Endocrinology

Daring to look beyond evidence

Today I attended, along with a lot of others, the much awaited debate about the Paleo diet in Trendo 2017(The Annual Endocine Conference). The hall was jam packed and both the speakers did a fantastic job. This is an issue that I have been ruminating for quite a while now.I had been skeptical about the Paleo diet – the scientific aspect of it. It was a knee jerk reaction. Knee jerk reactions are rarely right – so I decided to do what every doctor has been taught : look at the evidence.
I started the search at a familiar place – PubMed. As expected, there weren’t many studies. . There were studies of short duration, some of which showed great effect and others didn’t. Even the pattern was familiar, just like the place where I started. In fact I couldn’t find a single trial from India. I guess we are content to ask questions and want others to come up with answers.
However, the absence of evidence is not evidence of absence of effect.
Like all searches, I was left with more questions than answers. What exactly is Paleo diet? How far back in human history do we go? Should we just emulate the caveman’s diet or his whole life style? Somehow, drinking butter tea in plush AC rooms alone without working hard like the cave man seemed counter intuitive.
It was at this stage, that I stumbled onto a Facebook group called Arokiyam Nalvazhvu(Healthy Life in Tamil). I can hear the evidence based snobs scoffing . After all , a social network isn’t a traditional place to find answers to one of the fundamental questions of science – how and what should we eat? The group had over 3.5 lakh members, almost all of whom are either taking Paleo diet or planning to. [Talk of big data :-). This would be brilliant data mining project, for those who love to work with unstructure data]. Now this diet isn’t a standardized intervention, these were mostly prescribed by hobbyists who had no background in medicine. I saw some doctors as members of the group too. I decided to become a lurker.
Here’s how the group works:
Members post the pre and post images of themselves and their blood test reports. Several admins are there who approve the post and given them a unique id. The member has to take the requisite blood tests and post in the same thread. Within a couple of days, a paleo diet chart is given. It has its own menu and can be expensive, but if the member requests there are cheaper options as well. After 100 days, the member posts his lab tests/photos or both.The remarkable thing is the dedication of the admins. I have never seen patient empowerment on such a grand scale. Those who follow the diet religiously and lose weight, in turn become evangelists of Paleo and welcome new comers and start mentoring. It is a virtuous cycle. The best part is all of this is done absolutely free of cost.
Interestingly, Paleo has spawned several entrepreneurs as well. The people are home delivering Paleo ingredients. There are even a few Paleo diet hotels around. The members and admins actively go out and raise awareness.
I must say that the photos of people weighing over 150 kgs and becoming 90 kg after paleo are far more impressive than p values <0.05. Of course, this is not to say that statistics is unimportant – quite the contrary. It is to emphasize that just because the data is not available in nice and easy spreadsheets or published in some top tier journal, doesn’t mean there is no data.
In the most unexpected of places, I did learn a few things that aren’t readily understood about Paleo diet. These are not the attributes of the diet itself. They are the extras- the sidekicks. Just like in the best of tales, the sidekicks save the day, even when the hero is down and out.

  •  Paleo diet is like a religion. It’s more a way a life than a diet. Just like religion acts as a vehicle to take good ideas and principles to the masses, the Paleo brand helps in bringing common sense and not so common sense dietary principles to the masses. Just like religion, there are high priests,evangelists and followers. Just like religion, there is a strong sense of belonging – for which people give their love and labor for free. Just like religion, it has spawned a parallel economy, where members enrich themselves and others through innovative business models.
  • Just like religion, Paleo has its own issues. Since there’s no universal agreement on even what constitutes Paleo diet ( you can be pretty sure that the cave man didn’t take butter tea!), there are often conflicting views on some topics. These conflicts are resolved not through research, but personal experience of the admins and volunteers. However unlike religions, the group and the shared culture, ultimately puts the power in the hands of the people. 
  • Paleo diet groups are like corporations – they work with a clear hierarchy. They use data to continuously refine the advice and through rapid iteration understand what works and what doesn’t.Unlike corporations, they don’t operate for profit and don’t chase the bottom line. 
  • Paleo diet groups are like cooperative societies. Through the sheer strength of numbers, they are able to bargain with the labs and vendors and reduce the prices.
  • Paleo diet groups are like schools – where the pupils are educated on a radically new diet and the pitfalls to watch out for. The advice may not always be in sync with what the medical community believes, but there can be no denying that it has worked in the short term for many people. The long term health effects of ketosis are largely unknown.

