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.

Complement deficiencies

For some reason, many students react as if learning about complement deficiencies were anathema.  However, if you understand the preceding two posts, you'll understand why particular inherited deficiencies of complement components have the clinical effects that they do.

For instance, deficiencies of C3, factor H or Factor I result in recurrent pyogenic (bacterial) infections, which is consistent with C3's role in opsonisation.

Furthermore, you'd assume that deficiencies of the 'final pathway' components C5 to C8 would lead to less lysis of microrganisms, and you'd be correct.  A weird thing though: it seems as though your susceptibility to Neiserria (meningitidis or gonorrhoea) is particularly increased. Another weird thing: a the lack of C9 seems not to be clinically relevant. 

Lastly, defects of the classical pathway components (C1, C2, C4) result in a predisposition to develop 'immune complex' disorders like SLE.  This is consistent with the classical pathway's role in clearing immune complexes.

There!  See, not so bad?  That's most of it, anyway...

Why do you get polyuria in diabetes?

Polyuria (excessive volume of urine production) is common in uncontrolled diabetes. Under normal conditions the kidney can't help filtering some of the glucose in our blood stream. To urinate that out would be an unforgivable waste, and thankfully the kidney usually reabsorbs all the filtered glucose back into the bloodstream.

Usually, that is. If the glucose level in the blood is too high, its capacity for reabsorption of gluocse is exceeded, and some of the glucose is lost in the urine. (Actually, this may be a good thing, since it helps to lower the blood glucose level if the latter is pathologically high.) The rough threshold for this in a (non-pregnant) person is about 10 mmol of glucose per litre. More than this, and some will end up in your urine.

But why does more glucose in your urine lead to more urine being produced? The answer is that glucose is a powerful osmolyte. Like a handful of other substances (sodium, urea, mannitol, etc.) it has the ability to induce water to follow it, by osmosis, wherever it goes. And since there is more glucose than normal in the urine, there will also therefore be more water than usual in the urine - i.e. polyuria.

[In fact, most of the acute complications of diabetes (e.g. diabetic ketoacidosis, or hyperosmolar coma) are largely due to the hyperosmolarity of the blood, secondary to high blood glucose levels. This induces water to leave cells, including those in the brain, which is the usual cause of death in these patients.]

Largely, this whole debacle accounts for the three classic symptoms of uncontrolled diabetes:

• polyuria
• polydypsia (excessive ingestion of water, to make up for the extra water lost in the urine), and
• polyphagia (excessive eating, to make up for the calories you keep urinating away).

Why do you get nocturia in cardiac failure?

Nocturia is the name for needing to urinate excessively at night. It is one of the less obvious clinical features of cardiac failure (it has other causes too, though), and I find that unless you specifically ask your patients about it, they seldom volunteer the information.

The reason that it occurs in the context of cardiac failure is simple. In this condition, by definition, the heart isn't able to adequately perfuse the tissues, and those tissues include the kidneys. At night, however, such patients are obviously (like the rest of us) lying down. With the entire body flat, fluid that has pooled in the extremities during the day finds it easier to return to the heart, and consequently the cardiac output at night in these patients is slightly increased. All this means that the kidneys can filter more blood, but at the expense of making more urine - all at night.

How is it possible to have a "silent" myocardial infarction?

The term "silent myocardial infarction" refers to a painless (or almost painless) heart attack, as opposed to the classic extreme central chest 'heaviness'. It is actually frighteningly common: as much as 25% of myocardial infarctions (MIs) may be 'silent'. This is why you should do an E.C.G. (E.K.G.) and pull blood for cardiac markers if you are even slightly concerned about an MI.

'Silent' MIs are typically found in three groups of patients: the elderly, diabetics, and heart transplant patients. In the latter case, it is easy to discern the pathogenesis: the nerves from the donor's heart are simply never properly connected to the recipient. However, in the case of the elderly or diabetics, the pathogenesis is controversial. One influential theory favours an autonomic neuropathy secondary to diabetes, although other authors even contend that the difference is a statistical artifact - there are more heart attacks in diabetes anyway, so there are more 'silent' MIs too, without there being an increased incidence of them.

