced by the marrow of the vertebrae, sternum and ribs.  The half-life of the various components is often quite short.  Half the platelets produced today will be gone in 4 days, and neutrophils only last about 8 hours! Furthermore, you require an enormously large number of cells in the blood stream.  Erythrocytes, for instance, are typically present in a concentration of 5 billion cells per millilitre.  (Think of that the next time you spill a drop of blood.)

The upshot of all this is that the marrow must be continually producing an enormous amount of new cells.  When you add it all up, the figure actually comes out as 100 billion cells per day.

By far the most numerous cell type is the red blood cell (erythrocyte), which outnumbers white blood cells by 700 to 1. Platelets have a concentration of 150 to 450 million per millilitre.  Overall, a typical thin smear of blood, once stained appropriately, looks something like this:

(a) points to two of the many red blood cells, (b) is a neutrophil, (c) is an eosinophil and (d) is a lymphocyte.  Notice how many red cells there are, compared with other cell types.  Those little dots in between the cells are mostly platelets.

What is 2,3-DPG?

2,3-DPG stands for 2,3-diphosphoglycerate, and it's a compound that is found in red blood cells. It is almost always mentioned in conjunction with the oxygen-haemoglobin dissociation curve, which looks something like this:

Under conditions of hypoxia lasting more than about two to three hours, the concentration of 2,3-DPG increases substantially.  It binds to haemoglobin, facilitating the release of its oxygen molecules.  The effect of this is that at any given partial pressure of oxygen, more oxygen is released than would otherwise have been, and so increased 2,3-DPG levels mean that the tissues get more oxygen.  Since this was all a response to hypoxia in the first place, order is thereby restored to your body.

There are three other factors that also increase oxygen dissociation from haemoglobin, namely a decreased pH, increased carbon dioxide concentration, and increased temperature.  The first two of these also make sense: hypoxia causes lactate generation and thus a decreased pH, and poor blood flow to an area causes carbon dioxide to build up.  In either case, the implication is that the tissues aren't getting enough oxygen, and so more oxygen is duly deposited there.  I'm not sure about the last one, though.  Perhaps, instead of being an 'adaptation', it's simply an unavoidable effect of changing the temperature.  (Many molecules, like enzymes, are quite specific as to what temperature they prefer; even a 1 or 2 degree Celsius difference can deform or destroy them.)  Thoughts?

P.S. Unhelpfully, increasing the amount of oxygen that haemoglobin gives up for at any particular partial pressure is sometimes known as 'shifting the curve to the right', since this is what the new oxygen-haemoglobin curve would look like, when compared to the first one. 

What is the Frank-Starling mechanism of the heart?

How does the body know how much blood to send to each of the various tissues in the body? Well, if their metabolic needs stayed constant, the body could be pre-programmed to distribute blood accordingly in a set fashion. But what if they changed? What if (as happens, of course) our skeletal muscles required lots more blood flow during exercise, and our guts required far less blood flow during the same period? How would the body know how to adjust its pattern of blood distribution?

The answer is: it leaves this decision largely up to the tissues themselves. On the whole, the byproducts of metabolism (low oxygen, high carbon dioxide, adenosine [from the hydrolysis of ATP], etc.) will build up whenever the cells in a particular area increase their rate of metabolism. The local vessels sense these substances, and dilate - thus increasing blood flow to the tissues that need it! Clever, no?

This does pose a little problem for the heart though. The amount of blood it receives by the end of each diastole (i.e. the "end diastolic volume") is obviously dependent on how much blood flows through the tissues and back to the heart - a factor which we've just noted the tissues determine for themselves. Thus the heart can't "know" in advance how much blood it's going to receive, and thus have to pump out, each time.

To cope with this problem, it is equipped with the Frank-Starling mechanism. Fundamentally, this is the heart's ability to match its stroke volume to the end diastolic volume it receives; in other words, it is the ability to pump out more (or less) blood if it receives more (or less) blood.

