Laboratory Testing

Be informed and be your own advocate


BY DR. BAYNE FRENCH

Most of us have a primary care provider. A select few of you may be fortunate enough to possess one with a sense of humor. And even rarer air might be one who spends a portion of their time studying health and wellness. Indoctrinated and dogmatic yes, but a truly unique soul that realizes the status quo sucks. And is willing to spend their limited time studying about a different, more effective way to help people that have bestowed their trust in them for health guidance. An awesome responsibility. This may seem quite easy. And in thinking that you would be a hypocrite. The marketing guru Seth Godin notes that a better way of doing things requires significant change. “They fly in the face of the status quo, and inertia is a powerful force”. Instituting any meaningful change is marketing…discovering “better” and sharing that journey.

The abbreviated lab testing for wellness and screening purposes that has suffused our medical training and consumer (patient) lives is inadequate. It finds a liver that is already fatty, arterial intimal lining that is already atherosclerotic, a midsection that is already obese, and knees that are already arthritic.

But the message of “better” needs to be delivered to an aligned audience in order to gain “customer traction”. That traction may lead to a micro-market of people that are better informed, thus more capable of advocating for their wellness. Basically, you need to want to reduce your risk of getting MAD (Myriad American Diseases) and have the temerity to seek it out. This is not radical originality. These tests have been around for ages. I’m not making the assertion that these tests will save your life and you must insist your provider order them for you stat! Nor is it an exhaustive list. I want this to be an introduction of what else exists, why I order what I do, and what that can mean for you.

Uric Acid (UA)

UA is the end-product of purine metabolism, formed in a multi-step manner. An important catalyzing enzyme is XO, a most affectionate little protein. Purines are nitrogen containing organic compounds found in high concentration in meat and meat products. Lentils, mushrooms, peas, spinach, asparagus, oatmeal, cauliflower and other non-animals also are dense with purines. So is beer damnit. If you read my last Pulitzer-worthy article on NAFLD/Fatty Liver Disease you recall that fructose is a potent driver of UA formation. Sugar is 50% fructose, and high fructose corn syrup is, well, higher.

When UA crystalizes in joints, the disease gout results. Why some experience gout with relatively low UA levels, and others never get gout at a very high UA level is not at all understood. Like most things in my profession of choice.

The actions of XO generate reactive oxygen species (free radicals) as byproducts. This is the fundamental reason UA is thought to harm the vascular system, but there are other mechanisms as well. The consequences are varied but appear to be elevated blood pressure, hypertrophy of muscle within the arterial wall, arterial stiffening, and elevated C-reactive protein (CRP, discussed later). But the lack of a clear causal mechanism between UA and cardiovascular disease (CVD) has led to this correlation being largely “ignored”, according to Muiesan et al. European Cardiology article in 2016. The familiar question being is this just an observed association or is there causality.

I was shocked to learn that a UA-CVD connection was first made in 1879! In 1889 a physician proposed a lower purine diet to prevent hypertension CVD. Oh to be a fly on that chamber wall…”You want us to stop eating gravy and beer?! Have you gone mad? To the rack with you!”

Many studies performed since the 1960’s show an association between UA levels and vascular disease at a level of 5-5.5. These are levels below recommendations from European and American rheumatology groups, which is <6. In addition, many studies in the last 50 years have supported UA as an independent risk factor for CVD. This is a statistical designation, one of strength, but still does not necessarily mean causality. There is much as yet that remains unknown. What is apparent however is that elevated UA is strongly associated with CVD irrespective of the presence of gout.

So what can be done about it? There are medications that reduce UA levels. No compelling evidence exists however that their use reduces the development of CVD. Functional Medicine trained physicians and Naturopathic physicians can likely competently advise realistic dietary recommendations to lower UA levels. I see the biggest reductions in patients that adopt a diet well balanced in quality plant and animal food. Many individuals can continue to enjoy higher purine animal product, even organ meats, without gout and with a UA level below 5 by reducing or eliminating beer and carb, especially sugar.