I'll leave you with a case that I saw today. A 58 year old diabetic and hypertensive woman developed sudden shortness of breath, and on examination wheezes were prevalent bilaterally. Had she been a chronic smoker, I may have put this down to a COPD exacerbation, but she hadn't so much as touched a cigarette in her life, and nor did she have a history of asthma. There were no overt signs of cardiac failure, but both the ECG and troponin-T revealed her to have had an MI. The wheezes were evidently from mild left-sided cardiac failure, secondary to her MI. Makes you think, doesn't it?

What do antibiotics do for acne?

To understand why tetracycline antibiotics (note: not just any antibiotic) work in acne, we need to review acne's pathogenesis.

The problem all begins when our skin's pores get blocked. Contrary to popular belief, this has nothing to do with 'being dirty' - washing your face with soap and water won't help prevent acne. Rather, the pores get plugged with skin cells (keratinocytes), which fail to slough off properly in this condition. As you can see from the picture on the right, the skin 'pores' are where the hair follicles exit. Each one has its own sebaceous gland, which is the white ball sticking out to the side of each follicle. These glands produce sebum, an oily substance that lubricates the skin.

The plugged pores, together with sebum as a food source, provide a nice safe haven for the overgrowth of a normal skin commensal (the bacterium Priopionibacterium acnes) to take place within the structure. The body senses this proliferation of bacteria, and sends in its arsenal of neutrophils, which creates pus out of the whole mess. Furthermore, the follicle wall takes 'friendly fire' from the neutrophils' destructive enzymes, which can eventually lead to the structure bursting. The debris, now in the (deeper) dermis layer of the skin, only attracts more immune system attention, resulting in more inflammation. Thus, we progress from a blocked follicle to a pustule with inflammed surrounding skin.

Did that all make sense? One thing you can't fail to notice is that a certain bacterium - P. acnes - has a lot to answer for. And this is exactly why certain antibiotics can improve acne symptoms. With the troublesome bacterium out the way, the skin is not nearly so badly affected. (Of course, there are other treatments on offer as well.)

What is atopy?

Atopy is a genetically-determined predisposition to develop localised allergic reactions to inhaled or ingested allergens. Let's break that down.

1. A genetically-determined predisposition - About 50% of atopic individuals have a family member that also suffers from atopy. Without a family history, the childhood incidence of atopy is about 12.5%, but this climbs to 20% if one parent is atopic, 45% if both parents are atopic, and 30% if one sibling is atopic. If both parents are atopic and they suffer from the same specific manifestation (e.g. asthma, or allergic eczema) then the unfortunate child has over a 70% chance of developing atopy.


2. Localised - Common allergic conditions include certain forms of asthma, eczema, rhinitis (hay fever) and conjunctivitis. However, allergies can cause many other diseases, and not all causes of these conditions are due to allergies. For instance, conjunctivitis may be caused by viruses or bacteria too.


3. Allergic reactions - Note that the conditions are necessarily allergic; that is, they are primarily mediated by IgE antibodies directed at the particular allergen. Not all allergies occur in atopic people, though. It is possible to have an allergic drug reaction, for example, without being an atopic individual.

How does asthma cause a pneumothorax?

Firstly, we should remind ourselves that asthma very seldom causes a pneumothorax. Nonetheless, it is a (rare) recognised complication. How does it happen?

Asthma is an obstructive lung disease. By this I mean that the primary abnormality is that less air can be breathed out than normal. Therefore at the end of a full expiration, there is a greater 'residual volume' of air in the lungs than usual.

Compounding the problem of increased amounts of 'useless' air stuck in the lungs, asthmatic patients will tend to forcefully exhale as well as cough excessively, the latter in particular dramatically increasing the force exerted on the lungs.

Normally this force quickly forces most of the air out of the lungs, but in an asthmatic, the air can't escape as easily or as fully as before. The increased force may therefore cause part of the lung to 'burst' and communicate with the pleural space. This causes a pneumothorax.

