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Differences in Pathology with Dr Mark Donohoe

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Mark Donohoe Pathology

What's normal and abnormal varies according to your education and your focus in your medical or healthcare practice.

In this episode Dr Mark Donohoe returns to FX Medicine for both a practical and philosophical discussion on testing and pathology.

Mark talks about the differences between natural medicine practitioners and doctors in their approaches to testing, and how we can work together to find a middle ground. He also provides insight as to which tests which might not be giving us accurate enough results, how to optimise tests for certain conditions, and why there are so many variations in reference ranges and between laboratories. 

Covered in this episode

[00:51] Welcoming back Dr Mark Donohoe
[01:34] What defines a “normal” test result?
[04:25] Random testing: timing matters
[07:03] The challenge of functional medicine 
[10:26] Identifying disease vs optimising heath
[19:52] Hormone testing
[22:51] Getting to the bottom of a thyroid condition
[28:33] Are more tests really the answer?
[32:41] Variations in reference ranges between labs
[40:01] The problem with testing protocols 
[44:13] Testing after an IBS diagnosis
[51:44] Vitamin D testing
[54:43] Cautions on drawing conclusions from treatment after testing
[58:28] Thanking Mark and final comments

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us in the studio again today is Dr Mark Donohoe. He earned his medical degree from Sydney Uni in 1980 and worked around the central coast of New South Wales, honing his medical skills. And this is where his interest in integrative medicine sparked because patients weren't fitting into the boxes of diagnoses and treatments, which were drummed into him in medical school. 

Mark is considered one of the fathers of integrative medicine in Australia, and he's been the vanguard for all patients health throughout his whole career. Welcome back to FX Medicine, Mark. How are you doing?

Mark: Good. I'm happy to be a father rather than the grandfather for a change. I'm getting younger. And that's what happens when you do lifestyle medicine.

Andrew: Well, you're ageing disgracefully, which is wonderful to see. Today, we're going to be talking about interpretation of test results, which are many and varied. And there's a lot of controversy here. 

So, I guess one of the first issues that we have to talk about is who decides what's normal?

Mark: There is a statistical normal and there's a normal for the individual. And these things are at odds. And it probably, when you get down to it, this is one of the great divisions between the way orthodox medical profession assesses normality and abnormality. It's on a statistical basis. And if you move to the lifestyle medicine, to naturopathy, you move to people who are trying to encourage the regrowth of health, they're saying what's normal for this individual. 

A good example is a vitamin B12 level of 220. It's on the low end of the range doctor looks at and says, "Well, it's not going to cause anaemia, statistically, that fits within the 200 to around about 500 range, no problem.” The natural health care practitioner/integrative practitioner is going to look at it and say, "Hang on, this person is a heavy meat eater. The amount of B12 going in the mouth is enormous. Why is this a vegan or vegetarian type of range of vitamin B12?" 

So, you have a statistical normal range saying that there is no problem there, you have a deeper range saying it's inappropriate, that result for that individual raises a red flag for me, and I'm going to pay attention to it. And I think in a fairly deep level, that's one of the dichotomies that we have, if your job is firstly to make sure the person doesn't have a disease, you want quick and dirty tests that say, "Yep, not a problem, I'm not going to go down that way.” If you are looking to optimise health, you look at 200 as a B12 level and say, "Hang on, if this person is a lousy methylator, that's disastrous, that is the equivalent of potentially pernicious anaemia for that person." 

So, I do think that normal means different things to different groups. As people become more involved in the individual story, normal is related to the expected normal for that person, which is a much tighter range than the statistical normal of pathology results. When the pathologist sends their report back, they have a range that typically is for the not sick population all the way from around 18 years to 75 years of age. And so, we get different normal concepts. The doctor's job is often to triage, make sure that there is no disease and move on fairly quickly. The naturopath and the integrative practitioner's job is to try and see what can be interpreted to optimise health. And those normal ranges mean different things. 

And I think that at the core of what we're talking about today, what's normal and abnormal varies according to your education and your focus in your medical or healthcare practice.

Andrew: So, sometimes with a test, I’m trying to think of one at the moment, but you'll get very... Well, hormones, there you go, female hormonal cycle. At certain stages of the female menstrual cycle, you'll get expected norms of peaks and levels of various hormones at various stages, and they'll change with flux throughout the cycle. What you're saying is we should be looking at these peaks and troughs and relevant levels for more than just what is orthodoxly accepted. Basically B12, we should be taking into account the lifestyle of that patient rather than, "That is normal. End of story. Don't care what you eat."

Mark: Okay. Well, you've raised one other issue there. And that is testing is in many ways in humans critically dependent on the time of day, the time of month, there's a whole lot of variables. 

Andrew: Yeah. Yeah.

Mark: And when you get a normal range, say for oestrogen, they do make a difference of follicular cycle or follicular part of the cycle, the luteal phase, so the first half and the second half of the cycle. So, you do get in that one area quite good divisions. For male hormones, for immunology, you want to get a morning sample. And if you get an afternoon sample, it's not as reliable a test. So, there are a lot of subtleties in testing. Most tests are best taken early in the morning, where we've got good sample size, we have a really restricted range.

For a lot of tests, doing random testing is not much good. A good example, cortisol. Doctors do cortisol testing quite a lot. The morning peak of cortisol should be around about two to three times higher than the afternoon. Do doctors test it? No, because they're mainly interested in finding out do you have Cushing's syndrome or Cushing's disease? Or do you have Addison's? 

Whereas what a natural healthcare practitioner may be looking at is, are you under stress? Has the body got this kind of high cortisol 24 hours a day? And eventually, does it crash? Does it go down to low morning and low afternoon? Do they fall right off the medical scale? No, they don't. If they do, you're sending them to an endocrinologist and the endocrinologist is looking at adrenal disease.

But there is a big difference between adrenals not covering all the bases for you where you have exhausted, in a sense, you've exhausted your adrenal reserves and gone down to a very low level of function. Is that Addison's disease? No. It isn't, and a doctor and an endocrinologist will rightly say, "That's not a disease, that's just a metabolic state." So, that division, I think, is critical that we've got to be careful about what we're testing and what we're interpreting. 

