Endocrinology

Ships of Theseus

Back in the day when I was student, I used to fondly think of medical conferences as the modern day equivalent of Epidaurus in Ancient Greece.A grand annual meeting of enlightened minds discussing important things with a noble purpose. I suppose I was blue pilled and naive.

This idea persisted even as I got into MD and was involved in a conference (like other pgs of my batch). Ironically most people from my batch, never attended conferences outside Jipmer.It seemed odd, but then work kept us busy. Slowly, things started to look different. More and more conferences didn’t resemble the idyllic knowledge meets that I had believed them to be. Try as might, I couldn’t shake the feeling that something was amiss.

In the movie Matrix , Morpheus offers Neo two choices – the blue pill and the red pill. The blue pill allows him to forget everything, continue as usual as if nothing has happened. “Take the red pill and I shall show you how deep the rabbit hole goes”, says Morpheus. As Neo reaches for the red pill, Morpheus cautions – know that this will give you the truth, nothing else. In a sense, this fork in the path is hardly unique to Neo. All of us, at some point face this – we can to either continue to live in our cozy web of fantasy or face the reality. Sadly, unlike Neo we aren’t always offered the choice.

As I got older and joined DM, I started going to more and more conferences and CMEs. I didn’t choose the red pill. It was shoved down my throat.

Many people it seemed came to conferences just to collect bags and have a good dinner with booze. The grandeur of the conferences I attended couldn’t mask the poverty of meaningful research. To add insult to injury, number of conferences and events steadily increased . Of course, you can’t conduct events without money. Somebody has to pay the bills. The industry pitched in. This meant that the content of the talks have a binary choice – be purely utilitarian or commercial. The former is to satisfy the large number of general practitioners who are fishing for that nugget of wisdom which they can implement in their practice. The latter is more insidious and has been actively banned in some countries. Nevertheless, premium slots and premium speakers are often about some drug or the other. It was as if the entire enchilada is geared towards teaching doctors what to prescribe, without getting into any boring nuances. Of course educating the generalist working in the trenches is a worthy goal in itself – provided it doesn’t devolve into mere sound bites.

The kind of difficult talks and long discussions needed to clarify a concept usually don’t have many takers. It requires much more effort to both give and listen to such talks. Consequently it needs to be protected. Think of the governmental choice between constructing a shopping mall vs a park in vacant plot. If the choices are purely dictated by revenue, this would be a no-brainer. However a government, unlike a corporation, ought to have the mettle to rise above the bottom line, numbers and do what is good, but not profitable.

As I contemplate the meaning of conferences, talks, CMEs and other meetings I have attended,I am reminded of the Ship of Theseus. The legendary Greek king Theseus won many naval battles and the people kept his ship in the shore , as a reminnder of his bravery. As the years rolled by, the planks of the ship started to rot and get damaged. Old ones were replaced by new planks and over a few centuries, precious little of the original ship remained. If the entire ship were to be replaced by new parts, does the ship still retain its identity? This philosophical conundrum has baffled men far better than I can ever be. How much of the ship can be replaced while keeping the identity intact?What is the last plank that when replaced completely changes the identify of the ship? Does the ship have an identity of its own at all – or is it irrevocably tied to the brave king ? Is identity ever independent of time?

The original creed of the medical conference, (if it ever really existed) has somehow been hit by a terrible mutation. While most doctors would claim that the big Pharma and the money are responsible, I know deep down that our community owed a big mea culpa too. Like the Ship of Theseus, conferences are in danger of losing their identity. How much commercialisation can we allow before a medical conference ceases to be one?

It’s time we had a serious conversation about conferences.

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Post transplant diabetes

Yesterday I saw a patient with post transplant diabetes. I guess this is a good time to share a presentation on this topic I did a while ago, when I was in final year DM. The purpose is to make it easier for those who make a presentation on this topic to get started and to give a brief 2 minute refresher for the time strapped DM/MD pg going for exam.

