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Date: 25-04-2013 Discussion about Vitamin D

By Dr. Georgi Abraham.

Discussion about Vitamin D 



Mr. Vaibhav:  Hello friends, it is an honor to be having Dr. Georgi Abraham with us today.  Dr. Georgi Abraham actually needs no introduction and he has been kind to allow us this interview today, but just for the benefit of the viewer I would like to briefly introduce Dr. Georgi and his achievements.  Dr. Georgi Abraham currently is a professor of medicine at Pondicherry Institute of Medical Sciences, Puducherry, and is also a consultant nephrologist at Madras Medical Mission Hospital, Chennai.  Other than clinical work and teaching, Dr. Georgi has research interests, which are focused on metabolic bone disease, vitamin D homeostasis, nutrition, and tailoring to reduce the dosage of immunosuppression in transplantation.


Dr. Georgi, it is indeed a pleasure to have you with us and many thanks for taking out time.  Dr. Georgi my question to you would be why is this interest in vitamin D all of a sudden or what is it really that has triggered your interest in vitamin D?


Dr. Georgi Abraham:  Vaibhav, I am delighted to be here and thank you for this interaction.


Basically, nutrition is very important for population at large.  Unless we eat and especially vitamins are supplemented in our diet, we may not have a healthy life.  Especially D, because it is important in bone health and also in other aspects of our daily life, and if you have vitamin D deficiency, you can be sick and it may also lead to various other complications which may not be obvious initially, they may be certain.  For example, my parents lived up to the age of late 90s, both of them were healthy, they lived in a village with enough sunlight exposure, and my mother when she got very old she developed metabolic bone disease and I was wondering why my mother developed metabolic bone disease and has it got anything to do with the diet she eats or the environment she lives in and hence this interest of vitamin triggered me to look at both healthy population and people with chronic kidney disease.


Mr. Vaibhav:  Thank you, this brings me to the first question of today's session.  Dr. Georgi, it is observed in many studies that vitamin D deficiency is very rampant even in a tropical country like India.  Can you please explain the reason for this?


Dr. Georgi Abraham:  Vaibhav, it is a very interesting question.  We have a lot of sunlight in our country, despite that why are our population vitamin D deficient?  Is it because of the way we live, is it because we are in enclosed environment with air conditioning and do not go out?  No, that is not the reason.  We have a brown skin and it looks that brown skin people do not have the ability to convert 7-dihydroxycholecalciferol to cholecalciferol despite we getting enough sunlight.  So, this is something to do with our skin.  So, we may have to look at our skin and see that what is happening and research needs to be done whether anything which is done outside on the skin can improve this conversion and help us in getting enough vitamin D into our body.


Mr. Vaibhav:  That was a good explanation because that is one question which keeps coming to our mind again and again as to despite of abundant sunshine, why do Indians are vitamin D deficient.  Sir, you have generated a lot of extensive and original data on vitamin D, especially vitamin D status in Tamil Nadu.  What is your observation about vitamin D deficiency among your patients? And I ask this question especially because Tamil Nadu is known to have the least cloud cover which allow direct UV rays exposure from sun and hence the natural vitamin D synthesis.


Dr. Georgi Abraham:  Vaibhav, I could tell you that while looking at my patients with chronic kidney disease and I find that there are a subset of population who are on dialysis, others have been transplanted, and another subset of patients have chronic kidney disease at various stages who are not on dialysis.  While especially looking at the dialysis population we have 2 types of dialysis population whom we take care of; the chronic peritoneal dialysis patients as well as the maintenance hemodialysis patients.  We found that about 50% of the chronic peritoneal dialysis patients when they initiate peritoneal dialysis they are vitamin D3 deficient, i.e., the levels are below 30 ng/mL and in the hemodialysis population we found it less often.  Maybe, they have been on vitamin D before or probably for some other reason we found the deficiency only in about early 30% of the population.  However, in transplant population we found something very intriguing.  We found that about 73% of our transplant recipients had vitamin D deficiency necessitating vitamin D supplementation in them.  So, it looks that different illness and different treatment pattern have different effects on vitamin D levels in our patient population.