My takeaway message, in a sense, is doctors have to first test to make sure you don't have a disease. If a doctor misses a disease, that's a problem.

Andrew: Bad. And we're seeing it.

Mark: Yeah, we do. And we see a lot of the time that the pressure on doctors is high. The amount of testing that they're willing to do because Medicare will come and visit you is low. And there are stuff-ups where we have missed disease in days past, in years past, we would have taken the time and we would have found it. 

I think the answer though is the doctors are this first step of a medical process. If you don't have a disease, and the doctors are convinced of that, then the secondary thing is, why are you not healthy? And doctors until recently joined in kind of lifestyle medicine, some involved in integrative medicine. That's not been the doctors' business before. Doctors have largely had the job of making sure that you don't have diabetes, you're not about to have a heart attack, you do not have cancer. These are really important tasks to do. And the tests are well suited for those answers. What they're poorly suited for is the chronic degenerative low grade, the fatiguing, the weak...

Andrew: And the homeostatic mechanism, the homeostatic cycles.

Mark: Yeah. And so, interpretation of that has never been part of pathology. We think of pathology as the testing for abnormalities that indicate disease. And doctors sometimes become pretty intolerant about 300 pages of other testing that's cost $1,000 in various places around the world, where to make sense of it, you need a PhD in making sense of that one thing. 

And so, the medical profession, in one sense, has good, quick, cost-effective ways of saying yes or no to disease states and then has a history of largely leaving people who don't fall into those disease states floundering a little. The next step is, "Doctor, what do I do?" "You should be grateful you don't have cancer. You should be grateful we've already got you on Metformin for your diabetes. What do you mean, what else can I do?"

Now, doctors are definitely getting better at prescribing lifestyle, exercise, of getting people to nutritionists and dieticians. But until recently, that job was left to other healthcare practitioners. And those other healthcare practitioners have used a range of tests which do not have a cut-off point for “you have a disease or not.” We already know that the person doesn't have a disease because they've seen doctors who've excluded it. Our job then is to say, "Well, what's wrong? Why is the engine malfunctioning?" We used this thing in the past where, in a sense, doctors are smash repairers. When things go nastily wrong, you want a smash repairer, you don't want a mechanic. However, you don't go to a smash repairer for maintenance of the car, you go to them when the disasters happen.

And I think naturopathy, integrative medicine, and the new lifestyle medicine is focusing on, “Okay, we've got disease out of the way, so why is this person not well and what are the factors that contribute?” That's where it gets tricky because when you've got multiple factors, you can do, say, amino acid testing, you can do nutritional testing, you find things moderately out of whack. And every specialist will say, "But that's not a disease," which is true. But when enough things go just to the edges of normality, correction of them has got the opportunity to restore a person's health. It doesn't fix their disease, but it does restore a sense of energy, our brain comes back, function comes back. And that's why we term it functional medicine.

Andrew: We've seen cholesterol.

Mark: Yes.

Andrew: You and I were discussing it earlier back in your day. It was 7.5 millimoles per litre, and it went to 6.5, then it went down to, was it 6? And then 5.5. And now, it's how low can you go? Why is that not done to catch these people at the outer limits of normal for, say, neutrophils? So, it seems like, certainly when there's a new drug on the horizon, the parameters had to be changed.

Mark: If you have a drug solution to solve a problem, then you can make a strong argument that pharmacology can sometimes drive research. Now, we have one that's live at the moment that is related to this indirectly. And that is, what's normal blood pressure? The new guidelines, the American guidelines are aim for 120 on 80. The general thing has been 140 on 90 over many years. The Italians have come out and done a study to say, if you just simply call hypertension, if you take the new guidelines, 61% of the population has hypertension, you triple the amount of people that are on medications, who does it serve to have that lower number? And what's the absolute risk, the total risk? You can make a case that if we aim for that, we will reduce heart attacks by 31%. Sounds fabulous, but only for the people at high risk, you don't make it a guideline for the population.

And I've already seen patients who are falling over, they're getting dizziness. These are 60, 70-year-old people for whom the push down to the lowest level of blood pressure is just bloody dangerous for them. To them, the worst outcome, rather than having a cardiac risk, is to fall over a buster hip, end up in a nursing home, have a stroke on the other side of it.

Andrew: Have a stroke from a fall.

Mark: Yeah. And we sometimes make the test result or the research result, we act as though it is a gold standard before anyone's really gone the extra distance, at least in blood pressure. There's a fair conversation in the cardiology section of our profession to say, "Hang on, that is ridiculous." And then you have the argument. And over the years, I think it is probably going to come to about 135 on 85, and we’ll say, look, those should be goals. But don't get too carried away with that. I have 70 and 80-year-old people, 180 on 100 has been their blood pressure forever, doctors have been telling them that they're going to die.

Andrew: Well, they are, eventually.

Mark: Well, they are eventually. And there are some people that for whom the risk is high and nothing seems to have ever gone wrong in their families, and other people who seem to be at no risk or low risk for whom these heart attacks just occur. So, we're forever trying to go for “What's the surrogates, what does the research tell us? What numbers should we be after?” And I think precision personalised medicine is a way through that, that not every person is just part of a statistical bell curve. There are some people on the family history where you know, everyone's dying in their 40s and 50s. You don't need genetic tests, you don't need cholesterol tests to pay a lot of attention to those people. You've got other people for whom everyone has had cholesterols in the 7, 8, 9 range, and who live into their 80s and 90s. Perfectly well, back in Italy on a Mediterranean diet, but just living their normal lives.

And I think the move from statistical pathology to precision and personalised medicine is a journey that we're right in the middle of now, genetics is part of it. But the old story of the family history, what's happened to your mother, your father, what's happened to your uncles, aunts, what's happened to your grandparents has always given doctors a bit of a genetic profile of the person in front of them. And you categorise them and say, I have a suspicion you're at risk. How do you put your finger on it? They look grey, they don't look right, they're struggling for breath. And you know that that's the person you pay attention to. The other one, that's the 70-year-old jogger coming in with a cholesterol of 6.5 and an HDL of about, say, 25% of that. You look at them, and you say, "Well, I know that this is not a high risk for you, you have done all the testing that I need of running up hills to know that you're not getting angina, that the cardiovascular risk is low. I'll do a coronary calcium score on you. Make sure it's zero. And if you're zero there, we can let you go about your life." 
And I think the move from statistical where the cardiologists will give everybody a statin, I think there's value to that after you've had a cardiac event. I don't think there's any doubt any longer that statins are valuable to people who've had a cardiovascular...

