Lysosomal Storage Diseases

From time to time, a differential diagnosis includes such conditions as "Gaucher's disease", or "mucopolysaccharidoses" - names that ring bells only by being familiarly unfamiliar. I thought I'd provide a bit of context to a whole group of weird conditions collective known as lysosomal storage diseases.

Our cells have organelles called lysosomes, which are fundamentally packets of up to 50 destructive enzymes that can be hurled at whatever needs degrading - be it an old cellular component or a foreign microorganism. From time to time, a person can inherit a defective gene for one of the enzymes, and the result is predictable: you can't break down that substance. As a result, the substance accumulates in various tissues, which it can damage. This is what is meant by "lysosomal storage disease", although "storage" seems a bit polite - the substance clogs up the works despite the body's best efforts.

Let's concentrate on one semi-famous example: Gaucher's disease. This is caused by a deficiency of an enzyme called glucocerebrosidase, which is an enzyme that lysozymes use to degrade a lipid called (funnily enough) glucocerebroside. As a result, this fatty substance accumulates in organs like the liver, spleen, bone marrow, brain and lungs - and hence the condition finds its way onto your lists of splenomegaly causes.

Lysosomal storage diseases can be subdivided into four large groups, which I'll mention just for completeness' sake. There is more than one condition under each heading, of course:

• Lipid storage diseases (e.g. Gaucher's disease)
• Mucopolysaccharidoses - this weird name indicates only an inability to break down one of the glycosaminoglycans
• Glycoprotein storage disorders
• Mucoliposes

Collectively, the lysosomal storage diseases fall under the umbrella term "metabolic disorders", alongside things like Wilson's disease, haemochromatosis and countless other disorders caused by aberrant metabolic processing of a bodily substance.

Apoptosis

In several of our posts, we’ve touched on apoptosis. This is often called “programmed cell death” to distinguish it from necrosis. If apoptosis is orderly suicide, necrosis is a violent and unnatural death in which, unlike apoptosis, the cell doesn’t intend to die.

Apoptosis might seem like an odd idea, but it is simply a realisation of the need to occasionally delete one’s own cells. This requirement crops up again and again:

• To delete excess tissue in embryogenesis (e.g. creating a gut lumen out of a solid tube).
• To kill cells infected by a virus or other microorganism.
• To kill neoplastic cells.
• To kill cells that are irreparably damaged.
• To kill self-reactive lymphocytes (thereby ensuring immune tolerance).
• Etc.

In these cases, the body prefers to kill the cells by the orderly process of apoptosis, which doesn’t incite a costly and potentially damaging immunological reaction, rather than the messy process of necrosis, which does. (It’ll resort to the latter if it has to, though.)

There are three main conceptual stages to apoptosis.

1. Signal integration

Our cells are must constantly decide between two conflicting orders: to apoptose, or not to apoptose, as Bill might have said. Of course, usually the decision is the latter, but if the “apoptose now!” signals are particularly strong, the relevant cells are forced to change their minds. Things can also work in the opposite direction: if a cell has strong enough “don’t apoptose, you idiot!” signals it can survive a bombardment of signals that would cause any normal cell to apoptose. This is one trick that many cancers use to avoid this fate.

The main pro-apoptosis signals are fourfold:

· Mitochondrial damage

· Severe DNA damage

· Severe cell membrane damage

· Direct signal transduction

The latter means that apoptosis can also be brought about when specific substances bind to specific cellular receptors. One that crops up a lot in immunology is the Fas-Fas ligand interaction. For instance, an activated cytotoxic T cell expresses the Fas ligand, allowing this ligand to bind to the target cell’s Fas receptor. This interaction signals the target cell to commence apoptosis. Similarly, if enough TNF binds to receptors on a particular cell, apoptosis may also be induced.

2. Executioner pathway activation

If the “apoptose now!” signals preponderate, the cell becomes committed to apoptosis. The chief set of actors here appear to be the caspases, specific proteases that become activated as part of the evocatively-named “executioner pathway”.