It's a little like squeezing the air our of a balloon. If you allow the air to escape normally, the balloon simply deflates. However, if you gradually close off the balloon's outlet, you increase the odds of it bursting.

Do you always detect a leg DVT in the case of a pulmonary embolism?

Nope, but you usually do. Actually, I can do better than this: the figure is about 80%. Furthermore, if you don't detect a DVT in the legs, it is likely that this is only because the DVT is now sitting in the lungs!

While we're on the topic, let's throw a few more figures around carelessly:

• More than 95% of pulmonary thromboemboli originate from thrombi in the popliteal, femoral or ileal veins (although they have commonly propagated to there from the calf veins).
• DVTs arising below the popliteal veins that don't extend proximally are surprisingly not a risk factor for pulmonary emboli.
• Pulmonary embolism occurs in about half of patients with proximal (i.e. popliteal vein or above) DVTs.

How is coeliac disease diagnosed?

Coeliac disease goes by many names, including celiac disease, non-tropical sprue, and gluten-sensitive enteropathy. It is fundamentally an autoimmune disease of the small intestine that can develop at almost any time in our lives. The problem comes when susceptible people are exposed to a particular protein (gliadin) found in the gluten of wheat, barley and rye. This protein, in its modified form, goads the immune system into destructive action, but because the immune system is stupid, it also attacks the small bowel in the process. The clinical results vary, but include a chronic diarrhoea, bloating and abdominal cramps, weight loss and fatigue.

So, how do we diagnose coeliac disease? Well, the gold standard method would simply be to take a piece of the small intestine out and give it to the pathologists. This would be accomplished by means of endoscopy. Coeliac disease generates a particular histological picture, with villous atrophy, crypt cell hyperplasia and a lymphocytic infiltrate. Although highly suggestive, this profile is not unique to coeliac disease, but what really clinches the diagnosis is if this pathological histological picture resolves once the patient stops eating any gluten.

OK, that's all very well, of course, but sending every person with bloating for an endoscopy is a bit silly. Fortunately, there are also several serological tests that one can do, with excellent sensitivity and specificity. All of these blood tests measure an IgA antibody to a particular small bowel antigen, and include antigliadin, antiendomysial and anti-tissue transglutaminase. (Tissue glutaminase is the enzyme responsible for modifiying the gliadin in the intestine.) These antibodies, if present, should also resolve on elimination of gluten from the patient's diet.

So the bottom line is this: on history or examination, you can usually only get as far as to say that you might be dealing with gluten enteropathy. If this is the case, the usual next step is to do the blood tests. Should they come back positive, an endoscopic biopsy of the duodenum is warranted. Both of the latter two pathological indicators should resolve on a gluten-free diet in order to clinch the diagnosis.

What proportion of all strokes are ischaemic vs haemorrhagic?

As you correctly point out, strokes may be caused by two general mechanisms, both fortunately described by their names.

Ischaemic strokes are caused by arterial occlusion (e.g. by an embolus or a ruptured plaque which thromboses up).

Haemorrhagic strokes are caused by ruptured vessels. Leaking blood can compress and injure surrounding tissues, and can also cause a lack of blood to its usual supply areas downstream.

To answer your question then, ischaemic strokes in Western societies account for about 80% of all strokes, with haemorrhagic strokes making up the remainder.

This distinction is important, since if patients with ischaemic strokes can get intravenous thrombolysis within three hours (e.g. with the 'clot-buster' called recombinant tissue plasminogen activator), they tend to have a better outcome, provided there are no contraindications to this treatment. On the other hand, giving thrombolytic therapy to a patient with a haemorrhagic stroke could obviously kill them!

Although there are a few clinical guides to distinguishing which type of stroke the patient is having, they are unreliable, and the patient will need either a CT scan or an MRI to tell which type of stroke it is.

What is the hepatorenal syndrome?

The hepatorenal syndrome occurs in up to 10% of advanced cases of liver cirrhosis with ascites, and is characterised by renal failure due to severe vasoconstriction of the renal circulation. As you know, in liver failure there is underfilling of the arterial circulation from a combination of splanchnic vasodilatation and hypoalbuminaemia. The body attempts to compensate by retaining sodium and water at the kidneys, and by constricting its arterioles generally.