Andrew: Post STEMI. Post MI. Yeah.

Mark: Yeah. And that you don't pay attention to the cholesterol because cholesterol isn't actually that much of a risk factor. And secondly, it's very much a secondary risk factor that we accept now. Cholesterol itself is going through this transition. It used to be total cholesterol from the Framingham study, then it was LDL, HDL. Now, we've got the subfractions of the LDL and HDL. And each time, the medical profession gets dragged...

Andrew: But they are all subfractions.

Mark: I know. I know they're all subfractions.

Andrew: They are all subfractions, they're just wider subfractions.

Mark: But what we're looking to see is we're trying to peer in and predict the future from some tests that we're doing now, that's the value of these things. And I think everyone would now say the Framingham study, as it originally was reported, was not a great predictor. It became a little better with the HDL, LDL variations. But we still know that 50% of cardiac events are unpredictable. And then you delve into the deeper and deeper details. It's like fractals, every time you go deeper, you find that there's sub, sub, sub, sub, subsections.

Andrew: Maybe we should stop calling them sub, and call them better, they're better fractions.

Mark: Better fractions.

Andrew: They're sensitive fractions.

Mark: Yes. And I think that there is a value to trying to predict. But would it change your advice on lifestyle? Exercise? What would it actually change? I mean, it makes a very big difference to a doctor, do I or do I not prescribe statins? We now recognise the dangers of statins, we recognise the benefits of statins, you want to give it to the right people. And so, this concept of total cardiac risk has appeared. And it's a valuable thing, a valuable tool. But it's still only a measure of four or five different factors, your blood pressure, your age, your sex, your weight, your height, they give a crude estimate. I think that some of the genetics test of saying, “Well, here's the genes, maybe it’s the methylation genes,” that's a really useful one. Why? Because you see people with these homozygous 677T variants, where the brother and the father have died in their 40s or 50s of preventable cardiovascular disease. That's the kind of stuff that we need to know, it doesn't show up as a cholesterol, it doesn't show up in any other way. But it does show up as cardiac events and cardiac mortality.

So, the move from statistical normal ranges that doctors use to exclude disease, that is the most valuable testing because you know that if you get a negative result, it's a negative. And you know if it's a positive, it's a positive. What happens if there is a grey area in between where you have to interpret it? And no pathologist puts on, “Oh, normal is this. Think about it a little bit more if it's this, think about it a lot more if it's this, and pay a lot of attention if it's this." We don't do that because the doctor glancing says, "Has it got an asterisk? Or has it not got an asterisk? Does it look red? Or is it in black type?" And when you glance down page after page of pathology, that has high value. But once the doctor says, "You're not at risk, we've done what we can medically," there is a separate range of testing, which I would think of as optimisation.

What do you now need to know about nutritional factors, about your genes, about the lifestyle, about the degree of exercise you're doing? What effects are they having on your health? And I think a lot of what the naturopaths and integrative doctors order are highly complex tests. So, good example, amino acids in urine, they vary around quite a bit, we do a lot of interpreting of the urinary amino acids. We do a lot of interpreting of comprehensive digestive stool analysis. Why do normal doctors not do that? Because you can't even read through the report in the 15 minutes that you've gotten in a consultation. You have to take a lot of time, be trained in it, and it's a whole new way of thinking.

So, I do see that there...we can have our cake and eat it in a sense. I think we've got a great medical profession for disease handling, and proximate risk prediction. And we can tell the people who are soon going to die of a heart attack, cancer, whose diabetes is getting out of control and is going to have major problems. But once we've done what we can for those people, I think there's a second level of optimising of lifestyle management, and of testing that has not a cutoff of good and bad, but has a range of that we're trying to bring into an optimum level. And doctors and pathology testing is for disease identification, not for optimising your health. 

The closest thing that I can think of is sports people get into this very highly, when you've got elite sportspeople, you do not accept a haemoglobin of 115 because you know that person, at 115, while technically may not fit into the anaemic range, is never going to perform as they should. And if you leave them iron deficient, the iron deficiency will percolate through and it will affect performance. You can say that for other people in the community as well. What we're aiming to do is optimise, not get the bare minimum of what do you need to avoid disease, but what do you need to stay healthy as a positive way of minimising disease risk in the future.

Andrew: Just getting back to that homeostatic mechanism that we spoke of earlier. If you ask a clinician the perfect blood pressure, they will never give you a range. If you ask, they'll give you a number of a systolic over a diastolic, and that in our textbooks was 120 over 80. And now as we've discussed, there is variation on that. But if you ask somebody what is the perfect temperature, they'll sometimes say 37 degrees, but more often they'll give you that range. 

Now, I just want to take that a little bit further. If you do one test on a female hormonal cycle and it's a standard middle of the cycle test, how are you going to medically diagnose delayed ovulation? If it doesn't occur on the day that it is supposed to be in the textbook because it's a woman who is an individual, who has her own specific life things going on and her own specific physiology, pathophysiology. How is any doctor going to medically diagnose a problem?

Mark: We try and get around it. I mean, in a specific case, I should answer it. We try and do a luteal phase and a follicular phase. So, we try and get two different parts of the cycle. We say, one week after you started...

Andrew: When would you do that?

Mark: Well, day seven, day...

Andrew: No, no. When would you...forgive me. When would you suspect enough on symptomatology to ask for those two tests rather than one?

Mark: All right. Well, I do see endocrinology as a dark art, right? The endocrine system, we're trying to have forever interpret what the pituitary hypothalamus, the brain, the stress hormones, all of these things going on together in an orchestrated hole from this tiny little overworked pituitary gland. And we're trying to say, “What are you doing with fertility in this woman given all the other circumstances?” So, the crudest measure is people come in and say this all the time, “Do you think I've reached menopause?” There's a simple answer. If you do day 7, and you do day 21, and there's a huge difference and you're producing much more oestrogen and much more progesterone on day 21, no, you haven't reached menopause. If they are basically the same, and the two pituitary hormones, FSH and LH are sky-high, values over 50, 75, 80, 100.