Iron

There exists very strong evidence of interplay between iron and the process of atherosclerosis, which then leads to CVD. Let’s review several purported mechanisms of the Iron-CVD Hypothesis:

1. Women who have had a hysterectomy (surgical menopause) or undergo natural menopause have the same risk of CVD as men. This suggests that menstrual blood loss may be protective. The notion that iron depletion can protect against CVD was suggested by Dr. Sullivan in 1981.

2. Iron stores in men start to rise in adolescents. This rise parallels the risk of CVD.

3. Iron stores in women start to increase at age 45, near the age when CVD starts to equal that of men.

4. CVD is low in geographic areas of frequent iron deficiency.

5. CVD is higher in women that use hormone replacement therapy, which decreases blood loss.

6. A large scale study over 18 years followed patients who had a genetic mutation disease Hereditary Hemochromatosis, which is characterized by high iron levels. These patients had a much higher incidence of both heart disease and stroke.

7. Studies on the effects of blood donation show CVD risk reduction. A study of 2682 men followed for 5.5 years found that blood donation reduced the risk of heart attack by 86%.

8. Exercise lowers iron levels. Exercise reduces CVD.

Salonon et al in 1992 performed a very interesting study of nearly 2000 Finnish men. The amount of stored iron as measured by ferritin was determined. Levels higher than 200, which is considered within normal range, had a 2.2-fold higher chance of having a heart attack. The risk was higher in the men that also had high levels of LDL cholesterol, suggesting a “synergistic role of high iron stores and high LDL-cholesterol”. They also found that for each milligram of iron consumed there was a 5% increased risk of CVD.

Studies that follow a cohort of subjects over time, preferably many years, are longitudinal studies. Catastrophic problems from some intervention or treatment, and allergic reactions occur relatively early but major problems can take years. Assurance of safety about any medical intervention when long term studies do not exist is a half-truth. Kadoglou et al performed a longitudinal study (mean of 7.7 years) and divided 5,471 patients into quartiles based on ferritin levels. Covariates like BMI, smoking status, exercise levels, and even wealth were adjusted for to make all the groups quite similar. Men in the highest ferritin quartile had a much higher incidence of CVD death. Interesting, this association was not seen with women.

It appears that the type of iron consumed makes a big difference. Heme iron is derived from hemoglobin, a protein that binds oxygen in red blood cells. This type of iron is found in animals, which we eat, presumably in their dead form. Non-heme iron is the plant form of iron. This type of iron is poorly absorbed from our small intestines. This is important for members of the vegetarian proclivity. Other studies took iron consumption to a higher level, differentiating between the two types of iron eaten. Only heme iron was associated with an increase in CVD. Red meat eaters beware! Snowdon et al found a 60% increase in the risk of a fatal heart attack (the Big One) in men who ate meat 6 days a week compared to men who ate meat less than once a week. Or maybe a bulging mid-section, deconditioned status, cigarettes, sleep apnea, elevated uric acid, and multiple micronutrient deficiencies are also involved?

Brian Frank I have good news for you. Exercise is a terrific way to lower iron levels, which means you’ll probably live to be 137 years old. I’ve read dozens of purported health benefits of exercise from dozens of sources. None of them mentioned the iron lowering benefits of exercise. Physical training reduces iron by numerous mechanisms, and a significant reduction of iron stores (ferritin) is seen at only 6 weeks of aerobic training. Also, strength training increases the demand for iron for the skeletal muscle protein myoglobin, so iron is pulled out of other tissues. Which is exactly what blood donation or menstrual blood loss performs. Furthermore, duration and frequency of physical activity were inversely related to ferritin levels. More exercise…lower iron stores…lower heart disease.

So what about that synergy between LDL cholesterol and iron? I’ll keep it brief. As described by the Haber-Weiss reaction, metal-catalyzed free radical formation occurs to all kinds of molecules. The metal is iron, and in this case the molecule is cholesterol carried around in our LDL particles. Highly toxic hydroxyl radicals are generated. These free radicals cause oxidative damage to cholesterol, in a process called lipid peroxidation. Native (normal, undamaged) LDL can (and should) enter the arterial wall without incident. Iron induced damage however leads to scavenger cells called macrophages taking up these damaged goods rendering foam cells. These foam cells are commonly found in atherosclerotic plaques.