3. Degradation

The caspases set about dismantling the cell. Cell specialisations (like cilia) and intercellular junctions are amongst the first to go, and the cell volume starts shrinking. The chromatin condenses, and both the chromosomes and the nucleus itself are cleaved into fragments. There is also a change in the cell membrane’s phospholipid content (it becomes high in phosphaditylserine, for what it’s worth). Interestingly, unlike in necrosis, the cell’s organelles remain unmolested. Eventually the cell is fragmented into several small apoptotic bodies.

The phosphaditylserine of the apoptotic bodies acts as a marker for phagocytes, so that they are soon engulfed and more thoroughly degraded.

The system is really quite efficient – the whole process can be over in minutes, with virtually no disruption to surrounding tissues since apoptosis doesn’t elicit a proper inflammatory response.

This is pretty much the level I’m happy with knowing, personally. The full story, in all its profligate detail, is utterly pointless unless that’s your area of research. If you don’t want to take my word for it, click here to see the entire pathway, and you’ll see what I mean. Go on, I dare you…

How does sepsis cause jaundice?

The pathogenesis here is multifactorial, and so breaking it down systematically is probably best.

• Haemolysis - There are many ways by which sepsis can cause haemolysis of red blood cells. Otherwise normal red cells can be haemolysed directly by certain organisms (e.g. C. perfringens, or in malaria) or else they may cause an autoimmune haemolytic anaemia. Furthermore, the drugs used to treat sepsis may cause haemolysis by a number of mechanisms.  Lastly, any these processes are exacerbated by any underlying red cell abnormalities, the classic case being glucose-6-phosphate dehydrogenase deficiency.


• Hepatic dysfunction - This is the most important cause in the majority of cases. Largely as a result of inflammatory cytokines, a large variety of abnormalities of bilirubin processing occur.  These include decreased bilirubin uptake, deficient intrahepatic processing (due, amongst other things, to a combination of hepatic ischaemia and hepatocellular injury) and intrahepatic cholestasis. 


• Extrahepatic biliary obstruction - Ascending cholangitis is fairly rare but an immensely important cause of jaundice to exclude in the septic patient.  It classically presents with the triad of fever, jaundice and right upper quadrant pain and is due to infection of a blocked hepatic or common bile duct.  This can be due to a gallstone, for instance.

Apologies for the brevity of the explanations here.  The full picture is absolutely vast, and you can read about it here if you need more detailed explanations.

How are calcium oxalate stones formed?

By far the commonest type of renal calculus ("kidney stone") is a calcium oxalate stone. Calcium (Ca²⁺) is of course a positively charged 'metal' ion in solution, and it readily binds to oxalate, a substance usually obtained from the diet, that - conveniently - has two negative charges on its ion. Under the right conditions, the two go together like hand in glove, forming a precipitate that can enlarge as the process repeats itself and new calcium oxalate comes out of solution.

What are these right conditions, though? Well, dehydration certainly helps. We all know that you can dissolve two teaspoons of sugar into a full cup of tea without a problem, but this is quite a lot more challenging with only a quarter cup. Ultimately, there has to be enough stuff to dissolve the salt, and this is a problem with dehydration.

On the other hand, you may just be ending up with too much calcium and oxalate salt in the kidneys despite adequate hydration. This would be the equivalent of trying to dissolve a whole bag of sugar in your tea. For instance, many people simply have idiopathic hypercalciuria, a condition in which (for no apparent reason) they just excrete too much calcium into the urine. In addition, hyperparathyroidism can also cause a generalised increase in serum calcium levels, which is reflected in an increased amount of calcium in the urine too. Furthermore, a high sodium diet may also result in hypercalciuria.

And so on. Either way, there must be increased amounts of calcium oxalate in the urine, or else there must be decreased fluid in the urine. This is the recipe for stone formation.