In short, the Paleo diet clearly goes beyond the boundaries of a diet – it’s more of a subaltern lifestyle. Some would even call it a social revolution – for it is of the people,by the people and for the people. There in lies its strength. It’s not an edifice built on multicenter clinical trials – but a belief system that has surprisingly worked for many people and continues to do so. Evidence is accumulating that it is effective in many lifestyle diseases. Even as the neo converts to the EBM decry the lack of evidence, we cannot forget that evidence often takes time. Seeing is believing ,but the reverse is true too – you need to believe in something strongly enough to see the results. For instance, if Gandhiji had asked for evidence that ahimsa can wrest political power from a powerful empire before embarking on the struggle, he would have come up with a nought – after all, there was no historical precedent- and we might have remained under imperial rule!

Our diet is very dear to us – which explain why we have a strong bias towards the status quo. When I see a morbidly obese man becoming fit in the short, without going under the surgeon’s scalpel, I know that’s special. It’s life changing. The biggest impact this search had on me was that now I find it impossibly hard to recommend bariatric surgery to anyone before a paleo trial – I cannot unsee the photos after all !
Of course, the jury is still out on the science of Paleo diet. However I am convinced that even good principles and ideas,like religion, require good packaging and branding. The social component of the Paleo groups is incredibly hard to replicate. We just can’t peddle good advice to people and expect it to catch on like wildfire. In that sense, Paleo might have already transcended the outer limits of conventional medicine.
I still remain a lurker in the group. I eat normal diet. I love statistics. However, when people quote meta analyses and p values, merely to buttress their belief system and show no effort to search for the truth, I chuckle inside. It takes a bit of humility and guts to say we don’t know. May be deep down, we don’t want to know.
May be we don’t want to look beyond evidence. When we do dare to look, the view is breathtaking.

Has my glucometer gone bonkers?

A common problem faced by many diabetic patients is the ‘perceived’ or real inaccuracy of their glucometer. This happens when the glucose reading on the meter is widely different from what is expected – say a very high value after a usual walk that is known to reduce blood glucose or a very low value in a patient who’s not experiencing any symptoms.

When such aberrations occur the common tendency is to blame the glucometer. Some people claim that their glucometer has gone bonkers!However that may not be a good idea.

There are several standards that a blood glucose meter should satisfy before coming to the market. You can access these ISO standards here. Specifically 99% of readings must fall within zones A and B of the Consensus Error Grid for type 1 diabetes. Let me explain further.

What is an error grid ?

When a glucometer is validated for clinical or regulatory purposes, the values measured by the glucometer is compared with a reference method (method comparison study). A scatter plot is drawn and a grid is superimposed on the scatter graph.

For example, a pair (300 mg/dl, 550 mg/dl) represents a large numerical discrepancy, but is unlikely to result in an adverse clinical outcome since in either case the patient will probably receive insulin. On the other hand, a discrepancy of 70 vs. 110 could have serious clinical consequences since hypoglycemic therapy may be administered in the former case, possibly erroneously.

An error grid basically gives clinical context to the discrepancy in measurement between the two methods. Two major systems are in use : Clarke’s error grid and Parke’s(consensus) error grid.Both systems place paired reference/test values into one of five zones – “A”, “B”, “C”, “D” or “E” based on the expected clinical impact of the discrepency.

This is how Clarke’s and Parke’s Error grids look like 

ega

ega2

 

For regulatory clearance , 99 % of the values must fall within zone A or B. So glucometers from standard companies have a high bar to clear before they reach our hands.

In spite of all this, occasionally we get patients complaining of discrepant values. Let’s see what can be done if we get discrepant values. By going through a check list of questions, we can identify whether the reading is inaccurate and the source of inaccuracy. 