So what do we do about this? Obtain an iron panel and ferritin level. If ferritin is higher than 300 for men and 200 for women Hemochromatosis genetic studies, another blood test, should be performed. Perhaps one day nontoxic oral iron chelating medication will be available. For now, blood donation is the best way to rid yourself of excess iron. There are well established protocols about how to do this but the optimal level of ferritin to shoot for is not known. Some authorities would say 50, others less than 150. A 2011 American Heart Journal study suggested that a level of 76.5 had the lowest CVD event rate. Ferritin is released from cells that are inflamed. Infection, inflammatory disorders, heck even a marathon can increase ferritin. These conditions also induce the production of ferritin in the liver. So high ferritin levels should always be interpreted with a C-reactive protein level, discussed below.

Diet as always should be honestly evaluated. I am an eater of animals. Most of which I caught, or shot and hauled out on my back. I eat animals that ate their native food, but the iron levels in their muscles are still very high. Which is why I try to limit it, and eat a lot of vegetables too.

Homocysteine

We possess a rather complicated structure called our genome, which resides within every cell of our body. In this genome are about 20,000 unique areas called genes which “code” for the production of proteins. They act like a blueprint for the construction of proteins. These 20,000 genes code for about 100,000 unique proteins within our human bodies. These proteins are made by linking only 20 amino acids together, in different orders and lengths. These 20 are protein amino acids. Nine of which are “essential”, meaning we cannot make them and must eat them. A “complete protein” is a food source that has all 9 and in general is animal in origin. Plants have protein but it is not complete, soy being the exception. There are many non-protein amino acids, meaning they are not directly used to build proteins. Homocysteine is one of them and is an intermediary in the metabolism of the non-essential amino acid methionine.

When methionine is needed, but low, B12 and folic acid help make it from homocysteine. When methionine is high, homocysteine is formed and vitamin B6 helps convert it to another amino acid cysteine. So there is a flux, depending on needs. Amazing right?

Why am I telling you all of this? So you’ll think I’m smart. And because homocysteine can drive many pathways contributing to CVD:

1. Direct damage blood vessel walls.

2. Interaction with LDL cholesterol (like iron) contributing to atherosclerosis.

3. Contributes to a reduction in nitric oxide resulting in blood vessel constriction.

4. Activates white blood cells (specifically monocytes) leading to inflammation.

5. Causes platelets in the blood to aggregate (stick to themselves).

6. Interferes with the livers ability to make a protein needed for HDL particles (“good” cholesterol).

Multiple studies have failed to show CVD event reductions despite the lowering of homocysteine. Thus the benefit of lowering strategies has been debated. You probably know the development of atherosclerosis takes decades. Biochemically it is apparent that homocysteine affects arterial health in a detrimental way. Most of the studies looking at B vitamin treatment followed patients for usually less than 5 years. These studies may thus be underpowered simply because duration of study was too short. In support of this notion is a meta-analysis performed by Wang et al and published in Lancet. No benefit from B vitamin treatment was seen in studies less than 36 months but statistically significant 29% reductions in CVD for studies over 36 months. Since CVD is the number one killer in America, and represents a multifactorial chronic problem, it makes sense to me to optimize as many modifiable contributors as possible.

Treatment options ideally to reduce homocysteine to <10:

1. Meat and eggs have high amounts of methionine, and may then increase homocysteine production. Animal product must be well balanced with fruits and vegetables.

2. Oral supplementation with 0.5 mg-5mg/day of folic acid reduces homocysteine by 25-30%.

3. B12 up to 1mg/day can lower homocysteine an additional 7%. Consider checking blood B12 levels to rule out pernicious anemia, or if you are vegetarian.

4. 5-25mg/day of B6.