Incidentally, it might be thought that a treatment for calcium oxalate stones would be to limit dietary calcium intake. Although on the face of it this makes intuitive sense, such action seems to have quite the opposite result: restricting calcium intake may result in more calcium oxalate stones. Why? Well, calcium is quite happy to bind to oxalate in the gut too, and doing so prevents either from being absorbed into the body in the first place. Decreasing your dietary calcium paradoxically means that more oxalate will be absorbed, thus threatening to cause the very renal calculi that you are trying to avoid.

How much radiation do you receive in an X-ray or a CT scan?

I've tried to cover this topic before, and I recited what one of the radiologists had told me, promising to check on the figures later. I have belatedly done so, and here are the results.

Background radiation (the low-level stuff that comes from outer space and the few naturally radiactive substaces on earth) is what all figures should be referred back to for comparison. We don't hide ourselves behind heavy lead aprons every day, and we are sensible not to. The average background radiation a person receives per year is 2.4 millisieverts per year. (That weird unit is a useful measure of the biological effect of radiation, rather than its physical effects, and so is more useful to use in answering this type of question.)

The humble X-ray is about 0.02 millisieverts, which is therefore equal to about 3 days worth of ambient radiation. Thus, apart from the slightly more contentious issue of irradiating pregnant women, you fundamentally have nothing to fear from X-rays.

CT scans are more difficult to quantify, since they vary quite a lot according to the size of the body area that is scanned, as well as how thin the 'slices' are. Nonetheless, CT scans typically are about 6-10 millisieverts. This is about 3-4 years worth of ambient radiation per scan, which is certainly more substantial than with X-rays. This suggests that it is worth doctors considering other diagnostic modalities that don't use ionizing radiation, although a single CT scan is still probably not worth worrying too much about, if the indication for it is valid.

Of course, everything has its risks. The most important thing is for the doctor to weigh up the (rather slight) risks of CT scans versus potentially not diagnosing the patient's condition timeously. Saving the patient from three years of background radiation won't earn you any plaudits if the patient is no longer around to enjoy them! Furthermore, although MRIs don't use ionizing radiation, they are more expensive, slower and not without their difficulties (especially around metalic objects!) compared with CT scans. Furthermore, CT scans are better at showing up certain types of pathologies. And although ultrasound scans are quick, cheap and radiation free they are simply not good enough imagers of many things to be a replacement more than some of the time.

The issue is impossible to resolve if we consider all cases as a whole. It is far better for each case to be individualised.

A novel way to look at cigarettes

Everyone, including every single smoker, knows that cigarettes are bad for you. But how bad? As usual, the real world defies our attempts to accurately capture its essence, and we often have to turn to tables and tables of data before getting any sort of answer.

At the end of last millennium, scientists in Britain took a different approach, and calculated the average amount that each cigarette shaves off your life. Their answer: 11 minutes.

Of course, such a round figure comes with a long list of caveats, since the figure "relies on averages, assumes the health effects of smoking are evenly spread throughout a smoker's lifetime and presupposes that the number of cigarettes smoked throughout a lifetime is constant."

But, it has the merit of being an in-your-face, striking statistic, as contrasted with the more common, easily-forgettable type. Along these lines, there's an online smoking calculator available that'll do the maths for you, and then morbidly tell you how much shorter you'll make your life should you continue, amongst other things. Another aspect of the calculator works out how much cigarettes are costing you, and comes up with surprisingly high figures!

Hat tip to AH for the heads up on the calculator

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).

Why is the liver so good at regeneration?

It's true. You can remove up to 75% of the organ, and it will regrow!

Once we reach adult form, our organs vary in their ability to regenerate, but in general they largely don't. The exceptions to this rule are instructive. Skin regenerates well, and the reason is obvious: it is exposed to constant wear-and-tear from brushes with the environment. The endothelium lining the gut also regenerates quickly, and again this is probably to cope with the wear-and-tear of food in transit.