How is this possible? Well, let's say that the venous return is abnormally high. By definition this means that the heart is sitting with quite a lot of blood in its ventricles when the time comes for it to contract. Compared with normal, that is, the end diastolic volume is high. This extra volume of blood distends the ventricle more than normal, stretching the cardiac muscle cells and causing them to contract with extra strength. And this extra strength forces the extra blood out during systole. Thus, the heart adjusts its stroke volume (i.e. the amount of blood it ejects with each contraction) to cater for increased or decreased amounts of venous return.

(At a molecular level, what is happening is that the extra stretch increases troponin C's affinity for calcium, facilitating the formation of a greater than normal amount of crossbridges. If this is Greek to you, fear not, for we shall cover muscle contraction in a separate post.)

There are limits to the Frank-Starling mechanism; you can't just keep filling the heart with more and more blood and expect it to cope! Eventually, the heart's muscle cells are stretched to capacity and any further increase in venous return can't be expelled. With a healthy heart and body, this almost never happens, but the limits of the Frank-Starling mechanism begin to be noticeable when patients have cardiac failure.

Does your heart rate go up or down when you stand up?

When you stand up, you present the cardiovascular system with a problem. When supine, blood flowed almost effortlessly back to your heart, but an upright posture means that blood tends to pool (in your legs especially). The effect of this decreased venous return is that the heart's stroke volume (and thus cardiac output) is also reduced, which would tend to decrease your blood pressure, in accordance with the famous equation:

blood pressure = (stroke volume x heart rate) x total peripheral resistance

But the equation also suggests two ways to compensate for a decreased stroke volume: you can increase the peripheral arteriolar resistance (i.e. vasoconstrict) and you can increase the heart rate. Both of these responses are mediated by the autonomic nervous system, and the result is that the brain's perfusion is utterly unaffected by your upright posture.

Of course, that only applies if your autonomic nervous system is alright. In the elderly, and in diabetics in particular, for instance, this reflex can be slow and ineffective, resulting in light-headedness and even fainting if the patient stands up too quickly.

How does aspirin cause peptic ulcers?

Members of the non-steroidal anti-inflammatory group of drugs (NSAIDs) are amongst the most 'ulcerogenic' of medications. Why? As this post explains, the NSAIDs work by inhibiting cycloxygenase, an enzyme crucial to prostaglandin production. The connection with the stomach is that prostaglandins have at least three protective effects on the stomach lining:

• Prostaglandins stimulate mucus secretion to coat the stomach


• Prostaglandins cause the secretion of bicarbonate, a base that neutralises excess stomach acid.


• Prostaglandins cause vasodilatation, increasing blood flow the the stomach's mucosal layer and thereby ensuring its rapid healing.

It doesn't take a genius to notice that a sustained deficiency of prostaglandins (as occurs with NSAID use for more than a week or two) therefore predisposes you to peptic ulcers. If it is really necessary to give NSAIDs, some form of antacid medication must be given too (e.g. simply antacids, or even proton pump inhibitors).

Which has a greater affinity for oxygen: fetal or adult haemoglobin?

Recall that at the placenta, the mother's blood comes incredibly close to touching that of her baby - but never does. It passes so near, however, that for the purposes of this thought experiment, we can think of it all as one large pool of blood.

The mother's haemoglobin must obviously start out with the oxygen - only she is in a position to pluck it out the air via her lungs (the baby's lungs are filled with fluid!). Now how is this oxygen to get to the baby? If the baby's fetal haemoglobin had a lesser affinity for it than the mother's adult haemoglobin did, then not much oxygen would get across the placenta, would it?

No, fetal haemoglobin must bind oxygen more avidly than adult haemoglobin, so that it can strip oxygen off the mother's red blood cells, and carry it to the baby's own greedy body.

(Mothers take note: once again your cute little baby is sucking the life from your body. Parasite.)