Andrew: Not just FSH, but LH.

Mark: Do the pair of them because menopause is a complicated little area. And sometimes you have the oestrogen still percolating through and very high oestrogen levels and low progesterone. And other women have very high progesterone levels and no oestrogen. So you give the stimulus, one of the hormone productions still seems to work. The other one goes sky high because the stimulus is saying, "Give me more, give me more, give me more." And it compensates for it. And so, we do make interpretations of that. The failure of progesterone and oestrogen, there's two orders of magnitude difference between those levels. One of them is a high concentration in the bloodstream compared to the other, progesterone is way, way higher than oestrogen. Oestrogen is in effect the degradation product of testosterone and a way of getting rid of some of the sterol hormones through the system.

So, we do make those interpretations. One I would like to address though, is an endocrine thyroid. There is a massive divide between the medical profession with the thyroid and between all other practitioners, including integrative practitioners. Why is it that thyroiditis and thyroid cancer have gone up by at least a factor of 200% over a decade? What is going on in the environment? What's happening with that? 
So, still, we have, me and my colleagues do a TSH test. It's cheap, effective. And if you've got classical hypothyroidism, TSH is raised. And you say, "Oh, you're hypothyroid, let's give you Oroxine or Eutroxsig or any form of thyroxin." And the TSH comes down, problem solved. And so, for the vast majority of the medical profession, it's do a TSH, normalise the TSH, go home, and live with that for the rest of your life.

Andrew: But it doesn’t ask why.

Mark: That's true. So, the second issue is, well, we also have a kind of epidemic when you double or triple the incidence of something in the population, failing to ask why is just giving symptomatic treatment. Thyroiditis, what we used to call just Hashimoto's disease has escalated out of control. Thyroid cancer is rising at 6% per year. Why would that be happening? Well, part of it is we're better at diagnosing it. But there is at least most of that which is occurring for unknown reasons. There is clear links between coeliac genetics and thyroiditis, as the gluten goes up in the diet, you can expect that there will be a triggered inflammatory response because the same immunological mechanisms that cause coeliac disease cause thyroiditis.

Andrew: But is there more gluten in the diet?

Mark: There is, but the gluten in the diet may now change. There's a kind of social move now that's completely unrelated to doctors. If you're in the suburbs north of Sydney here and you don't ask for gluten-free, someone looks at you and says, "Do you not want the gluten-free variant?" 

Andrew: You’re not hip.

Mark: And so, the population swings in a way that makes no sense at all with the medical profession. We know only 1% of people get coeliac disease. There is now extraintestinal coeliac disease. So, we now have a concept in medicine that for every one coeliac case, there may be up to five others which are thyroiditis, type one diabetes, there are other expressions of coeliac genetics. Why is this important? Because in the medical profession, we look for thyroid disease and we treat underactive or overactive thyroid and we've got very effective drugs that do the job very quickly.

When you ask why, you say, “Oh, hang on. Maybe this is gluten triggering an immune reaction causing inflammation nodules, the thyroid's under stress, why is the TSH not high?” Because the pituitary is low that you can't flog an inflamed gland any more than you can run on a broken ankle. The TSH drops down because the body's is saying, "Well, there's no point asking this broken gland for any more." So, if you can do something, if you can replenish the iodine, if the iodine is deficient, you stop the thyroid from working so hard. If you can use selenium, 200 micrograms of selenium is the evidence based dose for reducing thyroiditis or reducing the antibodies that thyroid peroxidase antibodies, the group on the integrative and the naturopathic side are really interested in “Why did it happen and what can we do to stop it?”

Whereas the medical approach is more, what's broken? And how do we fix it? And I think that that decides why one group will go off and do very complicated thyroid tests and look at ultrasounds and have a look at the thyroid peroxidase antibodies and do all of that. While doctors say, "Well, what's the point of that? It's going to fail anyway." And in our experience with it on the integrative and naturopathic side is, it doesn't fail if you don't have the same circumstance. If you get the people off the gluten, you give them the selenium, if you provide for the iodine, if you give the body a chance to recover, the thyroid, like every other gland has got the capacity to recover. 

And so, the fiddling on one side, what I'm saying is the integrative and naturopathic fiddling is only fiddling if your mindset is, “Is it diseased or is it not diseased?” And when are we waiting to give replacement therapy? Or when are we giving something to settle down an overactive thyroid?

Andrew: So, the treatment decides the test you’d use?

Mark: What you can do defines what test you want to know about. And there's no point knowing about a whole lot of things of gluten reactivity, gluten genetics, all of those types of things if you're only going to do Oroxine or not Oroxine, if that's the only decision making. And why do I not regard that as a problem? Doctors covering hypothyroid or hypothyroid patients is a really important first step because that is a disease. The process of the disease and what you do to understand it requires a lot more investigation. And so, the tests on the other side are not, “Do you have the disease or not?” Because that's established. They are, “What is the process that's going on? What's the functional way in which this is progressing? And do we have tests that can tell us are you selenium replete? Have you got enough iodine?”

I think one thing that should be done in Australia is iodine, urinary iodine testing isn't...it's still not available under Medicare. It's way more important than most of the other nutrients that we're looking at because it is so common. And if instead of it being an $80 test that everyone avoids doing, then you can make the argument, okay, don't test it, just take a couple of milligrams of iodine every week of your life. But if you can identify that 30% of people who are low on iodine, the thyroiditis in that group can be diminished radically if you just had a simple test that said, "Get the iodine up." 

So, they come together a bit. I’m encouraged because I'm in an area of lifestyle medicine, integrative medicine, and orthodox medicine. I see the movement of doctors, I've given a couple of talks. Newcastle recently, up in Queensland, there's a lot more doctors, standard old GPs, attending lifestyle medicine and nutritional medicine in those areas to try and expand their skills. Not to become a naturopath, but to understand why there should not be a war between two groups, one doing a group of tests that are statistically based, and the others getting into the minutiae.

