5 TESTS that SHOULD be in Your ANNUAL PHYSICAL (but are not).

Change happens when you ask for them

Introduction

One of my ongoing frustrations with the healthcare system is the slow progress in improving how annual physicals are done. The intent is to assess your overall health status and to catch problems before they advance to a level where treatment options and efficacy is reduced.

We can all guess the reasons why tests are limited. Keep costs low, do not over test as it is a waste on money (here I remind everyone of its purpose is to catch problems early). However, there is more to this than just $$, part of the issue is that the business of medicine is too slow. The practice of medicine can be classified as a slow adopter on new information and thinking. When societal costs are involved the pace slows down even further.

The purpose of this newsletter is to bring to your attention 5 tests that should be done in order to truly get a strong picture of your overall health status. Some may not agree with the choices, or have personal favorites that they wish to promote. That is great, it is part of healthy debate, and priorities may change with the demographics of the population one is testing. While applaud the recent inclusion of vitamin D, the reality is that we can do much more.

1) Cardiovascular Health: ADMA

When I discovered some 35 years ago that the lining of blood vessels (endothelium) was dysfunctional and a critical early drover of cardiovascular disease (Endothelium & CV disease) it set off an entirely new approach to managing cardiovascular health. It remains the most common denominator of hypertension. Nevertheless there are still critical gaps in how we assess this key factor.

In this context the purpose of the endothelium is to release gasotransmitters (nitric oxide and hydrogen sulfide) which promote vasodilation and limit platelet aggregation. In essence keep the pipes open and flowing. In hypertension, the production of nitric oxide is limited. Nitric oxide is produced from the amino acid, L-arginine, which is then converted to citrulline.

In cardiovascular disease and with some drugs there is an increase in the circulating levels of an arginine analog called ADMA (asymmetric dimethyl arginine), and this form of arginine that possesses and extra methyl group competes with L-arginine for nitric oxide synthase, but ADMA cannot be used to make nitric oxide. Hence, scenarios where ADMA levels are elevated results in a compromised ability to make nitric oxide (ADMA & Nitric Oxide).

Indeed, elevated levels of ADMA is both a prognostic indicator of severity and outcomes for a number of diseases including pulmonary hypertension (Pulmonary hypertension & ADMA), glaucoma (Glaucoma severity & AMDA), sleep apnea (Sleep apnea, hypoxia & ADMA), venous thrombosis (Thrombus & ADMA) to name just a few.

One of the more disturbing drivers of high levels of ADMA (and its chemical relative SDMA) are the drugs used for gastric reflux, specifically the Proton Pump Inhibitors (PPIs). This is an unintentional consequence because it was unknown at the time of their development that they also inhibit another enzyme called DDAH, and the purpose of DDAH is to degrade these high levels of ADMA. So if you take a PPI for reflux you place yourself at very high risk for numerous cardiovascular-driven morbidity and mortality where the data indicates a 68% increase in death (Mortality and PPIs).

Very large studies have determined this outcome but because PPIs are now over the-counter-drugs (and therefore very safe?) the FDA has not issued warnings. Another case of too big to fail.

Here are some of the critical studies on PPIs and ADMA-driven outcomes.

• Vascular calcification & Kidney disease (Kidney disease & PPI)

• Dementia (Dementia & PPI)

• Heart Disease and Myocardial Infarction (Myocardial Infarction & PPIs)

An alternative pharmacotherapy that does not interfere with nitric oxide production are the histamine receptor antagonists (famotidine, ranitidine) as they do not affect the activity of DDAH.

2) Tenascin C

Tenascin C is a glycoprotein (a protein with attached sugar residues) that forms an important part of the matrix. Recently, high levels of Tenascin C are powerful prognosticators of cancer development, metastasis and death.

I outlined the importance of Tenascin C in another Substack newsletter (Tenascin C & Cancer). Briefly, we have focused on mutations as the primary driver of cancer. This is largely because we felt that the erroneous behavior was all driven by a defective code.

However, it is clear that this is not all the story by a long shot. Regulation of genetic switches are vitally important as well. This field of epigenetics plays a massive role in cell/tissue behavior and the aging process. The other critical element is to take the conversation beyond the cancer cells themselves to a better understanding of how they interact with their environment. The matrix is more than a protein/glycoprotein glue that holds tissues together. We now appreciate that the matrix can dictate cell behavior.

In the context of cancer and tenascin C, the high levels of tenascin C encourage cancer cells to misbehave (replicate) and then provide them a superhighway to other sites (metastasis). This is true for solid tumors and blood cancers. Studies have now shown that this matrix glycoprotein is a better indicator of how advanced and aggressive the cancer is, as well as the prognosis.

While this blood test may be necessary for everyone, those at risk or with a family history of cancer would be well served to have an assessment of tenascin C.

3) Gut Microbiome

With the advent of inexpensive, genetic profiling we have been able to finally document the species of microbes that live in our gut. The array of bacteria, yeasts and bacteriophages is indeed complex, with at least 10,000 species the flow information is daunting. While we may not fully appreciate the precise roles and interactions of these different species we have been able to define so serious bad boys and appreciate how some helpful species may help us regain the real estate that is the gut.