And the liver? Well, its regenerative abilities might be for a similar reason. The liver is the chief 'detoxifier' of the body. Via the portal venous system of the gut, it is in direct contact with any toxins absorbed from our food, and via the hepatic arterial system toxins from the rest of the body hit the liver. The liver has a formidable array of chemicals to neutralise this threat, but inevitably it must frequently be damaged while doing so. And it is believed that its remarkable regenerative abilities are an adaptation to deal with such damage - the liver can recover completely even if the majority of it is destroyed.

Why don't all organs have this ability, though? We'll cover that in another post...

Preventing transplant rejection

In the previous post, we covered the types of rejection that we see in transplanted organs. Obviously, we try to prevent this from happening as far as possible. There are two main ways that we do this.

Firstly, since most of the rejection centres around HLA mismatching, HLA types should be matched so far as possible. The closer the match, the less likely (and less vigorous) the rejection is likely to be. Although HLA matching is definitely first choice, for some transplants (especially the heart and the liver), there is simply not enough time to do this, and so we have to make do.

The other method that is used to prevent rejection is immunosuppressive therapy. As its name suggests, this seeks to dampen the immune response in order to save the transplanted organ. A wide variety of substances are used, including steroids, cyclosporine, azathioprine, antilymphocyte globulins and monoclonal anti-T cell antibodies. Of course, immunosuppressive therapy has the obvious drawback of increasing the recipient's susceptibility to a vast array of microorganisms and cancers. Nonetheless, provided you do transplants judiciously, this risk will still prove less harmful than the lack of a working heart/kidneys/etc. would!

More subtle immunosuppressive techniques are always being investigated, because the ability to transplant organs is primarily limited not by surgical difficultly, but rather by transplant rejection. Of course, stem cells promise a way around this, but this is still a long way off, and another topic completely.

Source: Robbins Pathologic Basis of Disease (6th Edn.), Cotran, Kumar, Collins

How is transplant rejection classified?

Immunological rejection of transplanted organs is divided into three categories, based on how long it takes for the rejection to develop. In each case, the time frame reflects the underlying process.

In hyperacute rejection, the transplanted organ is attacked virtually immediately, so that it begins to fail within hours or even minutes. In some cases, the surgeon doing the transplant can even tell that the organ is being rejected before he closes up! It appears that acute rejection is mediated by preformed antibodies, especially those directed against any non-matching HLA molecules in the transplanted organ.

You may ask where these antibodies come from, since they are there before the organ is transplanted. There are several sources, including blood transfusions (platelets and white cells are a bountiful source of HLA molecules), pregnancy (fetal HLA molecules may enter the mother's circulation), or previous transplants. Whatever the source, these antibodies are directed against, and lodge in, the vessel wall of the transplanted organ. They then activate complement in massive amounts, which ultimately leads to both the direct and indirect destruction of tissue, including thrombosis of the organ's vessels.

Next up is acute rejection. This is largely due to a T-cell driven cell mediated immunity attack, due to HLA compatibility. Antibodies do play a secondary role too, however. Acute rejection typically occurs 10-30 days after transplantation, and is characterised by an infiltrate of lymphocytes and macrophages.

Chronic rejection occurs gradually, over months to years. It is unclear what causes chronic rejection, but it may simply be a less vigorous form of acute rejection, especially when much acute rejection these days is prevented by immunosuppressive therapy. In some cases, this immunosuppressive therapy may so limit the inflammatory response that effects are only seen after many months.

In the next post, we'll briefly mention the main ways that we try to prevent rejection.

What is a "paradoxical embolus"?

An embolus is a detached intravascular mass of some kind that is carried by the blood to some distal point, where it lodges. Over 99% of emboli come from thrombi, although rare causes include fat emboli (usually from broken bones), amniotic fluid emboli and air emboli.