And I think the risk that within minutiae is we over interfere. So, if medicine has a risk factor it is, "Hey, I've given you Oroxine, go home." And then do nothing else about it. The risk on the other side is we turn minor abnormalities that may even be self-correcting into treatable illnesses that we go on treating for long, long periods of time. We put people on restrictive diets, sometimes very unnecessarily, but we don't know whether we're doing good or not. So, I do see the merging across being part of precision and personalised medicine. Medicine's grabbing for it, it doesn't have a history of being able to do it. The naturopathy on the other side do not have a history of clear diagnosis of disease states. And there needs to be, to use that term, there needs to be way more of a conversation between the groups. There could be exclusion diagnostics, you don't have the disease, let's go back to fixing up what your complaints are and use the more, if you like, the deeper tests of function, rather than tests of pathology to cross that barrier.

Andrew: I'm going to generalise. I'm going to make a general statement. So, forgive me here. But when you're talking about the conversation, one of the issues or a combination of the issues that I've seen is there are groups of naturopaths, for instance, that in the past have done bolus testing, a huge amount of testing, which is considered just inappropriate by GPs, and they're getting refusals because there's no seemingly real clinical need to do these tests. The tests are viewed in ratios and groups and what's happened. But the pushback... Thyroid is one, but there are others. And basically, the naturopaths have been asking for a battery of tests.

Mark: A GP has an obligation to make up their own mind. And so, that is what I would expect would happen. If you come from different world views, the GP has to administer a Medicare system. So that's the correct way that the GP should act, make sure they think that there is value.

Andrew: Conversely, not necessarily related to this, but conversely, there's this refusal by some GPs, that there is more to look at. And the endocrinologist is a classic, there is no reason to look at any more antibodies or anything like that. I've looked at FSH, I've looked at TSH. And so, there's this refusal. Do you think it would benefit Australia's and the world's healthcare, and indeed the patients', if there was more pilot/copilot decision-making thing here where it is the duty of the copilot to challenge the pilot on their decisions?

Mark: Wow, there are pathologies limitations, they are not accredited to say that... NATA, just to explain, is the National Testing Authority. Basically, they give spiked samples, they give standard samples, laboratories have to find results that fall within range with a high reliability. And so, you expect no more than 5% to 10% variability between two different pathologists, you have a high reliability. 

However, mislabeling of a tube is a thing that happens relatively regularly. And you can see it when a test result comes back. And as a doctor, you look at the previous ones, you look at the person, and you say that just does not make sense. No one knows exactly what's gone wrong in those circumstances, but a rapid retest sorts the problem out.

Andrew: You've just said 5% to 10% variability between tests, labs, right?

Mark: Yeah.

Andrew: Okay. Let's take those blood tests that come back. And they are "within range" but they're at the very margin of normal, why isn't there a standard variation to say this is actually blue area?

Mark: Yeah. So, rather than black and red, you could have a orangey and aggradation that gave more information. I don't think anyone would have a great problem with that, because I do see in my practice with people who've been chronically ill, you look at a result that has just occurred that is clearly abnormal, and you track back along the last three years, and it's been going down and down and down, there was a trend. And until it crosses the line, there's no asterisk, there's no red print. And that is a risk factor to a person who is going downhill. Some of them, like liver function tests much more commonly going uphill where the ALT has been good, healthy 16, these are the transaminase enzymes, good, healthy 16. And I see them and the test that I've got back is 48 to 50, just out of the range, but for four years, it has been going up.

There's another one, which I want to just shout out because it is unreliable, and we need to all pay attention to it, is anti-nuclear antibody. I had a patient just three years back, two labs done on the same day, one anti-nuclear antibody negative, the other one 640 to 1280. One of them had the rheumatologist make the decision that this was lupus. The other test done on the same time says no bother about any autoimmune disease. So, I talked to the rheumatologist and he said, anti-nuclear antibody is one of those tests that, depending on the kit, depending on what you see, you get very, very different results. Two different laboratories having a fourfold difference, eight fold difference is not that unusual. 

Andrew: Why is that important? 

Mark: Because one would have gone on methotrexate and the other one's going to be told go home, there's no reason for your joint pains. Those are the kind of variations...

Andrew: Both are probably inappropriate in this instance.

Mark: That is absolutely right. This is just a poor test because they're measuring different things. We had this with Candida antibodies years ago. There was one laboratory, one very good laboratory where the results were clinically meaningful almost 100% of the time. The laboratory went broke, shut down, test kits were available to others. Now, the tests are almost meaningless. You'd get this if the person is near death, they finally show Candida antibodies because they're near death, that's the only reason for doing it. And other laboratories that never find that there's no problem, and in other words, there's always a problem with Candida, why? Because it's a normal commensal organism.

Andrew: Yeah, I've always questioned that, it's a commensal, why? If we've got antibodies to it, does that mean that you've got a problem with it?

Mark: Yeah. Now that lies in the whole thing of immunology, have you got rising antibodies? Meaning that the problem is rising and falling, or was there a big event back in the past, which it's just declining, and it's on the way down to normal.

Andrew: But if you got a response to those antibodies, is it not just the presence of the antibody, but have you got an inflammatory process going on that your body doesn't like, and it’s taken...?

Mark: Have you got a clinically relevant thing? And that I think is a major difference between the two groups. If we kind of divide them up, clinically relevant to a doctor means you're showing signs of inflammation, you have got culturable Candida, say in this case, we know where it is at the base of the oesophagus, it's in a dangerous area, those things are critical to doctors. 

Whereas when we come to the other side, just having the antibodies can be seen to be a problem. Who's right? Well, clearly these guys are right in a sense that if you don't treat it, there's a life-threatening disease. If on the other side, you drop the Candida, you give strong antifungals, you go out of your way to do it, and nothing changes, then you haven’t helped that person. And I think a call that we could kind of make today is when you don't have clear statistical definitions of disease states and not, the rest of it is not a yes-no answer, it is let's test and see if this is important for you, have we got something that will do no harm that may be able to make a change?