Unfortunately, the delicate kidneys suffer greatly from this vasoconstriction of their circulation, and end up exhibiting signs of failure. Hepatorenal syndrome may be further divided up into two types based on the pattern of decline. In type 1, there is rapid deterioration - if an initial serum creatinine is over 2.5 mg/dl (221 µmol/l), this figure will double within two weeks. These patients have a median survival of less than one month without therapy. Type 2 is slightly more benign, with its decline progressing more slowly than in type 1.

Treatment usually centres around vasoconstrictor drugs, in combination with albumin (although other modalities, like transjugular intrahepatic portosystemic shunts, have been tried too). Vasoconstrictor plus albumin treatment is effective in two thirds of these patients. It might seem a little odd to be treating with vasoconstrictors, seeing as I defined hepatorenal syndrome as being due to vasoconstriction! However, the primary haemodynamic problem in cirrhosis is the splanchnic vasodilatation (more on this here) - it's this vasodilatation that causes the compensatory systemic vasoconstriction that causes the hepatorenal syndrome in turn. Giving the body a little help with vasoconstrictors and albumin actually causes a net increase in renal perfusion, and thus helps resolve the hepatorenal syndrome.

The recommendation at present is to try the above therapy for 5-15 days, until the serum creatinine concentration drops to below 1.5 mg/dl (about 133 µmol/l). Recurrence of this syndrome is rare after this regimen, and patients who respond to it tend to live longer.

Main source: Gines P, Cardenas A, Arroyo V, Rodes J. Management of Cirrhosis and Ascites. NEJM 2004;350;1646-54

Can anger or exercise ever precipitate a heart attack?

Yes. Heart attacks (myocardial infarctions) are almost always believed to occur when an atheromatous plaque ruptures. The exposure of this material to the blood stream triggers the coagulation cascade, and the resulting thrombus occludes one of the coronary vessels. The tissue that depended on this vessel for perfusion will therefore soon die (if the thrombus is not removed or degraded), and the result is a heart attack.

Exactly what causes the atheromatous plaque to rupture is a matter of intense research at the moment - after all, it may have been sitting there fairly benignly for a decade or two. One of the logical candidates would be the flow rate through the coronary vessels. The faster blood rushes around the bends of these vessels, the more likely the blood is to tear off a bit of the plaque (technically, this would be due to increased "shear stress" on the atheromas).

During strenuous exercise or heightened emotional states (like anger and, sadly, sex) the heart is asked (by the sympathetic nervous system) to pump faster and more strongly. In order to facilitate this, the coronary vessels dilate to allow more blood through per second - with the intention that this blood will provide extra energy for the heart's increased demands. Unfortunately, very rarely this has the undesired effect of rupturing an atheromatous plaque that a patient might have, and thus potentially precipitating a heart attack.

One final thing: this does not mean that exercise is bad for you! Even if you do have coronary artery plaques, mild-moderate exercise will reduce your risk of having a heart attack. It lowers your blood pressure, it lowers your weight and it even directly lowers your risk of a myocardial infarction. Just take it easy and don't strain your body too much - intense exercise is the worry here.

Hashimoto's Thyroiditis

Hashimoto's thyroiditis is one of the commonest causes of hypothyroidism in adults. It is an autoimmune disease where, for reasons that are still partially unclear, the body fires its arsenal at its own thyroid gland. The symptoms are largely those of hypothyroidism of any cause (e.g. fatigue, weight gain, bradycardia, slow-relaxing reflexes, etc.). Treatment is by replacement of T4 (levothyroxine), one of the two hormones produced by the thyroid gland.

Andrew Louis has asked a few questions about the disease which we'll go into one by one.