When a deep vein thrombosis (DVT) forms, the major risk is that a piece of it breaks off and lodges somewhere in the pulmonary circulation. The pulmonary capillaries are so small that even red blood cells can't make it through with out outrageous contortions, and so for all intents and purposes, dangerous clots can go no further. Any emboli from a DVT will cause pulmonary problems, but they can't, for instance, lodge in the systemic arterial system.

Except that, very rarely, they do. But how? Such "paradoxical emboli" arise when a great coincidence occurs: the patient has a DVT and the patient has some cardiac lesion whereby the right side communicates with the left side. Usually, this is an atrial septal defect. In such a case, it is possible for a DVT's embolus to bypass the lung's capillary filters altogether and skip straight to the left heart. From there, it can go on its merry way and block off a part of the systemic circulation. How rude!

Which is worse for cells: hypoxia or ischaemia?

That's a really good question.

Hypoxia is inadequate oxygen supply at the cellular (or, better, mitochondrial) level. By contrast, ischaemia is a lack of blood supply to a cell/tissue/organ/etc. Let's assume, for simplicity, that patient A's cells are exposed to total hypoxia (i.e. anoxia - absolutely no oxygen), whereas patient B's cells are exposed to total ischaemia. Which is worse?

As it turns out, patient B is in considerably more trouble, all other things being equal.

Patient A suffers only hypoxia. Hypoxia is fundamentally detrimental to our cells because it forces them to metabolise anaerobically (in the absence of oxygen). Metabolising in this manner produces energy (ATP) much less efficiently than can be formed in the presence of oxygen, and energy is thus often not produced quickly enough to meet a cell's needs.

So patient A isn't sitting pretty either, but why is patient B even worse? Well, if you cut off blood flow to a cell, you obviously induce hypoxia there too, since the blood stream normally carries fresh oxygen to the tissues. However, you also cut off all nutrient supplies to the cell. Thus, unless it stores nutrients (e.g glycogen), a cell can't even undergo anaerobic metabolism for very long. Once the local nutrients like glucose are used up, the cell can't do anything more to produce ATP.

So, all other things being equal, ischaemia is worse than hypoxia for a cell, measure for measure.

What are the characteristic X-ray features of osteoarthritis?

This is a classic question, and a useful answer to memorise. The characteristic changes of osteoarthritis (OA) are:

• Narrowing of joint space - The 'space' between most joints that you can see on X-rays is due to the intervening cartilage not showing up. In OA, the progressive loss of cartilage thickness that occurs causes the joint space to appear narrowed.


• Subchondral sclerosis - probably as a compensatory reaction to the increased stresses transmitted to the more exposed bone, the bone under the defective cartilage becomes thicker and harder (i.e. sclerotic)


• Subchondral cyst formation - The traumatised bone underlying the affected cartilage sometimes displays areas of cystic degeneration, forming fluid-filled 'sacs'.
  


• Osteophyte formation - As the disease progresses, cartilage in the peripheral unstressed areas proliferates and ossifies. The resultant bony outgrowths are called osteophytes, and it is believed that they function to improve the joint space congruence. This interpretation is controversial, however, and the osteophytes are often a major cause of pain.

The image below (of the knee joint) shows all the above apart from cyst formation. The black arrows point to subchondral sclerosis, the white arrow points to a small osteophyte and the black arrowheads indicate the joint space narrowing. The image is from the Atlas of Radiological Images, contained in the "Harrison's e supplement".

There's also a nice diagram of the changes here.

What types of fractures are there?

That's a useful question. There are a number of different things you can say about a fracture, and these include:

• Closed (i.e. simple) or open (i.e. compound). If the skin overlying the fracture is intact, the fracture is 'closed', whereas if it is breached then the fracture is called 'open'.