5. Consider checking for MTHFR gene mutation. 10% of you have this genetic abnormality which interferes with creating an active form of folic acid. Given the ubiquity of this genetic problem I am in the habit of just recommending people use the methylated form of folic acid, which removes that required activation step. Vitamin B2 also becomes very useful in those with this mutation, lowering homocysteine levels by 22-40%.

Vitamin D3

While vitamin D3 is synthesized in our skin, many factors affect the degree to which this synthesis occurs (season, duration, geography, clothing, skin color, sunscreen, blood cholesterol levels and use of cholesterol medications, etc).

The traditional teaching about vitamin D has been that it enhances calcium absorption from the intestine. Without it bone health suffers. A much expanded role of vitamin D though exists. Calcitriol is the metabolically active metabolite of vitamin D (the body adds two hydroxyl groups to vitamin D to form calcitriol) and acts more like a fat-soluble hormone, interacting directly with our DNA. This is epigenetics…the interaction of environment including nutrition with our genome. Studies have supported that optimal vitamin D levels affect cardiovascular health, proper immune system function, mood, numerous neurologic processes, healthy blood sugar, and even periodontal health.

What about vitamin D2? D2 is found in plants and D3 in animals. D3 is much more potent such that 1 IU (international unit) of D3 equals 4 IU of D2. Consequently extremely high doses of D2 are required to correct a deficiency. I have spoken to a few clinicians more intellectually gifted than myself that feel this represents an unnatural situation. Consequently I have never treated a vitamin D deficiency with vitamin D2. Ever.

“Toxicity” is commonly asked about. I have seen patients use 10,000 IU of D3 hundreds of times for weeks and months to correct a deficiency, and have never seen an issue with overdose. I take 4000 IU every morning, year round. And what blood level of vitamin D should you strive for? Not sure. A level of 30 in Montana or Alaska in March is pretty darn good. A level of 30 in August though is not good, and could be single digits in March. Strive for 50, because it’s the most I ever scored in a basketball game. Recheck levels in 2-3 months.

C-Reactive Protein

CRP is a normal part of our immune/inflammatory system and will increase in response to any inflammatory stimuli (surgery, infection, trauma, a Spartan Ultra-Beast). It is a NONSPECIFIC marker of inflammation in the body.

In medicine, it is used to help diagnose or rule out inflammatory diseases and also to help assess the risk of CVD. Inflammation is essential for the development of atherosclerosis. Of course numerous compounds are also involved but CRP is particularly attractive as a lab test because it is stable, has a long half-life, no circadian excursions, and is not overly expensive to measure. Many, many large studies have demonstrated the predictive value of CRP for CVD events. Moreover, several studies have demonstrated CRP as a therapeutic target for reducing risk.

There are standard CRP measurements and high-sensitivity CRP measurements (hs-CRP). The high-sensitivity is more capable at detecting mild elevations and is a superior test. Level cutoffs vary depending on the institution or medical society but lower is better. Customary units of measurement are milligrams per liter (mg/L)

  • Low risk: <1
  • Intermediate risk: 1-3
  • High risk: >3. If over 10 an inflammatory disease process needs to be considered.

There is nothing in my experience more potent at lowering CRP levels than dramatic lifestyle improvements. Reducing all carb sources, especially sugar. Increasing nuts, fiber, fruits and vegetables. We already described how exercise reduces toxic iron levels and it too reduces CRP. The patients with obesity that I work closely with over time that lose and maintain weight loss commonly have a few point reductions in their CRP. Numerous medications can also lower CRP levels. These include statins, aspirin, niacin, metformin and my favorite…fish oil.

Hemoglobin A1c

Whether in your water bottle or in your blood stream, sugar is toxic. It creates inflammatory havoc whether you’re an endurance athlete or someone afflicted with obesity. Sugar sticks (covalently bonds) to fats and proteins, and never lets go. What results are Advanced Glycation End Products, ironically termed AGE. These compounds accumulate systemically, in numerous tissues from the brain to blood vessels. They perturb cellular signaling and function. They have been implicated in many disease processes including small and large blood vessel disease. If your goal is to gum up your cellular machinery and “age” at an accelerated rate you know now what to consume and fuel with. Interestingly this sinister action of glycation (NOT glycosylation, a totally different process) has resulted in a measurable test that provides outstanding prognostic data, the hemoglobin A1c, or A1c for short.