Mr. Vaibhav:  Now, Dr. Georgi which form of vitamin D should we assay to get a correct picture of vitamin D status of a patient and what is the recommended upper limit of plasma concentration.


Dr. Georgi Abraham:  Very interesting question because we need to look at the vitamin D in different ways.  When we do the assays, we usually look for 25-hydroxyvitamin D3 level.  It has been expressed in different CMB Programs in India and abroad that 25-hydroxyvitamin D3, even though it is an inactive form of vitamin D3, is a measure of vitamin D levels in the body.  However, I have seen some publications abroad where they look at 1,25-dihydoxyvitamin D3.  However, this is not practiced very commonly.  Now, when we look at the vitamin D3 level, a level 30 ng/mL and above is considered to be normal, 30-15 is considered to be insufficient, and 15-7 is moderate deficiency, and less than 7 is severe deficiency.  I have seen this even in doctors who are most of the time indoors who are among the general population and also seen in chronic kidney disease patient and in other subsets of patients.  So, I would suffice to say that 25-hydroxyvitamin D3 estimation is sufficient enough to know the vitamin D level in a individual who is healthy as well as who has some other co-morbidities.


Mr. Vaibhav:  Dr. Georgi, can you explain how the physiologic actions of vitamin D are affected in patients with CKD compared with persons with normal kidney function?


Dr. Georgi Abraham:  Well, what does vitamin D do?  We all thought from earlier information that vitamin D mainly controls calcium-phosphorus homeostasis with the help of parathyroid hormone.  However, we also know that this endocrine function is not the only action of vitamin D.  Vitamin D has also got nonendocrine, paracrine functions, which are important to keep us healthy.  For example, our immune system and our cardiovascular system and also other endocrine system including, if you have a co-morbid condition like diabetes, vitamin D has its implications and play a role in maintaining the normal homeostasis.


Mr. Vaibhav:  Thank you, Dr. Georgi.  There is one question which keeps coming up, because with the new data and new literature which has come out it is now being seen that the enzyme 1-alphahydoxylase in kidneys which convert 25-hydroxy D to the calcitriol or the active form of vitamin D3, the same enzyme is also present in almost all peripheral tissues.  I am particularly talking about the non-renal tissues, which incidentally have vitamin D receptors as well.  So, does this vitamin D have some nonclassical actions?


Dr. Georgi Abraham:  Yes, you are quite right, we have seen 1-alphahydoxylase in the skin, in heart, in vessels, macrophages, and it is also widely distributed across the nephron and we you look at the extra-renal distribution of 1-alphahydoxylase.  Earlier on people thought that these are 2 different entities; however, they are by the same gene product, which is seen in the kidney as well as in the extra-renal tissue, but however the functions in extra-renal tissues are different from those seen in the kidney.  So, one should take into account what does this vitamin D do in the myocardium, especially in the cardiomyocyte?  What does it do in the blood vessels?  What does it do in the macrophages, which are part of the immune system?  What does it do in other parts of the body?  So, this should be analyzed and one should have some information as well as insight into this when we look at vitamin D and how supplementation of vitamin D helps in protecting our body.


Mr. Vaibhav:  Dr. Georgi, cardiovascular disease is one of the major causes of death in CKD patients.  Is there any causal association between the occurrence of high rate of cardiovascular abnormalities like LV dysfunction and vitamin D deficiency found in CKD?


Dr. Georgi Abraham:  Recently, there has been a very interesting publication from Denmark looking at a large cohort of nearly over 10,000 patients, general population, looking at their vitamin D level who were not getting supplemental vitamin D and looking at their cardiovascular status.  It was reported that both in men and women, those who have lower vitamin D levels, i.e., 1 to 2 quartile compared to 50-100 percentile they had more cardiovascular death from myocardial infarction, from left ventricle heart failure, left ventricular hypertrophy, atherogenesis.  So, this points to the fact that vitamin D is very important in the function of the heart, the vessels, and also other cardiovascular diseases so that we can be protected from cardiovascular incident and cardiovascular morbidity and mortality by maintaining our vitamin D within normal limits.