Here’s the link to download the presentation as a pptx file

Post transplant diabetes

Vitamin D in pediatrics and dermatology

Vitamin D in pediatrics and dermatology

Since I have been giving a few presentations lately, I thought it would be a good idea to share each of them as blog posts. Now before anyone points out, this is the simplest and laziest way to make a blog post. However it is probably of some use to someone- that’s the point of this blog anyway.

This is a presentation I gave for the MagnaCode endocrine update 2018. As you might guess by going through the presentation, I am not a big fan of the use of vitamin D for any random symptom. 🙂

Vitamin D in pediatrics and dermatology

Do debates actually harm medicine?

It was during the second year of DM , I was exposed to an interesting kind of academic activity in a conference -the medical debate. The issue in question was a thorny one – with conflicting data. The speakers were excellent and put forth brilliant points for and against the motion. As it so happened, they were both comparable not just in their credentials as doctors but also in their public speaking and debating skills.
As I attended more conferences, it soon became clear the debates were a fixture in many medical conferences and were eagerly awaited by the audience. The speakers in turn tried to do as much justice to the topic as possible. Unfortunately there were some problems

  • Some speakers were better than others – and their point of view was more likely to resonate with the audience
  • Even if the speakers were convinced of the other person’s argument to some extent, it soon became a contest in hyperbole

Most importantly it became a contest between individuals and not ideas. This is of course, entirely predictable to anyone who knows how the human mind works. We back people with ideas, not just ideas. Arjuna vs Karna, Tesla vs Edison, Steve Jobs vs Bill Gates – we revel in the great individual rivalries. You might scoff at this rather ridiculous over simplification. After all, the attendees of conferences are highly educated people, not given to emotional support of one speaker or the other.
Unfortunately, education doesn’t make us immune to biases and blind spots. The nature of the debate means that, the speakers have little incentive to expound on the gray areas and are forced to make emphatic statements in front of an audience baying for certainty. Medical science is rife with uncertainty and it is this uncertainty that make it interesting. To dissect the gray zone in which the debate occurs, the speakers and the audience need to know a lot of details. Some of these details like statistics are boring to the average listener ,but is at least available in public domain. Others are effectively hidden from the prying eyes of the public and are probably sleeping safe in the digital vaults of the companies that conduct the studies.
The need for certainty of the average audience member and the near universal reluctance to dig deeper into difficult topics makes it much harder to convey the nuances involved. At the end of the day, the audience are at risk of taking home the message they understand / like the best – setting the stage for eloquence based medicine. So I wondered, if the non-specialist audience could be influenced by the better speaker in the debate, would it make sense for the companies to ask for a particular speaker to speak for their product? Perhaps I’m being too cynical – I will leave it to your judgment. The moderator of the debate should be a person with impeccable credentials and should be able to rise above the need to simply give the audience some satisfying soundbites. Luckily in most debates this is the case – but not always.
More than posters, oral paper presentations and invited orations, debates spark enormous interest. With great popularity,comes great responsibility. Sometimes, I wonder if the moderator should make slide – instead of , or after the rebuttal. People remember what they see – so this should probably tilt the balance towards the truth (if one is known).

nayagan
After every debate, I’m reminded of the final scene in the Kamal movie Nayagan, where the don’s grandson asks him a very simple question “Neenga nallavara,kettavara? (Are you a good man or bad man?)” – to which Kamal replies ‘I don’t now”. Some audience are like Kamal’s grandson – hoping for a simple answer to a very complex and nuanced question. I wish we had Kamals to tell them the truth.

The T-score tamasha

Elderly people fracture when they fall, more often than the youngsters. In order to know who is at high risk, so that we can intervene before the fracture, doctors measure how much bone a person has. This is called bone mineral density (we also need to measure bone quality, not just quantity – but that’s a post for another day)

Bone mineral density is measured by a machine called DEXA.(dual energy xray absorptiometry). What we are measuring is the content of the mineral per unit volume. However only have two dimensional measurement – so we express it as gm /cm2.
Now imagine this – you are checking blood glucose and want to know if it’s normal. You have a value and if it exceeds a particular number, you have diabetes. Unfortunately in bone density, we don’t compare the g/cm2 units . Instead we have two unwieldy scores called T scores and Z scores. The T score is (to put simply) as measure of how far away from the avg bone density of a person in the prime of youth. The Z score is a measure of how far away from your peer group (age). Both these change depending on who you take as reference.
In 1994, the WHO defined osteoporosis as T score of less than /equal to -2.5. This means that approx 1/100 people in their 30s have a bone density as low. Pretty simple.
Unlike bone density, no other parameter in modern medicine is compared to the values in the youth. We don’t say only 1 in 1/100 young women have higher waist circumference (thankfully), even though many biological parameters get worse with aging.