Hemoglobin is a protein in our red blood cells that carries oxygen. Sugar glycates it, and gives us an idea of blood sugar levels for the lifespan of the red blood cell, which is about 3 months. Traditionally a fasting blood sugar is relied on to screen for diabetes or prediabetes, the A1c being reserved only for those with already diagnosed diabetes and followed to determine effectiveness of treatment. This has changed a lot in the last few years, many providers screening many non-diabetic patients with an A1c, me included.

Like with many tests, no uniform optimal levels are agreed upon. Traditionally, labs will report 6.0 or less as normal. Functional Medicine practitioners consider <5.3 as optimal, 5.4-6.0 as being concerning, and over 6.0 as very abnormal. Diabetes is 6.5 or higher. Elevated A1c levels are directly associated with diseases of the eyes, brain and other nerves, heart and other cardiovascular tissues, liver (by driving NAFLD/fatty liver disease), and kidney.

There are many contributors to an elevated A1c, and understanding these unhealthy influences then drives corrective action:

1. Excessive carb consumption, especially sugar. The only patients I’ve ever seen cure diabetes and obesity have done it by adopting a mindful, and sustainably enjoyable low carb, higher fat diet. Their A1c’s plummet.

2. Artificial sweeteners. Yes, sadly aspartame, sucralose and saccharin increase A1c. Don’t consume them despite what many doctors, dieticians and diabetic educators still inexplicably advise. The plant extract Stevia does not appear to cause this problem.

3. Poor sleep. Chronic sleep deprivation results in stress hormones that drive up blood sugar. Getting at least 7 restorative hours per night is critical not just to quality of life and accident prevention, but overall chronic disease risk reduction.

4. Stress. Chronically elevated cortisol (stress hormone) levels lead to insulin resistance. Persistent elevated blood sugar results, driving up the glycation of hemoglobin. When you figure out how to manage stress in a competent way I’d sure like to know.

5. Low muscle mass. The bulk of lean body mass correlates with A1c, so do your pushups!

Complete thyroid testing

I now look at the thyroid and it’s testing completely differently than how I was trained. It didn’t take long to realize that massaging thyroid numbers into normal range did not always result in a patient feeling much better. “What!? You HAVE to be feeling better! Your numbers are perfect!” didn’t go over too well. Yep, my approach sucked like a bucket of ticks. Fortunately, in my limited arsenal of attributes I have two that have served me well…I despise dogma; and I care little about what other people think of me. Rivaled only perhaps by the traditional approach to cholesterol, thyroid analysis and treatment is contentious and fraught with emotion. And I don’t understand why. Let’s go over some basic thyroid hormonal sequence and function:

  • The hypothalamus is part of the brain. It secretes Thyroid Releasing Hormone (TRH) that has an arduous journey of several millimeters to the pituitary gland.
  • The pituitary responds to the TRH by releasing Thyroid Stimulating Hormone (TSH). This is the test we are mostly familiar with and many times is relied upon alone to diagnose thyroid disorders. Most labs report the normal range as 0.3-5.0. Some medical academies and societies feel the upper limit of normal should be closer to 2.5-3.0. Most functional medicine providers feel <1.5 is optimal.
  • TSH travels via the blood stream (like all hormones do) to the thyroid gland, which then responds by releasing T4 (90%) and T3 (10%). After its release, T4 must be converted to T3, the workhorse hormone. Optimal free T4 is >1.2 and free T3 >3.6.
  • T4 and T3 released from the thyroid are bound to Thyroid Binding Globulin (TBG). Only unbound T4 and T3 are capable of performing any work. They are in a constant state of flux. Attaching and detaching, depending on the metabolic needs of the body.
  • T4 MUST be converted to T3 to exert any biological activity. But some T4 gets converted to Reverse T3 (RT3). The problems here are two-fold: RT3 is not an active hormone, meaning it is incapable of doing any work at all. Similar to my kids when it’s time to mow the lawn or clean out the duck coop. Secondly, it will attach to the T3 receptors on cells, thus blocking them.
  • A fairly complete suite of thyroid tests consists of the venerable TSH, Free T3, Free T4, anti-thyroid antibodies, TBG, and RT3.