Mr. Vaibhav:  Dr. Georgi what is the role of vitamin D on the RAAS system and especially in patients who are diabetic?


Dr. Georgi Abraham:  The renin-angiotensin system is important in a number of ways in health as well as disease because you need a normal renin-angiotensin system, but when you are diseased or when you have over stimulation of the renin-angiotensin system, it can lead to complications.  For example, the vitamin D levels if they are low, there could be activation of the renin-angiotensin system, as a result you can have high blood pressure, you may have cardiovascular abnormalities.  So, if your vitamin D levels are normal, it will down regulate the renin-angiotensin system and keeps it under normal control, thereby it would reduce your blood pressure and it would also have an impact on your diabetic control because it is said that patients with insulin resistance, when they are supplemented with vitamin D if the vitamin D levels are low, this would lead to improvement of the insulin resistance and also in patients with diabetic neuropathy, it has been shown recently and published in Kidney International and other major medical journals, that supplementing vitamin D and bringing the level back to normal can lead to amelioration of the proteinuria and this can be used as a modality of treatment for proteinuria in patients with diabetic neuropathy.


Mr. Vaibhav:  Dr. Georgi a lot has been talked about vitamin D and its effect on the immune system.  What are your views and opinions of vitamin D and its effect on the immune system?


Dr. Georgi Abraham:  Just to quote a simple example, one of my colleagues who is a young cardiologist was admitted with pneumonia in our hospital.  So, when I looked at him there is no reason for him to get pneumonia because he is a young, vibrant, trendy man.  So, when we did the investigations we found that his phosphorus levels were low and when we looked at his vitamin D, it was very low at less than 5 ng/mL.  So, vitamin D plays a major role in keeping your immune system and also maintaining immune surveillance, so when you have less vitamin D levels and as a result you also develop hypophosphatemia, this can lead to infections, which can sometimes be dangerous and it can lead to increased morbidity and mortality, especially people who are elderly and fragile.


Mr. Vaibhav:  Thank you that explains it, Dr. Georgi, because we always felt that it is a vitamin so it will have some effect on building the immunity, but we really did not know that there was so much for vitamin D than it is really been seen.


Dr. Georgi, albuminuria is a hallmark of diabetic neuropathy, is there any evidence that vitamin D may have anti proteinuric effect via the RAAS or angiotensin-mediated mechanism?


Dr. Georgi Abraham:  Yes, you are quite right and vitamin D has a effect on the renin-angiotensin systems because we all know that there is up regulation of renin-angiotensin system when you have diabetic kidney disease so we want to bring it back to normal, so vitamin D supplementation will definitely help in reducing the proteinuria and especially albuminuria in patients with diabetic neuropathy and this may also have a beneficial effect in bringing the blood pressure under control because you are blocking the renin-angiotensin system which is overstimulated.


Mr. Vaibhav:  Dr. Georgi this is going to really help a lot of doctors across the country.  There are so many brands and so many molecules of vitamin D which are available and being sold in India like cholecalciferol; calcidiol; calcitriol, the active form of vitamin D.  Will you please give us a broad outline about the indication of each of them and their major limitations?


Dr. Georgi Abraham:  Previously, we were mainly using in our chronic kidney disease patients the prohormone alfacalcidol because it was cheap and then came the calcitriol or 1,25-dihydroxycholecalciferol, which is the active form of vitamin.  However, we found that when the 25-hydroxycholecalciferols were low we would like to replenish them with cholecalciferol and as a result we found that cholecalciferol came to the market and this was really a boost to the physicians taking care of patients with vitamin D deficiency.  Even my own family there are a number of people who have vitamin D deficiency as well as vitamin D insufficiency, so I was looking for a substitute and I found that some of the preparations were easily taken and some of the preparations were not that popular so one has to choose which is the best one depending upon the palatability, the ease of use, and the efficacy of that.