And so, say for those people with high Candida antibodies, if you give them antifungal herbs or nystatin or if you even use Diflucan, and there is rapid resolution of symptoms, and the antibodies are falling, then you can make a very strong case that although it wasn't a fatal or potentially fatal disease, it was an inflammatory process that that person was struggling with. If you do all of that and nothing changes, irrespective of what happens to the antibodies, you haven't done any good for the person. So, doctors will act on test results to normalise test results as a surrogate of fixing a problem that will otherwise happen without much doubt in the future. Over this side, where we're doing functional testing, we're saying we're trying to change function to optimise health. If it helps you, we have to pay a lot of attention to symptoms, the doctor will not need to pay attention to symptoms. If you have chemotherapy and radiotherapy for the cancer, that's what you've done. And you're resting a lot on that technology having fixed your problem. Whereas the other side is looking always for optimise, optimise, optimise. I think the risk on our side in nutritional, environmental, integrative, naturopathic healthcare is that we over stress tests and under stress what we're really doing, which is trying to optimise the health of a person, and we are looking at what we can get from genetics testing, and everything else, as a kind of high-cost way of figuring out what's the next step for us to do.

Now, sometimes I see naturopaths, I see doctors, the story is great, the person understands what has been going on for them, they know that the gluten shouldn't be in their diet, they figured out methylation, they make sure their B12 and folate is good, and they're on a path to recovery. And that is fabulous, but unprovable, that what you did was helpful. Whereas the doctor has done chemo and radiotherapy over here, they've got good evidence because that person is either gonna die or not die, and they just count the bodies at the end of it. I don't have a problem with either side, I cross that boundary, I do a lot of functional testing, and I do a lot of medical testing for strict disease states. A third of all the patients that come to me with chronic, with supposedly chronic fatigue syndrome, have got a medically definable disease, it's just that everyone put it down to CFS too early, should have done some testing for the thyroid, should have done some testing for adrenal function and didn't do it.

And that's one of the dangers that as doctors try and be more holistic, you can sometimes lose sight of the fact that the testing that you should do to make sure the person doesn't have a disease should still be done. And the risk of the other side is naturopaths wanting to be more a doctor, they think that taking the tests on is adding science to what they do. And these tests are uninterpretable a lot of the time and meaningless and effectively become here's the story that I want to tell. How do I know that? Because I do the same test for every person that walks in, they all do the same amino acid gastrointestinal test. It is a protocol of here's the things that I look at to interpret you. And that is not individualised.

Andrew: No. This is the problem I have with, as you say, a protocol test battery. And that is that where is the care in there? That to me speaks of poor knowledge. That's what I would suspect is that somebody doesn't know what's going on, so do this, and hopefully, something will come up as a red flag.

Mark: Can I be more cynical?

Andrew: Yes, please.

Mark: Sometimes I think it is that you know that your tests are going to show abnormalities in almost anybody that you test. Everybody has weak points somewhere. And if you do a broad enough battery of functional tests, you will identify weak points. The question is, is that relevant to the person and their future health? Or is that just a protocol that you have administered in order to administer a herb, a pill, a potion, vitamins, minerals. If all you're doing is providing a permission slip for you to go and sell $300 a week worth of prescription medications or supplements or herbs, and then that's... I don't think that's an ethical practice.

Andrew: No, not all.

Mark: So if it really is...

Andrew: And that's pretty public.

Mark: I know everybody, and I have had people come back where the parents have said, "Well, I had the testing and it was just as abnormal. Why am I not sick?" And it's a really good question. So, there is more to it. The functional testings risk is you over-diagnose irrelevant things. The orthodox medical testing, the risk is that you under-diagnose preventable things. We're trying to find that middle ground and it is not easy to do. And often doctors use, “Is it on the Medicare Benefits Schedule?” The MBS is a kind of surrogate marker for a doctor of, well, it must be proven unorthodox, so I can then use it. And even that's not true, you can do a thousand tests on a Medicare Benefits...

Andrew: Coronary artery calcium.

Mark: Yeah. So, that's a very good example of one way because it never went on the schedule, there was a very slow uptake of doctors. What would you like to know about a person who you wonder about whether their cardiovascular risk is high? We don't want to give angiograms to everybody. Do the coronary artery calcium. The patient comes back and says, "That cost me 200 bucks." And we feel a bit embarrassed about it in medicine. So, that is a good example, I think of one where the coronary artery calcium will go on the Medicare Benefits Schedule. And eventually, doctors will get quite comfortable about early referral for coronary artery calcium scoring. And that provides a divider of those people with a cholesterol that you're not worried about. If their score is zero or close to zero, you can be comforted by that, that this is not a person you have to pay a lot of attention to.

Andrew: Well, there's still a caveat there. And that is that it checks for calcium, it doesn't check for atheromas. So, you can still have a fibrous cap without calcium, still be at risk. So there is always that sort of other section.

Mark: I know. There is.

Andrew: And of course the only way to check that is by doing the angiogram, which carries a high risk and should only be done under defined...

Mark: Yeah, we do the CT angiograms, they're pretty good these days. So, you can still go ahead and do it. And Ross Walker's a good friend of ours. And over the years, Ross is a very particular type of person, he has taken the coronary calcium scoring, and I think there is a grudging acceptance by the profession that if you had to pick one and you're on a desert island, you take the coronary artery calcium scoring as that thing that you would rather do and use sphygmomanometer, what's the blood pressure, what's the coronary artery calcium score?

It is a great dividing line to say, “Pay a lot of attention, don't pay as much attention.” It doesn't tell you who's going to have the heart attack, there are still going to be people with zero scores who have heart attacks. But there are going to be a lot more in the 400 to 1000 range that are going to have heart attacks with the same blood pressure and the same other risk factors. 

So, that's a test, which is a good triage test. It is not, “Here's your clean bill of health,” but it is the thing that you can watch over time and I do have patients where their score was zero, score was zero, score was 40, score was 160, score was 350. And as the years have gone past, it was never the good predictor we'd hope of what's going to happen in 10 years. It was what's happening at that time, and should you be paying attention now.