How did this happen?

Back in the 1990s, when DEXA machines became commercial, only three companies were making the machines. They still do. Norland, Hologic and GE. Let’s take a detour and see how a DEXA machine works. It is surprisingly similar to an Xray. X rays are passed from the top and are received at the bottom. The patient lies down in the middle. If the patient’s bone block more X rays from reaching the receiver, we conclude she has more bone. Or bone mineral. Pretty simple right? Well not quite.
From this generalization, we need to convert the attenuation( the loss of xrays while passing through the patient) into an estimate of bone density. Since the patient isn’t a skeleton, the Xrays pass through other stuff like muscles, fat and organs, each of which cause some attenuation. This is also why we can calculate the fat and muscle mass with a DEXA machine. The algorithms which convert this attenuation into the bone mineral density estimate – in gm/cm2 are complex and proprietary.
Because of this proprietary algorithms, the same person’s bone mineral density when measured by a GE Lunar would be, say 6% higher than the same bone mineral density measured by a Hologic machine. Now that’s like saying you measure tomatoes by two balances and one shows 1 kg and the other shows a little more. The natural tendency is to ask which is right? Or perhaps work towards standardizing the measurement.
To standardize measurement, the companies had to work together on the innards of the DEXA machine. Alas – they didn’t. Instead, they decided to bring in a statistical definition based on T and Z scores.

Ever since, the doctor community adopted what the big corporate boys decided. Unfortunately not all doctors like numbers (I know some who absolutely detest math). This has caused a situation where just to interpret a bone density measurement, you need to deal with unwiedly concepts like mean, standard deviation, scores etc. As a side effect, it has made doctors learn these concepts well and think about how their population varies compared with the Caucasians. (a thinking that’s almost never seen when interpreting any other test).

When a change comes, it brings both good stuff and bad stuff along. The yin and yang, the dark and light always exist together. It’s upto us to focus on the good.

Walking beer factories !

Let’s start with a fundamental question – do you need to drink to get drunk? The surprising answer is no. Our body can make ethanol, thus making us walking beer factories. This phenomenon of endogenous ethanol production is called Auto-Brewery.

Auto-brewery is fascinating and very few doctors would think about this when encountering a patient who they think is drunk. Imagine the plight of a teetotaler trying to persuade the doctor that he is drunk,but not because he drank 🙂

How does this happen?

While very little is known about the auto-brewery syndrome, the following are considered necessary for its development

  1. High carbohydrate intake
  2. Prolonged stay of the food in the gut due to
    1. Gut dysmotility
    2. Surgical alteration , creating a ‘vat’
  3. Colonization by organizations which cause fermentation of carbohydrates
    1. Candida spp
    2. Sacharomyces cerevisiae – both due to prolonged antibiotic therapy

Implications

  • Medical
    • Chronic -The above 3 conditions tend to coexist in one of the commonest patient groups- obese diabetics. They may have autonomic dysfunction leading to intestinal dysmotility. Many of these patients also have Non Alcoholic Fatty liver disease -NAFLD. If a subgroup of these patients have endogenous ethanol production, their liver disease may well be ‘alcoholic’. There is very little data to support or refute this claim. In a study of blood alcohol levels, the diabetic patients were found to have 5 times as much BAC (blood alcohol concentration) as non diabetics (1). While the authors conclude that this is not enough to be picked up in routine breath analyser tests, the implications of such long standing increased BAC on liver are intriguing, to say the least.
    • Acute- Acute alcohol intoxication has been reported in a patient who hasn’t touched alcohol in 30 years (2) ! Some cases of metabolic encephalopathy in which no apparent cause is forthcoming may be due to ethanol intoxication from endogenous production. However we must be careful to rule out the usual suspects and should only entertain this diagnosis if BAC is high in a teetotaler or abstinent patient.
  • Medico legal
    • It is unlikely that endogenous ethanol production is severe enough to cause positive breath analyser test in cases of drunken drive (3). This line of argument also doesn’t hold much water in the courts if the published medico legal literature is anything to go by.