1. Why do we assess the success or failure of the treatment by measuring TSH levels? Why not T3 or T4?

With Hashimoto's thyroiditis, one has some residual thyroid function, just not enough to produce sufficient quantities of T4 and T3, which are therefore low. The level of TSH (which orders the thyroid to produce T4 and T3) will be higher than normal, which is fundamentally analogous to the body screaming at the thyroid to produce more hormones. This screaming does work a bit, as it forces what remains of the thyroid gland to work harder and make more of the thyroid hormones.

If you replace T4 a little, but not completely, you may end up with normal T4 levels - but only because the pituitary, via TSH, is still forcing the functional parts of the gland to work harder than normal. Only when T4 has been completely replaced will this screaming match stop, and the TSH will return to normal.

This is why TSH is a better measure of the success, or failure, of our treatment than T4.


2. Do patients benefit from T3 replacement?

In theory, giving T4 alone should be enough, since the body naturally converts some T4 to the more potent T3. However, some studies suggest that patients report feeling better, symptomatically, when given T3 together with their T4. More studies are needed on this at present, but it might be worth a try in some patients. However, taking T3 alone is not recommended, because T3 has a much shorter half-life than T4. This means that T3 would have to be taken 3-4 times per day and you would have to cope with levels of T3 that would fluctuate quite a lot (which can cause odd symptoms).


3. Can patients with Hashimoto's thyroiditis have normal TSHs and yet be symptomatic?

No, not for all intents and purposes. Autoimmune destruction of the gland will reduce its output of T4 and T3. This should stimulate the pituitary to produce more TSH than normal, as a way of signalling to the (remaining) thyroid to up its production levels.

However, it is possible to suffer from hypothyroidism despite normal TSH levels, although this is rare. It involves some sort of anterior pituitary pathology, whereby this gland is unable to produce enough TSH for that patient, even though the TSH is still within population norms. T4 will be low in this case, providing for an easy measurement. This is not, however, Hashimoto's thyroiditis.


4. Is there a benefit between the synthetic and the natural preparations of thyroid replacement hormones?

'Natural' preparations are made from the thyroid tissues of other animals. However, they are not recommended, as the quantity and potency of the thyroid hormones can vary greatly between batches. Anyway, 'synthetic' levothyroxine is identical to thyroxine, which is the natural version of this hormone made by your own thyroid gland.


5. Since Hashimoto's disease is chronic, why have a a lifetime of monitoring and dose changes? Why not simply remove the thyroid all together?

Alas, removing the gland wouldn't avoid a lifetime of monitoring and potential dose changes. In fact, a treatment for many cases of hyperthyroidism involves removing the gland (either surgically or with radioactive iodine), thus rendering these patients hypothyroid as a consequence. And as with Hashimoto's thyroiditis, such people also need lifelong monitoring to get their thyroid hormone levels right. However, once they are stable, levels only need checking annually, or even less frequently.

Removing the gland also has several disadvantages. For one, no surgical procedure is without risk, especially when operating in the dangerous neck area. Furthermore, since there is some functional thyroid tissue remaining, it is best to leave it in place. The reason that the average person doesn't need to measure their thyroid hormone levels annually is because the body will naturally adjust its levels to match the demands of the time. As much as possible, this function should be left intact, even if it needs a little artificial supplementation. Removing the thyroid in its entirety would make the levels even harder to control.


6. How do the adrenal glands (and cortisol) relate?

Usually they don't really. However, Hashimoto's thyroiditis is associated with other autoimmune diseases in a minority of cases. One of these is Addison's disease, which is chronic insufficiency of the adrenal cortex. (It has many causes; this is just one of them.) This would result in low cortisol levels (but there are many other causes of this biochemical phenomenon too!).


7. I hear there are advances on the way to cure auto-immune disease. Do you know anything about this?

Auto-immune diseases can be treated by:

• Ignoring their cause and simply treating the symptoms - this is done in auto-immune thyroiditis and diabetes mellitus type 1, for instance. If you can get away with it safely, this is actually the best option.
• Trying to suppress the immune system in general - this rather drastic approach is reserved as a last resort against debilitating illnesses, but its place is well-established if used judiciously.
• Trying to modulate the immune system subtly - this newer approach is more promising, but amazingly difficult to get right. It can be done pharmacologically, or, even more recently, via gene therapy.

