Flushing out excess glucose from the blood

There are many kinds of oral drugs used for reducing high blood sugar in diabetes. Drugs like metformin, the sulphonylureas, the glinides, the dipeptidyl peptidase 4 inhibitors and the thiazolidinediones promote entry of glucose into body cells by different mechanisms - by reducing insulin resistance (metformin, thiazolidinediones), by increasing secretion of endogenous insulin (sulphonylureas, glinides) and by increasing levels of glucagon-like peptide 1(DPP4 inhibitors). Now we have a new class of oral drugs that reduces blood sugar by flushing out the excess glucose in the urine. By reducing reabsorption of glucose from the proximal tubules of the kidney, these drugs (called the sodium glucose co-transporter 2 inhibitors) lower blood sugar by allowing more glucose to be excreted in the urine. In effect, it reduces the renal threshold for glucose excretion. An advantage of this method is that by flushing out the excess glucose, instead of storing it inside cells, patients will lose weight. The disadvantage is that osmotic diuresis (by the glucose in the urine) can cause intravascular volume depletion and postural hypotension. Excess glucose in the perineal region can also predispose to candida infection in women. Whether this class of drugs will improve the morbidity and mortality associated with diabetes and whether it will be safe for all diabetics will be seen in the next few years.

Ref.: Canagliflozin, a new drug for diabetes

Good in one situation but not in another

In September 2009, the New England Journal of Medicine informed its readers that the RE-LY study showed evidence of the thrombin inhibitor Dabigatran being as effective as, if not better than, Warfarin for the prevention of thromboembolic events in patients with atrial fibrillation. Those patients with atrial fibrillation who took Dabigatran in a dose of 110 mg twice daily had the same rates of stroke as those who took Warfarin but had significantly lower rates of major hemorrhage. Those patients who took Dabigatran in a higher dose of 150 mg twice daily had the same rates of major hemorrhage as Warfarin but with lower rates of stroke. So, either way, we see a benefit of Dabigatran over Warfarin.

Can we conclude that Dabigatran is at least as good as Warfarin in preventing undesired thrombosis and thromboembolic phenomena in the body?

The RE-ALIGN study published in the New England Journal of Medicine in September 2013 tells us that we cannot make that generalisation. It appears that a drug that is good in one situation is not necessarily good in all situations. In this RE-ALIGN study, the investigators report that Dabigatran was not as effective as Warfarin in preventing thromboembolic complications in patients who had mechanical heart valves. Furthermore, it was associated with an increased risk of bleeding. The message they send us is: use Warfarin, not Dabigatran, for preventing thromboembolism in patients with mechanical heart valves.

What is the reason for this paradox? The authors of the RE-ALIGN study tell us that this could be because the mechanisms involved in the clotting of blood are different in atrial fibrillation and in mechanical heart valves. Stasis of blood in the atria is the cause of thrombosis in atrial fibrillation while contact of blood with the mechanical valve and the release of tissue factor after surgery are the mechanisms of thrombosis in those with mechanical heart valves. These differences make Dabigatran good in one situation but not in the other. This reminds me of something else which is good in one situation but not not in another: the combination of aspirin and clopidogrel is good in acute coronary syndromes but not in chronic stable angina.

Chronic stable angina and the ST segment deviation vector in ECG

Coronary artery disease, as all physicians know, presents in different ways in different people. We have anecdotes of people who die suddenly without ever being aware that their coronary arteries were blocked. On the other end of this coronary artery disease spectrum we have the condition called chronic stable angina where patients experience chest pain only on exertion. And in between these two extremes lie the various categories of acute coronary syndrome. Intuitively we might believe that the milder manifestation of chronic stable angina represents the benign end of the spectrum where the coronary arteries are only minimally involved. This is not always true because we have learnt that even in patients with chronic stable angina there can be extensive coronary involvement.

What matters in coronary artery disease are the answers to three questions: Which artery is blocked? Is that artery blocked proximally or distally? What is the degree to which it is blocked? And of the two coronary arteries and their branches, high grade blocks in the left main coronary artery and in the proximal portion of the left anterior descending artery are the most dangerous. So when faced with patients who have chronic stable angina, one of the important things I want to know is whether they have involvement of the left main coronary artery or the proximal portion of the left anterior descending artery. Determining the ST segment deviation vector from the ECG is an attempt to answer this question without a coronary angiogram.

The ST segment deviation vector is determined in much the same way as the cardiac axis is determined from the QRS complexes. We use the limb leads and look at the ST segments in them. Wherever ST segments are depressed, the vector is moving away from those leads and wherever ST segments are elevated, the vector is moving towards those leads. And the vector is perpendicular to any lead whose ST segment is neither elevated nor depressed. With these basic electrophysiological principles, we can proceed to determine the ST segment deviation vector, if any, in patients with chest pain. A general rule is that when the ST segment deviation vector is in the quadrant between minus 90 degrees and minus 180 degrees (the "aVR quadrant"), there is a high probability of significant stenosis in either the left main or the proximal left anterior descending coronary arteries.