The inaccuracy can result from three sources – patient, glucose strip and glucometer

  1. Wrong technique of pricking – usually minor
    • Did you clean your fingers before pricking? This is common in children with type 1 diabetes/ the active type 2 diabetics who play/engage in outdoor activities. A finger that is covered with grime is unlikely to be accurate.Hence accurate cleaning is essential.
    • Did you squeeze your finger hard? Squeezing fingers is not recommended because it leads to estimation of blood glucose in the interstitial fluid, not the capillary blood(the one we want). Choose a lancet , or prick with the appropriate size needle to ensure you get enough blood.
  1. Problem with glucose strip – uncommon
    • Did you store the glucose strip properly? There is a reason glucostrips are packaged in black plastic containers. Exposure to excessive heat/moisture can lead to inaccuracy in glucose readings. Make sure that the glucose strip is stored correctly.
    • Have you used the correct code ? Most modern gluco meters don’t require you to set the code manually.In case you are using a older version of glucometer, it is important to input the correct code. Otherwise wrong readings are possible.
    • Has your strip expired? Glucose strips, like medicines, have expiry dates. It is important to make sure that the strip you are using is not an ancient one.
  2. Problem with glucometer
    • Did you drop the glucometer recently? Glucometers are sensitive devices which should be handled with care. Dropping the glucometer from a height , (like any other electronic device) can result in glucometer malfunction.
    • Water/heat or any other physical damage to the glucometer? Physical damage to the glucometer is easy to detect. You will have to replace the glucometer in this case.

    If you have done all the steps correctly, and still have abnormal values, you need to don the Sherlock Holmes hat and see why it is happening.

    Here are the steps to be followed

    1. Recheck again – this is the first step. If the second value is very similar to the first one, then perhaps error is not random. This of course, doesn’t mean that the value is correct. There could still be a systematic error (an example is a weighing machine that always shows you are 5 kg heavier:-)) . Systematic errors rarely happen in glucometers, but they are possible.
    2. If the repeat value is significantly different, (in spite of keeping all other conditions constant), then the technique is not the culprit. So the issue is with either the glucose strip or the glucometer.
    3. You have two optionscheck blood glucose with the nearby reliable lab or use a control solution. Control solutions contain a known amount of glucose and if the glucometer is working properly, it should be able to give the expected value. It is sort of like measuring a known 1 kg stone in an electronic weighing machine.If the machine shows abnormal reading, then something is wrong with the machine. However control solutions are not commonly used. Most pharmacies don’t event stock them and the glucometer doesn’t come with the control solution. The solution has to be purchased separately (can be got online) and once opened can be used for 3 months only. However they can be conveniently used at home.

    Conclusions

    • Standard glucometers go through stringent quality checks
    • Whenever a discrepant glucose measurement is seen, think of the different levels where things can go wrong – patient, strip or glucometer
    • When in doubt measure in a standard lab or use a control solution.
    • As usual, proper patient education can avoid unnecessary confusion 

    Further reading

    1. Parkes, J. L., S. L. Slatin, S. Pardo, and B.H. Ginsberg. “A New Consensus Error Grid to Evaluate the Clinical Significance of Inaccuracies in the Measurement of Blood Glucose.” Diabetes Care 23, no. 8 (August 2000): 1143-48
    2. Pfutzner, Andreas, David C. Klonoff, Scott Pardo, and Joan L. Parkes. “Technical Aspects of the Parkes Error Grid.” Journal of Diabetes Science and Technology 7, no. 5 (September 2013): 1275-81

 

Progesterone perils

A lot of women are prescribed progesterone for the treatment of threatened abortion and staining during early pregnancy – with the ostensible purpose of saving the pregnancy. Unfortunately some doctors use progesterone as a kind of insurance against miscarriage and this practice is becoming increasingly common. The progesterone levels in the body are naturally higher during early pregnancy. So several doctors think that adding a bit of exogenous progesterone for support will have little or no adverse effects. However not all adverse events are immediately apparent.
A recent paper by Reinisch et al, in Archives of sexual behaviour had a provocative argument. The intake of synthetic progestin by the mother, called lutocyclin was associated with a higher risk of bisexuality in the child. As sexual behaviour and preference can only be discerned after puberty, this intriguing signal is very interesting. Several animal studies show that exposure to progesterone in the prenatal period can cause weird sexual behaviour in the offspring.However animals are largely free of the societal pressures that humans have to face – so the data cannot be directly extrapolated to humans.
The determinants of human sexuality are fiendishly complex. Many are unknown. It is conceivable that exposure of the developing fetal brain to exogenous hormones can have effects that are very hard to predict. To make matters worse, the long latent period between prenatal exposure and the first sexual behaviour makes it very hard to pin any adverse event on a particular drug / event. People with bad experience tend to remember the details that they feel might be related to the issue – the recall bias. Furtheremore it is impractical and unethical to round up a group of mothers, randomly split them into two groups and given one group progesterone and see what happens to their kids later on.So how can we investigate the possible link , between prenatal progesterone exposure and sexual preference in the child?
One way is to have a natural birth cohort. To identify the women who were given progesterone and track the children from birth and compare them with the children of women who were not given progesterone. As long as the children are of the same social background and have good follow up, we might be able to compare them. That’s what the authors did in the study.
They had tracked 34 individuals and found that the tendency for bisexuality (being attracted to both sexes) is higher in the children of mothers treated with progesterone. There was also a dose response effect – crucial in determining casuality. The Bradford hill criteria are commonly used to assess causality