However, I'm not aware of any established and proven treatment options apart from replacing the missing thyroid hormones pharmacologically. The rest is either nonsense (as in some 'alternative' naturopathic remedies) or still being studied. However, I'm not an endocrinologist, so if you've heard of anything new, let me know and I'll look into it. :)

Is it easy to reduce our dietary intakes of salt?

The sodium part of table salt (NaCl) has consistently been implicated as a factor in the pathogenesis of essential hypertension, and a reduced salt intake is reliably shown to reduce blood pressure in people suffering from mild to moderate hypertension.

The required intake of sodium per day is around 25 mmol, a typical western diet contains around six times that figure (and many eastern diets contain even more sodium). Thus, since excessive sodium can cause or aggravate hypertension, and since we definitely consume too much of it, it seems reasonable to make an effort to limit the amount of sodium we consume each day.

If you speak to your doctor about reducing your salt intake, he or she will probably advise you to refrain from adding salt to your meals - either during the cooking process or just before eating it. This is good advice, and the downside is rather negligible. After initially missing the salty taste, people's palates soon readjust and they often even report noticing the other flavours more than before.

But that's the easy part. Unfortunately, the salt that we add to our food only constitutes (by one study's reckoning) about 15% of the daily sodium intake. Where does the rest come from? From a variety of sources, but the number one culprit, by far, is... (drum roll)

... the sodium added to food during its processing. This goliath of the salt world accounts for almost 60% of the sodium passing by our lips each day. For instance, the bread that you buy at supermarkets has almost 200 times the amount of salt in it than the wheat from which it is made.

What this means is that if you are keen to reduce the salt in your diet, you actively need to start reading the nutritional labels on food packaging. Simply shunning things that taste salty isn't good enough, because that taste is often masked by sugars and other seasonings. A case in point: cereals contain much more salt than salty peanuts, yet in the former instance the other flavours hide any salty sensations, whereas in the latter case the salt is unmasked and entirely on the outside, making it easy to be detected.

In my opinion though, these efforts are worth it. If successful, they can allow you to take fewer medications, and at lower doses, and in mild cases of hypertension, reducing your blood pressure in this fashion can obviate the need for any medication at all.

What is non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is a fairly recently-recognised entity that incorporates a range of liver disease all characterised by a fatty liver not caused by alcohol.

It can be subdivided into three elements. In each case, there can be progression to the next stage, but most people don't progress there. The stages are:

• Steatosis (fatty liver) - simple fat accumulation within the hepatocytes (note, not the adipocytes). It is generally believed to be a harmless condition.


• Non-alcoholic steatohepatitis (NASH) - fatty accumulation as above plus associated surrounding inflammation and hepatocyte necrosis. Eventually, this process can progress to include fibrosis, which leads smoothly towards...


• Cirrhosis - obviously not limited to the NAFLD spectrum (it can be caused, and far more commonly is, by other things), but a definite potential outcome of long-standing NASH.

It is ultimately unclear what causes NAFLD. From what I can gather, the number one cause is insulin resistance. Insulin resistance refers to a disruption of the signalling pathways between insulin and the body's cells, and tends to cause alterations in the cellular handling of both carbohydrates and lipids. Of particular relevance, it appears to stimulate uptake of triglycerides by the liver, where they are subsequently stored in vesicles within the hepatocytes.

Although some authorities prefer to limit the definition of NAFLD to that caused by insulin resistance, most centres recognise insulin resistance as only the most common cause of NAFLD. The list of other causes is extensive, and includes drugs, toxins, malnutrition, total parenteral malnutrition, dyslipidaemias, etc.

Albeit controversially, it is also hypothesised that a second-hit is required to transform steatosis into NASH. Oxidative stress [Wiki defn: imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage], hormonal imbalances and mitochondrial abnormalities (secondary to fat accumulation) are potential suspects.