• A complete fracture occurs when the fracture cuts right through the bone - the periosteum on both sides is severed. Complete fractures can be further classified as being transverse, oblique, linear or spiral. These terms refer to the direction of a complete fracture relative to the long axis of the bone. They are pretty self-explanatory.



• An incomplete fracture occurs when a fracture only goes part of the way through the bone. A more succinct way of saying this is to state that the periosteum on at least one side remains intact. Incomplete fractures can be subdivided: A greenstick fracture occurs when the bone is bent or buckled but the fracture is incomplete - this is common in children. A stress fracture is a small crack in a bone's cortex due to repetitive strain on it. A compression fracture is a fracture of cancellous bone, and is commonly seen in vertebral bodies.



• A comminuted fracture is one in which there are more than two fragments of bone.



• A pathological fracture is a fracture that occurs through abnormal bone. Examples of processes causing abnormal bone include osteoporosis, Paget's disease and bone tumours.

You can see a nice picture of many of the above examples here.

How do leukocytes get from the blood into inflamed tissue?

This question deals with what is sometimes known as the leukocyte extravasation. It is classically divided into discrete steps, but there is little consensus on what these steps are! The version I favour is below...


1. Rolling

When a tissue is inflamed, the endothelium of its blood vessels (usually that of the post-capillary venules, where shear forces are least) expresses certain proteins on their surace called selectins. These selectins (principally P-selectin initially) bind with loose affinity to ligands on leukocytes. (For instance, P-selectin binds to PSGL-1 on leukocytes.) Since this affinity is loose, it has the effect of slowing the leukocytes down, and they now roll stutteringly along the endothelium.

How does the endothelium know to express its selectins? Resident macrophages in the tissue that happen to encounter a pathogen (or damaged tissue) secrete various cytokines in response. Some of these (e.g. IL-1 and TNFα) cause the surrounding blood vessel endothelium to express their selectins.


2. Activation

Now that the leukocyte is stumbling along the wall at a slower pace than before, it has the time to receive messages (via other cytokines) from the inflamed tissue and its endothelium. Rather than simply hope the right cytokines meet the right cell, the relevant cytokines are usually presented to the leukocyte. These cytokines usually have two binding sites, one for the leukocyte (obviously) but also one that attaches it (indirectly) to the endothelium. (For instance, a common case is for the cytokine to be attached to the heparin sulphate part of an endothelial proteoglycan.) Thus, the cytokines are ready and waiting, tethered to the endothelium, for the right leukocyte to pass by.


3. (Tight) Adhesion

Why is it important for the leukocyte to be activated? Well, part of the answer lies in what it does in response. Leukocytes (and other cells) have proteins known as integrins on their surfaces. Though they bind to many things, in the context of the present discussion their aim is ultimately to bind to complementary receptors on the endothelium. The problem is that the leukocyte's integrins are in a poor-affinity state, and so they don't bind well at all. Activation of the leukocyte, however, causes them to undergo a dramatic change in shape and thus switch to a high-affinity state. With this new-found superadhesiveness, the integrins bind to receptors belonging to the immunoglobulin superfamily. Examples of the latter include intercellular cellular adhesion molecules-1 and -2 (ICAM-1 and ICAM-2) and vascular cell adhesion molecule-1 (VCAM-1). ICAM seems most involved in this step.

The result of his strong binding is to cause the rolling leukocyte to come to a complete stop on the endothelium. It is now ready for its last step.


4. Transmigration and chemotaxis

Further cytokine-based signalling cause the leukocyte to change its shape. Starting with its leading edge, it becomes flattened and much thinner, and it works with proteins on the endothelium to basically get pulled through the spaces between endothelial cells. Its final barrier is the vascular basement membrane. There is no fancy, subtle trick to bypassing this stumbling block - the leukocyte simply secretes proteases that punch a hole the basement membrane!

It is now truly within the affected tissue, and homes into its target by means of chemotactic signals. This means that, like a blood hound, it detects the direction from which certain (inflammatory) chemicals are coming from, and moves towards them.