I use this information as a guide in deciding which patients with chronic stable angina should be referred for a coronary angiogram after an exercise stress test.

For an understanding of how ST segment deviations will look like in patient with significant blocks in the left main coronary and proximal left anterior descending coronary arteries, please see:
Proximal left anterior descending artery block
Left main coronary artery block

A patient with blepharospasm

The patient, a man in his early sixties, had been diagnosed as suffering from diabetes, hypertension and chronic renal failure. The notes in the patient's case record had however failed to record something that was very obvious. He had bilateral blepharospasm and used his hand to keep his eyes open when talking to me. He told me that he had seen a couple of doctors in various parts of the country for this disorder but nothing had helped. I listened sympathetically and, after the usual review of his various medical problems, prescribed him treatment for diabetes, hypertension and renal failure.

Later, I read an article on benign essential blepharospasm.

I realised that this condition, which was initially considered a psychiatric disorder, is now regarded as a form of focal dystonia affecting the orbicularis oculi and other muscles around the eyeball. No one knows where exactly the lesion is but it is generally regarded as a disorder of neural circuits that regulate blinking. The sensory component of this circuit is triggered by a variety of stimuli ranging from light, sensory stimuli from the trigeminal nerve, and strong emotions. The motor component is mediated by the facial nerve. Blepharospasm disappears when the patient is asleep and when deeply relaxed. Hence, there have been treatments designed to promote such relaxation using pharmacological and non-pharmacological methods. The results have been variable and no one method has been shown to be consistently better. Currently, the most effective treatment for benign essential blepharospasm is injection of Botox into the muscles around the eye. Botox is Botulinum A toxin. It inhibits the release of acetylcholine from presynaptic nerve terminals. The effect Botox injections can last from one to five months.

Ref: Medscape article

Nitrites in the urine of people without any urinary symptoms

Recently I tested the urine of  a male patient who had fever for 4 days with no localising symptoms and signs. The urine showed a trace of protein, some leukocytes and red blood cells (less than 10 cells per high power field). The urine nitrite test was positive. I wondered if this patient really had urinary infection because, if not for the positive urinary nitrite, I might have considered the urine protein and cellular abnormalities as being the result of the fever and not the cause of the fever. This led me to read an article in the American Family Physician which gave me some information as to why the urinary nitrite test may be falsely positive. I have quoted the relevant extract below:

Nitrites normally are not found in urine but result when bacteria reduce urinary nitrates to nitrites. Many gram-negative and some gram-positive organisms are capable of this conversion, and a positive dipstick nitrite test indicates that these organisms are present in significant numbers (i.e., more than 10,000 per mL). This test is specific but not highly sensitive. Thus, a positive result is helpful, but a negative result does not rule out UTI.⁶ The nitrite dipstick reagent is sensitive to air exposure, so containers should be closed immediately after removing a strip. After one week of exposure, one third of strips give false-positive results, and after two weeks, three fourths give false-positive results.³⁶ 

Diseases and "casual parentheses"

Wilfred Trotter, an English surgeon, once said: "Disease often tells its secrets in casual parentheses." This implies that we need to observe and listen carefully, often over a period of time, without prematurely concluding that we know what the problem is, if we are keen to make a correct diagnosis. In the Malaysian Family Physician there is a report of a young patient who presented with mild arthritis of the ankle joints after a short febrile illness.
I asked myself what I would have diagnosed at that point. I think I would have considered it to be part of a viral syndrome but would look carefully for evidence of septic arthritis.
A few days later this patient developed erythema nodosum - a localised painful inflammation of the subcutaneous tissue. Since erythema nodosum is the result of an immune response, I would at this stage have considered the possibility of a reactive arthritis and looked for infections in the urinary tract, gastrointestinal tract and also for streptococcal infections in the throat.
This case report in the Malaysian Family Physician has made me realise that the disease the patient really has is not what I am thinking about. The correct diagnosis revealed itself to the doctors only after yet more time. This appears to validate what Wilfred Trotter said.

Read the case report in the Malaysian Family Physician

Thrombolytic therapy in a patient with thrombocytopenia

A middle aged man was admitted to the hospital with dengue fever. He had a low platelet count of 60,000/cu.mm on admission. In the ward he developed chest pain and an acute anterior wall ST elevation myocardial infarction. The specialist in charge of the patient decided to administer Streptokinase believing that salvaging the ischemic myocardium outweighed the risk of bleeding. The patient had no bleeding complications from the Streptokinase even though his platelet count continued to fall to a level of 20000/cu.mm over the next few days.

This made me wonder if it was safe to administer thrombolytic therapy to people with pre-existing thrombocytopenia.

The evidence I found in the literature says that, if patients have no bleeding manifestations, it is relatively safe to administer thrombolytic therapy. Heparin, because of its potential to reduce platelet counts, may be more dangerous than Streptokinase. Even though this patient that I described above did not suffer any bleeding complications from thrombolysis, my intuitive feeling is that it is prudent to transfuse platelets if the platelet count is very low when thrombolytic therapy is contemplated.

Reference: An editorial in Clinical Cardiology