To conclude auto-brewery is an interesting medical oddity. As the mechanistic insights are still not very clear, we must be cautious in making this diagnosis. Whether auto-brewery is the culprit in a subset of diabetic patients with neuropathy with NAFLD is not known.

Further reading

  1. Hafez EM, Hamad MA, Fouad M, Abdel-Lateff A. Auto-brewery syndrome: Ethanol pseudo-toxicity in diabetic and hepatic patients. Hum Exp Toxicol. 2017 May;36(5):445–50.

  2. Welch BT, Coelho Prabhu N, Walkoff L, Trenkner SW. Auto-brewery Syndrome in the Setting of Long-standing Crohn’s Disease: A Case Report and Review of the Literature. J Crohns Colitis. 2016 Dec;10(12):1448–50.

  3. Logan BK, Jones AW. Endogenous ethanol “auto-brewery syndrome” as a drunk-driving defence challenge. Med Sci Law. 2000 Jul;40(3):206–15.

Drugs: Do we get what we pay for?

Most doctors are very particular about the insulin dosing : for a good reason. Small changes in insulin dosing can result in undesirable changes in blood glucose. Sometimes we give higher concentration of insulin when patients require a larger dose. One assumption is that the patient has some sort of insulin resistance/secretory defect and that the increased dose will take care of the problem. Endocrinologists also enquire about the insulin storage – and we have all met the occasional patient who has stored insulin in the freezer or made some egregious mistake in the insulin injection technique.

Hitherto, we have assumed that , if you buy a vial of insulin containing 300 Units of insulin, it contains 300 IU of insulin. After all, what could be more natural than this?.

Today I came across a study that challenges one of our most natural beliefs. You can read the paper here.

Study in brief

Carter and Heinemann purchased insulin vials from different pharmacies in the United States. They quantitatively tested the insulin concentration in 18 10-ml vials from two major manufacturers (if you are into diabetes management, you won’t get any brownie points for guessing). They used a standard analytic method – Quadrapole Time-of-Flight (QTOF) mass spectrometry to quantify insulin.

Unfortunately, not even a single sample contained the amount of insulin that it should contain. The concentrations ranged from 13.9 to 94.2 IU/ml ( for an insulin that should contain 95 IU/ml). The lossis slightly better with NPH insulin, as shown below. However NPH throws a different problem – high variability between vials.So a patient might get only 1/6th of the regular insulin that he pays for.Even the lot to lot difference is more – in essence, while we might prescribe some dose of insulin, only God knows what’s going in. ( call it luck if you are an atheist)

What makes this issue even more troublesome is that neither the patient nor the doctor can do anything about it. Even the pharmacist can’t do much about it, because the problem ( as postulated by the authors) is more proximal – perhaps a break in the cold chain.

This study is the first to show such huge loss of insulin at the last link in the cold chain (pharmacy). The study was not done in some remote African village- but in the USA. In a hot country like India, with poor knowledge about storage of insulin, I wonder what the situation will be. There are no similar data for analogue insulins.

We have had similar problems with thyroxine (especially the government supplied ones). Similar issue was noted with Vitamin D preparations in a study conducted by AIIMS.You can access it here.

Importance

 

  1. If the blood glucose control changes from month to month, it may have something to do with the lot to lot variability
  2. Endocrinology is more than just numbers.
  3. Much of our certainty may be ill founded. The numbers we encounter are at best, estimates and approximations.
  4. We need demand better drug quality control – after all our patients are paying for the drug.