causality

The children of mothers who were treated with higher doses for longer duration were more likely to have bisexuality. The sexual preferences were self reported. Interestingly heterosexual attraction was not diminished in those who reported bisexuality – it ‘s as if they had developed additional attraction to the same sex as well. This is different from a shift to homosexuality – thus showing that a bidimensional model where in both homo and heterosexuality exists in the same individual, with each one having high and low poles.

What do we make of this research?

As we all know , it takes a lot more than a single study to come to conclusions. However a single study which shows consistent findings, with a dose response effect, should raise some alarm. There are some doubts, whether the trade name lutocyclin ( made in late 1950’s, the time the birth cohort was established) was actually progesterone. However the author seems certain. The magnitude of effect and the numbers are small, but the effect itself appears concerning.
In the mean time, it is vitally important that we acknowledge the uncertainty surrounding the effects of prenatal hormone exposure. Studying the effects of such hormone use is very hard.
Hormones are to be used with care – a lot of things like metabolism, receptor affinity,distribution and post receptor mechanisms can result in varying effects in different individuals.

The most important question to ask before taking a hormone is – do I really need it?

Further reading

  1. Prenatal Exposure to Progesterone Affects Sexual Orientation in Humans

Marriage and the nocebo effect

 

Today morning, I opened The Lancet, to see an interesting Statin trial that looked at SAMS (Statin associated muscle symptoms). You can read the trial here


Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase

 

Statins are cholesterol lowering drugs that are sometimes associated with muscle pains. Unlike myopathy or myonecrosis, muscle pains have no objective  biochemical or histological component. The authors had analyzed the statin related adverse effects during the blinded(patient doesn’t know he’s taking statin) and the unblinded(patient knows he’s taking statin) phase of ASCOT trial. When the patients knew they were taking statins, they complained of muscle pains. When they didn’t know what they were taking, they had no symptoms !


In other words, their expectation of what statin might cause (after learning about it from net/other sources) influenced their symptoms. This fascinating phenomenon is called the nocebo effect.It’s the negative cousin of the well known placebo effect. It reflects changes in human psychobiology involving the brain, body, and behaviour rather than drug toxicity.Muscle related adverse effects are often low in randomized trials  compared with observational studies. The strength of this study is that these were the same patients, no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins.


This reminded me of some of the unfortunate posts on marriage I ve been seeing in Facebook and Quora of late. The liberal rants have an unmistakable pattern – they claim that marriage is the worst thing that can happen to a person. There are some sites (such as this one) whose only job appears to “educate” people on the evils of marriage and praise any and every form of decadence. You can see this in present day movies as well – the premise is that if you get married you are screwed. All these sources happen to think the plural of anecdote is data – it’s not.


It’s possible this can have a “nocebo effect” on our youth – for example,some of the fine boys I know appear to have become unusually nervous at the thought of getting married. Such negativity  may even become a self fulfilling doomsday prophecy. At the expense of committing the same sin as the liberals(the plural of anecdotes!), I must say there is nothing to be afraid of about marriage. Sure,occasional mishaps happen – but they are ,thankfully, still not the norm. Of course, our world view is colored by our own atomized experinces. I am also aware that just because,my experience is overwhelmingly positive doesn’t mean everyone’s will be the same. In any case, it’s important to keep an open mind. Negative thoughts are clearly useless.