Andrew: Okay. So, tests are appropriate because they tell you something. When does a test become appropriate? When does it become inappropriate? For instance, a gastroenterologist trying to help a person who's coming in with cramping, alternating diarrhoea, constipation, really bad cramping that's affecting their lifestyle, and their work experience. They look at the Rome criteria, and it shows up as a functional gastrointestinal problem, and they've diagnosed IBS.

Mark: So, what do you do next? So there are two things that we can even talk about. They're both of them interesting tests. One of them is straightforward. The people with a genetics, the so-called coeliac genetics with irritable bowel syndrome, have a fourfold higher rate of getting over their IBS by simply coming off gluten. So, there was a really good study published in GUT. And if the only thing you knew was their DQ2 or DQ8 genetics, do they hold those genetics? You don't have any other prior conviction, then people with irritable bowel syndrome have a fourfold higher recovery rate by just getting them off gluten. 

Now, the limitations of that trial is that these were people with severe disease. There was massive reduction in symptoms, but not a return to normal. But the dividing line was, do you carry the genes that would make gluten a risk factor or not? But clearly, those who genes carried, so-called coeliac genes, carried the risk factor. You can do something for those people by saying nothing more than “Come off gluten.” And there can be a good reason for doing the DQ2 and DQ8 tests. The DQ tests are available under Medicare, all the pathologists do it. And you're not diagnosing coeliac disease, you're saying “Is this person's health going to make a profound improvement if they go off gluten? I don't want to take them off gluten unless there is a good reason to think it.” 

The other big test that we do for those kinds of people is SIBO testing, small intestinal bacterial overgrowth. And SIBO testing is a great example, in my view, of the division between functional medicine and orthodox medicine. Why? You do the same thing, you administer the lactulose, you administer the glucose, you're measuring the same breath, you're measuring hydrogen and methane in the breath after the test, you're doing it at certain intervals. Two different laboratories, I'm not going to name them. There are two different laboratories, one that generally serves doctors keeps on saying that even though there is a massive hydrogen rise at 30 or 60 minutes, that that's not important because it's probably just gone very quickly to the large bowel. The other one interpreted as classic small intestinal bacterial growth needing either antibiotic or antibiotic herbal treatment.

The same test results looked by two different pathologists, there is no gold standard. There is only “We know that this is a problem.” In the medical literature of people with IBS, there is literatures that say that only 1% have SIBO, and another, the literature goes up to 28%. And this is of orthodox medical care. So if a more than a quarter of all of your IBS patients have SIBO, it's an important thing to know about. You would think we would have a test where there's a clear dividing line. And yet, what we have a test is you look at it with one set of eyes and you'd say, well, that's important that we're going to use, say, Rifaximin, if you're a doctor, or berberine, allium, and oregano if you're not a doctor, and maybe do a particular type of diet. But we can't even agree on that. 

So, that's a really good example to me that I know if I send it to one lab, they're going to give me permission to treat SIBO because they'll report “This is classic small intestinal bacterial overgrowth.” I know if I send that same test to another laboratory, they're going to say, "No, no, that's just rapid transit through the small bowel." And they want both methane and hydrogen to rise to very high levels all simultaneously before they will say otherwise. We've got to pick our path in between those and say, “What are we going to do for the person? What is the right way of going about treatment”? And it delays our ability to be able to help a person who's got clear small intestinal bacterial overgrowth. We might under-diagnose it if we're a doctor, and over-diagnose it if we're a naturopath.

Andrew: Okay. But looking at that test, I can understand people having a sugar coma because they had a massive dose of sugar. 

Mark: Yes.

Andrew: So, sugar is a food which is normally encountered and glucose is a food which is often encountered in way too high amounts in a bolus dose.

Mark: And sucrose as the...

Andrew: But lactulose?

Mark: Yeah, I know.

Andrew: Lactulose also helps to feed certain probiotics. I get that.

Mark: And in leaky gut, in the intestinal permeability, it is the sugar that also does get through and is excreted in the urine. 

Andrew: True. 

Mark: So, it has no access to the body unless you have got, I guess, intestinal permeability. So, yeah, lactulose is a funny choice, but it is there for a reason. And that is, it's fermentable.

Andrew: It's fermentable. But the reason is to provoke a spike. 

Mark: Yes.

Andrew: So, who's to say that that spike is just a normal, "Hey, food, thanks very much" or “That is a bad spike because that's way too high?” Where are the nomographs done?

Mark: They're not. So, I'm actually saying that out loud. There is no widely accepted standard for this, and that's why orthodox doctors, orthodox gastroenterologists can say, "A quarter of my patients with IBS have SIBO." And another one can say, "No, it's 1 in 100." It's rare or it's common. When you have those kinds of divisions of opinion, that's because you've got a test that is not a reliable test, and where the nomograph has not been achieved, where you have not got good population studies. So, assumptions have been made all the way through a lot of the functional testing to say, "Well, normal should be this, but it's not."

Andrew: So, this smacks of conditions which are medically accepted like, for instance, polycystic ovarian syndrome or disease and endometriosis, which was just ignored, or the diagnostic criteria wasn't clear. It'd be really interesting to speak to people like Mark Pimentel, who's done a lot of work with SIBO, an unorthodox medical practitioner, how he's found that journey to, not the least of which to validate these two methods.

Mark: I think we are also in these areas moving towards capturing data from practitioners as they do their work. And I think that that's something that we need to get used to, that when we think that a test has a value, then we're part of the test community. When we do those tests, we have a bit of an obligation to say, "What was the outcome of treatment?" And so, if we get used to this idea in our practices, not just to simply be, "I will treat you and you might get better," but to document when it does and when it doesn't. That's the best research around, these are real-life patients coming into medical practices, where we are taking guidelines from research that tells us it could be a big problem. And if what we do is we test that over and over and we find there is no problem there, we're not really doing anything useful, then we need to have a way of reporting back. 

There are 10,000 practitioners out there who would love to contribute what they know about their patients, and we capture none of it. We've got an idea that medical records may do the good job. That's not right. In medical practice, it's one person on another person, there's the Me2U patient, the person has their own control, that's hugely valuable knowledge that just goes down the drain as we cure, or don't cure, each patient.