Mr. Vaibhav:  That will definitely help Dr. Georgi.  I think that simplifies a lot of questions that lot of us have about which one to chose and in which indication.  Now, we talk about cholecalciferol, vitamin D3, and patients with CKD, what is the actual recommended dose and is there any role of high dose of vitamin D3, the 60,000 units, that I am talking about in a chronic kidney disease patient?


Dr. Georgi Abraham:  Certainly, yes, because as I told that patients on dialysis, a substantial number of them do have 25-hydroxyvitamin D3 deficiency and we know that vitamin D receptors are present in number of tissues in the body and there are also tissues which can convert 25-hydroxy vitamin D3 to 1,25-hydoxy vitamin D3 because of the presence of alpha hydroxylase in extra-renal tissues.  So, patients who are severely deficient in vitamin D3 or moderately deficient in vitamin D3, we can supplement them with high-dose, palatable and acceptable vitamin D3 supplements, and I would suggest that something which is palatable and which can be taken easily should be the supplement of choice for patients with chronic kidney disease.


Mr. Vaibhav:  Dr. Georgi, how serious is the risk of vitamin D overdosing resulting in vitamin D toxicity?


Dr. Georgi Abraham:  It is not very common, but it can happen.  For example, if somebody has only vitamin D insufficiency and if you give them a large dose of vitamin D without properly monitoring them, they can develop hypercalcemia, because one of the side effects of vitamin D supplementation is hypercalcemia because calcium is absorbed in the small intestine, normally about 15-16% of the ingested calcium is absorbed, but when you supplement vitamin D, it can go up to 25% and in patients who have only insufficiency if you give vitamin D, high dose, without proper monitoring, they can develop hypercalcemia and hence this should be kept in mind while prescribing vitamin D supplementation.


Mr. Vaibhav:  What are the obvious signs and symptoms of vitamin D toxicity?


Dr. Georgi Abraham:  In healthy general population with normally functioning kidney hypercalcemia can give rise to polyuria, i.e., excessive urination in large volume and it can also give rise in the long run to calcification in other tissues such as extravascular calcification, vascular calcification, and also it can give rise to renal stones and patients or people with hypercalcemia can develop psychiatric complications and also peptic ulcer disease and symptoms related to the gastrointestinal tract such as constipation.


Mr. Vaibhav:  That brings us to the last question of today's interview.  Dr. Georgi, is it true that only patients taking the high doses of calcitriol injections need to be worried about vitamin D toxicity?


Dr. Georgi Abraham:  Not necessarily.  As I have already alluded you, I have seen some patients with chronic kidney disease when they see an orthopedic doctor, they prefer to give them vitamin D injection and especially Arachitol in our country.  However, I had the bad experience of a patient, rare but this is to be highlighted, patient with rheumatoid arthritis who was taking methotrexate and steroids were given repeatedly vitamin D injections over many years along with calcium supplementation without properly monitoring the calcium and she developed significant hypercalcemia and nephrocalcinosis and came to me with end-stage renal failure, this is very sad.  So, I would like to highlight that when you are given high-dose vitamin D, especially injectable form with supplemental calcium, please be cautious and monitor the calcium level and vitamin D level and vitamin D level 25-hydroxyvitamin D3 level should not exceed 50 ng/mL.


Mr. Vaibhav:  Thank you, Dr. Georgi.  It was indeed real enlightenment as far as vitamin D and the extra effect of vitamin D are concerned.  It really threw a lot of light in terms of how vitamin D should be viewed and what are the real cautions and precautions that need to be taken when prescribing vitamin D.  Many thanks again on behalf of all of us, it was a pleasure to have you with us.


Dr. Georgi Abraham:  Thank you Vaibhav, I enjoyed it.  I hope we will have more interactions in future.

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