Diagnosis is primarily one of exclusion, but is suggested by:

• unexplained raised transaminases (AST, ALT) - things like viral hepatitis must be excluded


• in associated with an enlarged fatty liver - this can be presumptively shown on ultrasound (hyperechoic/bright liver), CT or even MRI. Only a liver biopsy is definitive, but this is usually not necessary.


• if a significant alcohol history can be excluded

Treatment is again controversial, and much more research is required before any sort of consensus can be reached. Currently, if the cause is insulin resistance, many authorities recommend treating the 'metabolic syndrome' aspects of the condition; specifically, weight loss, and (diabetic) drugs that reduce insulin resistance (metformin and the thiazolidinediones) are promising.

As you can probably tell, the entity of NAFLD is one in evolution. Much of the above will change, and most of the above would already be criticised by numerous people in the field. Be that as it may, it may perhaps still prove useful.

What else, apart from infections, causes a raised white cell count?

Most authorities agree that the normal range for leukocytes (white blood cells) is between about 4 and 11 x 10⁹ cells per litre.

The commonest cause of this is, as you rightly point out, infections (of various natures).

Apart from this, though, there are numerous other causes. The best way, in my opinion, to classify a leukocytosis (raised white cell count) is to think of the two main pathophysiological options. In other words, is the increase in the number of white cells an appropriate response by the bone marrow to a stimulus (e.g. an infection), or is due to inappropriate bone marrow activity (e.g. due to leukaemia)?

For those medical students who need substantially more information on the topic, I can heartily recommend this article on the topic from the American Family Physician journal. What follows is largely based upon it. If, however, you just need a rough summary/overview, read on...

Appropriately-responding bone marrow

• Infections (already covered)
• Inflammation/hypersensitivity - probably the second most common cause. Specific examples in this category include burns, autoimmune diseases (e.g. rheumatoid arthritis), tissue necrosis (e.g. muscle infarction) and severe allergic reactions. Remember, white cells don't just fight infections, they have other roles too. For instance, after extensive burns, they are required to mop up all the dead tissue, and so the patient mounts an immune response. (There are almost always bacteria to deal in addition)
• Bodily stress - e.g. seizures, overexertion. I'm not sure of the reason behind this one. Perhaps increasing leukocyte output is simply a general response to any stress, even if it is pointless in some instances?
• Drugs - this is a commonly overlooked category. Examples include corticosteroids, beta agonists and lithium.
• Splenectomy - the spleen usually houses a significant portion of the leukocyte pool, and so its removal causes a temporary increase in the white blood cell count. After a little while (weeks, usually), the body figures this out and the leukocytes return to their normal range.
• Haemolytic anaemia - the loss of red blood cells seems to signal a non-selective increase in both red and white blood cells. Again, why the non-selectivity...? Perhaps it is in a blind attempt to deal with the cause of the haemolytic anaemia, which may often been an infection. Or perhaps its to cope mopping up the debris, which again requires white blood cells. Suggestions?

Abnormal bone marrow

• Leukaemias (acute or chronic)
• Myeloproliferative disorders (e.g. polycythemia ruba vera)

Gulp! That last category is particularly nasty, isn't it. Shouldn't we fully investigate each patient with a leukocytosis, lest we miss a leukaemia?

No, we can relax a little more. The 'abnormal bone marrow' category accounts for well less than 1% of all leukocytoses. Imagine spending tens of thousands of (say) dollars every time we got a cold! Remember also that safe medicine is about knowing when not to investigate unnecessarily too.

So instead of unhinged panic based on one isolated lab reading, we should rather look at the broader picture confronting us. Most times, the cause will be obvious (e.g. an abscess), and we can always try to treat the immediate cause and see if the leukocytosis resolves. Also, there are a few warning signs/symptoms that we should be on the lookout for. If they are present, the patient warrants a more extensive workup. The list given from the American Family Physician journal's article is appropriate, I think:

• Leukocytosis > 30 x 10⁹ per litre
• Concurrent anaemia or thrombocytopenia
• Hepatomegaly, splenomegaly or generalised lymphadenopathy
• Bleeding, bruising or petechiae
• Chronic lethargy or significant weight loss
• Lift-threatening infection or immunosuppression

There is logic behind each of these criteria... but this post is long enough already. If you have any questions, leave a comment here, or send me an email.