Perhaps the most dramatic examples of microbiome-oriented therapy occurred with the management of Clostrodium difficile infections. This nasty infection can be endemic within hospitals and lead to severe patient morbidity and mortality. Indeed, it was in the case of nothing else can be done situation that the microbiome as a therapeutic agent revealed its true potential.

The treatment was a total gut microbiome transplant engineered via fecal microbiome transplant (FMT) where a sample of stool from a cohabitator (eg family member) is mixed with a saline solution to make a stool slushy (bear with me here, that is not a typo) and then inserted into the colon of the afflicted individual. There are now plenty of cases where patients who were on their death-bed were able to leave the hospital in days after the FMT.

It is likely that FMT or its smaller, more agreeable approaches of probiotics/prebiotics will be common health tools, especially given how antibiotics have created an army of resistant, nasty microbes (Gut Microbiome based therapeutics).

Potential targets for Optimizing the Health of the Microbiome include

• Gastrointestinal health

• Depression, anxiety, and stress management

• Dementia

• Cancer

• Cardiovascular disease

• Sports Performance

• Liver health

• Obesity

• Immunity

Taking us back to the thrust of this newsletter is Annual Physical Tests how do will we assess the status of our gut microbiome health? While it is not currently a mainstream test there are plenty of commercial enterprises that do just that, linking results to adjustments in diet and including supplements of prebiotics and probiotics to reclaim the real estate from the bad actors. However, that tool has not moved into the mainstream as yet - but it should as there is ample evidence of its importance.

In an article that I wrote as a prescient analysis of how we will assess and manipulate the microbiome for optimal health for NutraIngredients-USA (Our health 50 years into the future) I predicted that genomic advances and personalized medicine will merge 50 years into the future into a steady state analysis of our gut flora with SMART TOILETS. Here a bowel movement will be analyzed by the toilet, creating a profile of your microbiome and make suggestions as what elements are out of balance, and how to correct that. Indeed, I proposed that by the time you go to your kitchen a prepared cocktail of microbiota will have been constructed to be part of your daily meals.

The future of health management will be heavily focused on the microbiome, given that its represents 10x higher levels of DNA than our own DNA, and that there will be real-time adjustments in microbial balance through pro- pre-biotics.

However, bringing it back to today. While the tools exist to assess our microbiome it is not part of our Annual Health Assessments - and it needs to be. Further, with all tests we need to have it lead to actionable items, for the microbiome we have tools (diet, supplements) to correct problems that may be identified. One may argue as to how effective they are, but it is better than doing nothing and ignoring the importance of their role entirely.

4) Inflammation

Society has grown to accept that message that inflammation is a critical driver of poor health especially with aging, and its ramifications extend to all organs. Given the mountain of evidence that supports this thesis, there is very little in the way of testing that is done in the context of annual physicals to assess the current state of inflammation. The only marker that is used routinely is C-Reactive protein (CRP or hsCRP).

The question is “Is this the best we can do?”

I would pose that CRP alone is inadequate. The core problem is actually chronic inflammation, not acute (like an injury or a splinter etc.). Chronic inflammation is regulated at the gene expression level with gene switches activated by oxidants and free radicals, activating thousands of products that contribute to the inflammatory response. For the most part these genes are dormant. It is dangerous to have them turned on all the time - as in the case of chronic inflammation - they are tools that must be used sparingly on a need be basis.

Hence I would propose that health assessments would be best served with markers that are regulated transcriptionally (gene switches activated by oxidants).

There are many options but here I think being cost conservative I would push for IL-6 (IL-6 Inflammation In older Women). There many studies that show that health and IL-6 are intertwined, with high levels associated with pathology and effective interventions lowering IL-6 levels. Il-6 is also part of the cytokine storm that is present in the friendly-fire aspects of COVID19 (IL-6, Cytokine Storm and COVID19)

5) TMA: At the Intersection of Diet, Microbes and Cardiovascular Health

Trimethylamine is an intriguing molecule that is generated by gut microbes from various dietary components and then further modified in the liver to TMAO. The latter is quite pro-atherogenic and is considered as a major driver of atherosclerosis and cardiovascular disease.

However, we are still focused on arcane drivers of cardiovascular disease like cholesterol and lipoproteins. These are confusing to the public e.g., good vs bad cholesterol, which is confusing as it is not the cholesterol being measured but different lipoproteins and the real concern is whether the lipids are oxidized (that would mean they are rancid). Note cholesterol is not a lipid it is a steroid - the mother chemical of estrogen, cortisol, testosterone, progesterone, aldosterone etc. We really have done a disservice here in the way we describe the problem and assess its dangers.

So yes, let’s raise our game and include TMA/TMAO levels in our annual physicals.

As to the origins of TMA, there are those that push for it as a measure of red meat being bad for you, but that is more of a bias than data driven conclusions. For example, while vegetarians have lower levels than meat eaters, there is still 70% overlap in the blood levels. Further, the only way to eliminate TMA/TMAO levels is to use antibiotics to kill off the gut microbiome (TMA TMAO and Diet).

TMA and TMAO at its core are problems of a dysfunctional gut microbiome, less so a diet issue. Correcting it should involve interventions that target the microbiome.

So for our annual physicals, there is value in assessing our lipid profile but we need to make sure we include an assessment of whether the lipids are rancid (oxidized) or not. Plus we must add in an assessment of our TMA and TMAO levels. If high initiate interventions that correct the dysbiosis that is driving the problem.