And thus, via a number of clever steps, the leukocyte has moved from the blood stream to the exact site of injury or infection. It really is rather clever.

There's a nice Flash animation of the process to be found here.

What are the 5 stages of fracture healing?

In order for bones to heal after a fracture, it's necessary for the two (or more) parts to remain as stationary as possible. Significant movement between them seems to disrupt the healing process. Long before orthopaedic surgeons were around to insert pins and nails (etc.!), nature had her own way of ensuring fracture stability - it forms a bony splint around the fracture, called a callus.

But we're ahead of ourselves. There are five phase of fracture healing:

• Haematoma formation - almost inevitably, the forces that broke the bone also break blood vessels. As a result, the break becomes surrounded by a haematoma.
  


• Granulation tissue formation - within hours of the fracture, the haematoma begins to be reabsorbed and it is simultaneously replaced by an inflammatory infiltrate. With time, this acute inflammatory infiltrate develops into a chronic one, with fibroblasts and small new vessel formation. In addition, the cells under the periosteum and medulla proliferate.


• Callus formation - the predominant cell population changes to osteoblasts (which lay down new bone) and osteoclasts (which reabsorb old bone). The resulting cellular tissue, with enlarging islands of new bone, is called a callus.


• Consolidation - the bone laid down quickly in the callus is called woven bone, but in the consolidation stage it is replaced by the stronger lamellar bone. This process may take months.


• Remodelling - the healed bone's lamellae align themselves predominantly in the direction of the forces acting on the bone, and excessive bits of bone are reabsorbed.

There is a nice picture of the stages here.

This whole process takes an average of 6-8 weeks for upper limb fractures and 12-16 weeks for lower limb fractures, but there is a lot of variation in these figures. The biggest factor determining healing time is age - children heal much quicker (and much better) than adults.

Why is the liver such a common site for cancer metastasis?

Recall that most cancers spread haematogenously (i.e. via the blood stream); even the epithelial cancers that predominantly spread via the lymphatics can do so on occasion. Once you understand this, then it seems logical that the organs that receive the majority of the heart's blood tend to attract the majority of metastases (all things being equal).

The liver gets around 25% of the total cardiac output, via not one, but two sources:

• Arterial supply from the hepatic artery
• Venous supply from the portal vein

The latter drains blood from the gut, pancreas and spleen, and the former sends a whole chunk of the the blood from anywhere heading towards the liver.

The same factor is believed to be equally important in understanding why the lungs and brain are frequently afflicted by metastasis. Obviously, what makes a site ripe for metastasis isn't only the percentage of the cardiac output that passes through it, but it is certainly an important factor.

What is the pathogenesis of ascites in cirrhosis?

In advance: I'm aiming for medical students with this one, so apologies for assuming a certain level of terminology and understanding!

Recall that fluid filtration across capillary membranes is governed by Starling forces. Conceive of a system consisting blood in the capillaries, fluid in the interstitium, and a capillary wall that is capable of allowing a filtration of water in either direction. The forces tending towards pushing fluid out of the capillary - and thus making (interstitial) oedema - are the capillary hydrostatic pressure and the interstitial oncotic pressure. And the forces pulling water back into the capillary are of the interstitial hydrostatic pressure and the capillary oncotic pressure.

Which way the fluid will flow will depend on which set of forces is the stronger. Clearly, in ascites formation, the forces tending to push fluid out of the capillaries must be winning - either because the 'outward' forces are stronger than usual, or because the 'inward' forces are weaker than usual. I've found this a really good schema by which to think of the problem, since this works for pleural effusions, pedal oedema, and many other causes of fluid 'overload'.

In ascites, there are actually three mechanisms underlying the disturbance of the above forces.