PS: Here’s a pro tip: Stay away from the leftist/liberal websites that spew constant trash, if you can. You won’t regret it.

virtual journal club–steroid induced osteoporosis

Steroid induced osteoporosis is a common problem which needs to be addressed in patients on long term steroid therapy. The American College of Rheumatology has published guidelines on optimal management of glucocorticoid induced osteoporosis a few days back.

In this edition of the virtual journal club, I will focus on these guidelines. You can get the guidelines (free pdf) here.

Click on the video below to listen to the presentation.

If you don’t have the time, here’s the gist

  • Assess all patients on GC within first 6 months for fracture risk ( clinical

    DXA)

  • Risk stratification is key, adjust FRAX risk for GC use
  • Optimize Calcium (800 to 1000 mg) ,Vitamin D( 600 to 800 IU) and lifestyle
  • Oral bisphosphonates preferred treatment when pharmacological
    management is indicated
  • Follow up every year and reassess fracture risk

You can download the presentation (without author name Smile ) here.

If you like the post/video/presentation, feel free to share with your friends.

Sweet, naturally

Diabetic patients can have a a hard time getting used a life without their favorite sweets. Sweeteners aim to circumvent this perplexing problem by delinking sweet taste from calories. Ironically artificial sweeteners became popular much before the natural ones. The belief was that if the substance can taste sweet and has no calories, it was a godsend. Unfortunately that claim proved too good to be true for many artificial sweeteners.

Just because they didn’t have calories didn’t mean the artificial sweeteners were safe. Paradoxically they have been found to be linked with obesity in some cases. Even though these no calorie sweeteners aren’t metabolised by our body, the gut microbiome can metabolize it and the end products are toxic to the “good bacteria”. This eventually leads to “dysbiosis” (a change in the composition of bacteria in our gut) and defeats the purpose of taking sweeteners.

NATURAL SWEETENERS ARTIFICIAL SWEETENERS
Stevia Saccharin
Monk fruit Acesulfame
Miracle berry Aspartame
Kateme fruit Cyclamate
Licorice root Neohesperidin
HFCS (high fructose corn syrup)

With continuing demand for low colorie/non nutritive sweeteners, the natural ones have become more popular. Some of the main ones are

  1. Stevia
  2. Monk fruit (only extracted active ingredient can be used)
  3. Kateme fruit (probably not available in India)

Stevia

This is the most well known of the natural sweeteners and the best studied. Stevia is a plant native to Paraguay and Brazil and is intensely sweet – 250 times sweeter than sugar. The glcosides – stevioside and rebaudioside are responsible for this sweetness.Unlike other natural sweeteners stevia is easy to cultivate in urban homes and its leaves can be used fresh , without the need for industrial processing. Also because of its low cost, stevia has the potential to be the most popular natural sweetener.

In fact Stevia was featured in a recent TV show. (the video is in Tamil, but the visuals are fairly self explanatory)

The two important questions are

  1. Is this safe?
  2. Is this effective? ( for reducing weight/ reducing blood sugar/reducing cardiovascular risk)

Safety

  • Stevia started off on a bad note, with concerns of carcinogenecity, but the concerns were later found to be baseless. Consequently FDA has given it a GRAS status (Generally recognized as safe). In India, FSSAI has approved the use of stevia in various food products.
  • Like any other plant, stevia has a lot of other ingredients and the safety label given by FDA is for purified rebaudioside.
  • Data on pregnant women and children with type 1 diabetes are scarce – thus caution must be exercised.

Efficacy

  • Stevia has mixed reports of efficacy, but in reality it has not been studied as extensively as prescription drugs or even artificial sweeteners.
  • While the short term studies don’t show great benefit with Stevia in terms of glucose reduction, the longer term studies (>40 weeks) tend to show reduction in weight.

Monk Fruit

monkfruit

Monkfruit(Siraitia grosvenorii) is a subtropical melon grown in South East Asian countries. Legend has it that the fruit derives its moniker by virtue of having been cultivated by Chinese monks more than 800 years ago. Since the fruit is hard to store, it is usually not used in the fresh form. It becomes brown on drying. From the dry fruit, its active ingredient is extracted. These are glycosides – mainly mogrosides.(siamenoside and neomogroside are other glycosides)

Safety :

Rigoroussafety studies have not been carried out – partly because of the difficulty instandardizing the production of monk fruit extract. US FDA has given a GRAS-Generally recognized as safe (3)notice about its safety.