Jeremy

EDIT (12/02/08): What is very helpful in determining the cause of the leukocytosis is to get a breakdown of the proportions of the various subtypes of white blood cells - the 'diff. count'. For instance, very high eosinophils implies a parasite infection, perhaps... There's quite a lot more to the workup of a patient with an unexplained leukocytosis (including a peripheral smear, for instance), but I want to keep this post as focused as possible.

What's a good approach to hair loss?

Imagine the above as an exam question - what outline would your answer have? Mine is below... perhaps you have other ideas?

#1. Is the hair loss localised (patchy) or generalised?

• Hair loss that conforms to the typical male-pattern baldness, or the less well-known female version (thinning of the hair over the vertex), is probably due to the normal androgenic hormones - androgenic aloplecia.
• Well-circumscribed patches that develop suddenly with a normal scalp underneath are most likely aloplecia areata.
• Alternatively, localised hair loss can reflect a localised scarring process (e.g. a burn).
• Finally, significant traction on the hair - e.g. hairdressing techniques, or even psychiatric disorders - can cause hair loss. This can be generalised, but it usually only in the areas of the applied force.

#2. Is the underlying scalp normal or scarred?
A scarred underlying scalp reflects the end-point of many processes - for instance: burns, scalp infections, traction injuries and even metastatic deposits.

More commonly, the underlying scalp is normal, and the hair loss is generalised. In this case, the list is long, so it's helpful to subdivide the causes a bit. For instance:

• Hormonal - pregnancy, puerperium, virilisation
• Metabolic/Nutritional - thyroid dysfunction, iron deficiency
• Stress
• Drugs - corticosteroids, androgens, cytotoxics, anticonvulsants, allopurinol, methyldopa, etc.
• Infections - (secondary) syphilis

The list isn't exhaustive, but it's always helpful to have access to a broad schema for common presentations. Hope that helps.

True or false: in liver disease you are at risk of both hypoglycaemia and hyperglycaemia

True. Here's why.

The liver is the major site of the body's systemic glucose regulation. Basically, it can raise the blood glucose level by the process of gluconeogenesis or by breaking down its large supply of glycogen. So, if enough liver cells are destroyed in liver disease, you can get (life-threatening) attacks of hypoglycaemia.

Also, the blood supply from the gut passes via the liver before hitting the rest of the body - it gets there in the portal system. As the blood passes through the liver, the hepatocytes (liver cells) extract some of the glucose from the meal you've just eaten. However, in certain types of liver disease, particularly in cirrhosis, this delicate portal blood supply is disrupted and partially blocked. As a result, the blood backs up and finds alternative routes to the systemic circulation - thus bypassing the liver. As a result, there is less opportunity for the hepatocytes to remove glucose before it hits the systemic circulation - and the result can be hyperglycaemia.

Incidentally, this bypassing of the liver by the blood (in certain liver diseases) is referred to as portal-systemic shunting, and is a very important topic. Maybe we'll cover that at a later time.

What is the difference between lymphadenopathy and palapable lymph nodes?

Lymphadenopathy refers to lymph nodes pathologically increased in size. Palpable lymph nodes, on the other hand, refer to lymph nodes that you can feel, although they are normal size.

In most individuals, the only palpable lymph nodes are those around the inguinal canal. In all other cases, if you can feel the lymph nodes, they're enlarged, and there is some pathology causing them to be so.

Where it is worth remembering the distinction is in wasted patients (e.g. patients with cancer, or TB, or malnutrition). In these patients, the subcutaneous tissues are so thin that it is often possible to palpate normal (non-enlarged) lymph nodes. It would clearly be a mistake to call this lymphadenopathy.

To distinguish the two, some authorities recommend that 'lymphadenopathy' should refer only to lymph nodes greater than 1cm in diameter. Of course, this distinction is not absolute, but it is worth thinking about when feeling the lymph nodes of a wasted patient.