• Most obviously, the deranged liver architecture, characteristic of cirrhosis, partially obstructs the normal blood flow of the gut's portal venous system. This leads to portal hypertension (an increase in pressure in these veins). This increases the hydrostatic pressure in these veins, which tends towards local oedema formation (ascites).
• Then, there is a decreased serum albumin concentration. Normally, the liver is responsible for manufacturing enough albumin for the serum. Obviously, if the liver is failing, this function is often compromised. This leads to decreased capillary osmotic pressure.
• Finally, there is salt and water retention in cirrhosis, secondary to increased aldosterone secretion. The immediate cause for this hyperaldosteronism seems to be decreased renal perfusion, but the cause of this is a little unclear. It may simply be due to decreased intravascular volume from the above two causes. But there is increasing evidence arguing that portal hypertension somehow stimulates nitric oxide (NO) release. NO is a vasodilator, and the arterial dilation that ensues leads to relative (rather than absolute) arterial underfilling. This will of course lead to renal underperfusion, thus activating the renin-angiotensin system. Anyway, whatever the cause of the hyperaldosteronism, the result is increased capillary osmotic pressure.

So the net effect is an increased capillary hydrostatic pressure and a decreased capillary oncotic pressure. These are just the requirements for oedema to form. Obviously, the second and third mechanisms are in operation everywhere, which accounts for oedema formation in places other than the abdomen (e.g. pedal oedema). But all three mechanisms are firing in the portal venous system. This is why ascites is so much more common in liver cirrhosis than in other cases of fluid overload, like cardiac failure or nephrotic syndrome. In fact, cirrhosis accounts for about 75% of ascites cases.

Hope that helps!

How do cancers cause hypercalcaemia?

Two causes dominate the differential diagnosis of hypercalcaemia - primary hyperparathyroidism and cancer. Together they account for the raised calcium in around 90% of cases. The mechanism behind this in primary hyperparathyroidism may seem obvious enough, but what about in cancers?

One's initial reaction might be to blame it on the cancer eroding into bone, thereby releasing calcium. Actually, this is only of minor importance. The bulk of the hypercalcaemia is caused by humoral factors released by the tumour.

First up, and most common, is the awkwardly named parathyroid hormone related protein (PTHrP). Despite its title, it is actually produced by many cell types physiologically, acting at a local level (paracrine) and regulating such things as tooth development and cartilage growth. However, in many cancers it is overproduced and it spills out into the bloodstream. Unfortunately, one end of this protein is identical to its legitimate namesake (parathyroid hormone). The result: PTHrP binds to PTH's receptors, and the body dutifully raises the serum calcium.

In many haematogical malignancies (such as multiple myeloma, the lymphomas and the leukaemias) another method is prevalent, however. These tumours have a penchant to secrete a variety of substances that act on osteoclasts to increase bone resorption (and hence calcium 'liberation' into the blood stream). Together, these substances are called osteoclast activating factors, and they include such famous cytokines as IL-1, IL-6 and TNF-α. (Multiple myeloma is famous for 'punched out' lesions on bone X-rays, and osteoclast activating factors account for them).

These are the two main mechanisms behind cancer's hypercalcaemia. There are numerous other rarer ones, though, but we needn't trouble ourselves with them for now!

Is a scar stronger than normal skin?

Contrary to popular belief, a scar isn't as strong as normal skin.

I quote from the source below:

"When sutures are removed, usually at the end of the first week, wound strength is approximately 10% of the strength of unwounded skin, but it increases rapidly over the next 4 weeks. This rate of increase then slows at approximately the third month after the original incision and then reaches a plateau at about 70 to 80% of the tensile strength of unwounded skin, which may persist for life."

Although there is more collagen than before, the collagen isn't so efficiently structured, and the skin's elastin fibres are not regenerated at all. The reason that the scar's tensile strength increases over the first few months is due to changes in the collagen there: there's increased its synthesis, an increase in its fibre size and intricate crosslinking of these fibres.

Source: Robbins Pathologic Basis of Disease - 6th edn., Kotran et al.