Efficacy

There aren’t any long term studies on the efficacy of monk fruit, perhaps due to the difficulty in cultivation and the expense of import.

Katemfe fruit

thaumatin_katemfe_fruit

This is much less popular than the other two natural sweeteners. Very few long term studies exist. I am not sure if this is even available in India.

The following table compares the common natural sweeteners

STEVIA MONK FRUIT
Availability Better Difficult to obtain
Cost $ $$
Safety GRAS (generally regarded as safe) GRAS
Efficacy Short term : no benefits/ harms Limited data, but not much different from stevia
Long term : weight reduction
Use Fresh leaves can be used Fresh fruit cannot be consumed
Ease of growing Easy Difficult
Other uses Purified stevia extract doesn’t have other uses Purified form doesn’t have other uses

Things to remember

  • Just because something is natural doesn’t mean it is safe (even strychnine is natural). While occasional use of sweetener , for example in a family function , is likely to be safe, usage in pregnant women or children should not be encouraged
  • Taste matters – all natural sweeteners , to varying extent, produce some aftertaste. Ultimately long term use hinges heavily on taste and you can only experiment to see which taste you like
  • Purity and standardization – just like any plant product, it is very hard to standardize purity and manufacturing practices. Since the commercial products are not as well regulated as drugs, you might be getting stevia laced with glucose or other sweeteners too. Read the label, but don’t fully trust it if the company is unknown. You might be better off using the fresh leaves
  • “Side effects” – purified extracts are safe for consumption because they are predictable. But the plants has several other active ingredients which have not been well studied, even though they have been in use for centuries. While the modern reductionist approach is one we are used to, I wouldn’t discount the advantage /disadvantage of consuming the whole leaves/fruit products. Consider this – if you analyze Coke/Pepsi, you will get sugar as the main ingredient, and a variety of others in tiny quantities. Perhaps even the order of adding these ingredients matter, which is why their formula is a closely guarded secret. Just by extracting the main ingredient(sugar), we won’t get Coke/Pepsi. In the same way, the complex interactions between the ingredients in a plant can have unpredictable good /bad effects. Being alert is the prudent option.

Non nutritive sweeteners may never become mainstream. But for the diabetic with a sweet tooth, they may be a godsend. By following common sense, we can avoid the bitter aftertaste, in more ways than one.

Creating a wiki with nationwide contribution

I and my friend were the first batch DM students. Being the first batch meant we had some unusual benefits, but also some difficulties. For instance, when exams came, we had no seniors or any question banks to rely on. Luckily for us, we had a WhatsApp group from which we could keep a tab on what was going on elsewhere in the country.
Social media is great at connecting people. It encourages Brownian contact with people who you might otherwise not meet. However, it isn’t meant to be a repository of information. Anyone who has scrolled through a Facebook feed or WhatsApp group knows that the information shared there is essentially ephemeral. And that is good too (who wants to remember our friend’s dinner photos!).
So there is a need to collect and store information in a more efficient manner. Information that is both useful and fairly permanent. That’s where a wiki comes in. A wiki is a website that allows users to collaboratively add or edit content. Unlike a forum, there won’t be any talks, but there will be some option for comments. It will have contributions from DM Endocrine students from all institutes in India. It will be a private wiki and only those with invites can view the contents.

It will be built in phases

Phase 1 : Collecting and building a searchable question bank
Phase 2: Review presentations
Phase 3: Journal clubs – articles and /or papers
Phase 4 : Image challenges

The responsibility for maintaining the wiki will primarily rest with second year DM students in each institute by rotation. The time required will be less than one hour per month.One or more early career (post DM) member will help/coordinate the whole process in each phase. Further sections and functionality can be added as required. If we have sufficient support, then the whole project can be completed within mid 2017 (Of course, if no one feels it will be worthwhile, the project won’t take off or will be shelved soon)
Please take the following survey to refine the idea further and give your comments. (You will be able to view the results soon). Please feel free to give your comments.

Take the survey here