Andrew: We've mentioned previously a couple of tests which have been misused, if you like, or might not show the relevant data that we want to do to help patients. Recently in Australia, was it 2016, 2015, when both vitamin D and B12 were taken off the medical benefits schedule for screening. Now, vitamin D, I totally understand, we wasted millions. This is a paper by Kelly Belinsky at Westmead Hospital. And she found out that there were several instances of patients being tested, I think it was over 70 times. Now, I don't know anybody who would get a test done 70 times, let alone for vitamin D.

Mark: I do know how those occurred, because what was happening, I think was a failure of knowledge of the practitioners. What you measure is 25-hydroxyvitamin D. What you take if you're giving a supplement is vitamin D3, the unhydroxylated. What was frustrating a lot of doctors who were doing the testing was you'd have a vitamin D level of 30. You'd give them 1000 units of vitamin D, you'd measure it a month later — which was too soon, way too soon — you measure it a month later and it's 32. Go up to 2000, measure it a month later, it's 38. Go up to 5000, measure it a month later, and it's only 40. What was happening was the doctors were often ordering the tests expecting it to rise almost like lithium or a drug that you were taking where there would be a peak and you'll see it straight away.

And the second issue was it was always the liver not hydroxylating it. That was the problem. It didn't matter if you gave him 100,000 units of vitamin D3. The failure for the liver to produce the 25-hydroxy version of it was the reason that the test results always look bad. And I've seen that myself, you fix the liver of those people, their 25-hydroxy comes back to normal simply because the liver is now doing the hydroxylation.

Andrew: So, you got liver and kidney conversion, it could be another one.

Mark: The kidney was always thought to be the only conversion to the 1, 25. Every cell in the body has the ability to convert 25-hydroxy to 1, 25-dihydroxy. But what goes on is there's orders of magnitude change in the concentration, we can't easily measure the 1,25-dihydroxycholecalciferol, we can easily measure the 25-hydroxy. So, it was a measurement issue. Doctors were doing it because it was thought that vitamin D was not just any longer for bones, it was for heart disease, it was for cancers, it was for breast cancer. And so, there was an escalation of indications. And every doctor suddenly found their patients had these low vitamin D levels and thought that giving a month of treatment was going to be the answer. And I think what's worked out since that time is that the restriction of the benefits is you've got to have a good clinical reason to think it. The person isn't out in the sun. They're indoors the whole time. They've got dark skin. That all there is a metabolic issue.

Andrew: One quick last question. I need this. Tests which orthodoxy just poo-poos, totally, neurotransmitter tests, urinary neurotransmitter tests, this sort of surrogate marker of what might be happening, but the problem is that it can be affected by other factors coming in.

Mark: So many other factors.

Andrew: Pyrroles, Mauve factor, whatever you wanna call it, not accepted by orthodoxy.

Mark: No, not true. Pyrrole testing, when you get pyrroles up in the order of 200 to 300, our stock standard orthodox medical tests, that is pyrrole urea, which is no doubt whatsoever. The dividing line between normal and abnormal, people come back with values of 25, that is, 70% of the population has that. You can't call it a disorder when the vast majority of healthy humans have the same levels. So, the question about where you put your dividing line of the normal range is what I have a real problem with.

Andrew: So, that goes back to that acceptable normal range.

Mark: That's right. What do doctors want to know? What causes a disease. Psychiatric disease with pyrroles up in that area are quite high, and pyrrole management is important. Pyrrole management at 25 is probably not. I'm agnostic about the paediatricians who tell me that it is important for kids at those levels because we don't have the standard levels for kids at those levels. 

So, when I hear that the B6, the zinc, and the B12 work wonders in kids who have pyrroles above 25 and who are showing signs of autism spectrum disorders, hyperactivity and the like, I listen. Not because I know it's true, but because I will pay attention to a clinician who says, “It may not sound right, but it works in kids.” I know it doesn't work in adults, because I've seen the people, the adults who are treated. You give anyone a bit of B6, zinc, and B12, you're getting to do a bit of good for them. So, they feel better.

Andrew: And so the thing is you've measured something, you think it shows pathology or something wrong, you do the treatment, you get a benefit...

Mark: And you link the two things.

Andrew: And you link the two things together. So there’s the danger.

Mark: Yeah. And I think that that's the risk that we have when we get too complex in our interpretations. When we treat Lyme disease with antibiotics, we're forgetting it's an immunosuppressant. So, we always think, “I treated with this and proof will be that they're better.” That's a very weak correlation. There's many things we've done in medicine, where we did that, only to find out, "Wow, that was not a great idea." Antibiotics for sore throats were classic. They worked while we believed that they worked. Then as soon as we actually did any testing and found that they didn't work when blinded, we thought, “Oh my God, that's 50 horrifying years of overuse of antibiotics,” yes.

Andrew: Which has set up a horrible route to come.

Mark: But that goes outside. There's still the testing, in absolutely every one of these areas, there are clear abnormalities of biochemistry. And there are diagnostic, certainly, when you get to a particular level, pyrroles or anything else, there is a gray area in between, and then there is normality. And from my perspective, if more than 50% of the population has a value of the same or higher or lower as you do, that's not a disease predictor. You can make a case everybody's too fat, and so lipids may be a thing or blood sugar may be a thing to focus on. But that is...it's typically not to a medicine that we want something that finds the 50% or 60% or 70% because that's overload. Whereas if you're a natural practitioner, these 50%, 60%, 70% are too fat, who really need guidance and need impetus and need some pressure on them to make a change. Those tests are valuable for a high proportion of the population, the twain are not meeting right at the moment, and we've got to get that meeting to happen.

Andrew: Dr Mark Donohoe, I think with this one, we're going to leave with so many more questions than answers.

Mark: So, what else? What else is new about our discussions?

Andrew: But I do love the way that with your experience, you've seen what's gone in the past, you've seen the flow of patients, and you've seen what comes out at the end. And we really need to be...to take a responsible stance in treating our patients for the least amount of cost, not just for them, but for the Australian public purse. I think we really need to keep in our mind constantly, what are we doing and why are we doing it? And how is this going to benefit Mrs Jones in front of me? 

So, thank you very much again for joining us on FX Medicine.

Mark: It's been my pleasure, as always.

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.

Other episodes with Mark include

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