There is potential for dysfunction all down this brain/pituitary/thyroid axis:

  • The most common is Hashimoto’s Disease, which is an autoimmune attack on the thyroid. Anti-thyroid antibodies can be directly measured in this case. Many complimentary-minded providers strongly recommend complete gluten abstinence in this situation. The vast majority of these patients will need thyroid replacement eventually.
  • TBG may be elevated, primarily from elevated estrogen levels. If TBG is high, it will result in less free (unbound) thyroid hormone, causing hypothyroid symptoms. Treatment involves normalizing estrogen levels.
  • Thyroid Resistance. In this situation all thyroid tests are normal, but patients still exhibit hypothyroid symptoms. This is tricky because there are just so many reasons for feeling rotten. The problem is chronically elevated cortisol (stress hormone). This makes cells resistant to thyroid hormones.
  • Problems converting T4 to T3. There are dozens of nutritional deficiencies, medications, and lifestyle factors that inhibit the conversion of inactive T4 to the biologically active T3.
  • Excessive conversion of T4 to RT3. Certain infections, kidney disease, poor diet or extreme dieting, and bone marrow disease are some of the conditions that can drive the excessive formation of RT3.

I’ll give you a 50/50 chance of success in asking your medical provider to order these thyroid tests. Understand that they are responsible for everything they order and taking time to learn how to interpret these tests really doesn’t work too well in our production driven sick system. Cut them a little slack, they’re trying.

Omega-3 Index

In numerous other articles I’ve had the privilege to write for Endurance News, I’ve discussed the inflammatory properties of the “heart healthy” omega-6 vegetable oils. Corn, sun, safflower, canola, etc are really the only fats I avoid. They are ubiquitous in our food chain, delicious, and cheap. But unstable and easily oxidized into OXLAMS (Oxidized Linoleic Acid Metabolites) which serve an excellent roll in the development of myriad pathological conditions.

Omega-3 fats are antithetic to omega-6. They are anti-inflammatory and beneficial in so many ways. They consist primarily of EPA and DHA.

The cellular membrane is the wall around each cell. It consists of two layers of fatty molecules called phospholipids. Different types of fats may be incorporated into these barrier molecules, dramatically affecting cellular (and systemic) health.

The goal is simple: Minimize omega-6 fats and maximize omega-3 fats. Animals that ate their native foods have the best fat ratio in their meat and organs. Grain fed animals, well, don’t. Avoid vegetable oils, eat quality animal product, and supplement with fish oil.

A test exists called the Omega-3 Index where we can quantify our own fat profiles in the membranes of our red blood cells. I have never ordered this test, so have no experience with insurance coverage. Nor do I have any desire to interface with insurance companies unless forced. I have only helped patients interpret the results from home testing kits. For $50-100 and a drop of your blood you can obtain yet another healthful and preventative modality. Health Savings Accounts (HAS) or Flexible Spending Accounts (FSA) can be used to fund this test.

An unfavorable result with a higher risk of CVD is <4%. Intermediate risk is 4-8%. A low risk, optimal result is >8%.

Advanced lipoprotein testing

Nope. Not going there. This would be an entire article. Just know that there are emerging ways of looking at cholesterol that fly in the face of conventional. Hint #1, it has very little to do with your “bad” cholesterol. Hint #2, there is no “bad” cholesterol.

Conclusion

Remember your fictional doctor? The one with a sense of humor, eye contact, and doesn’t interrupt you? The one who studies not just the treatment of disease, but wellness? (Yes, I’m typecasting to make a point) I would advise that you change your own culture first. Don’t wait for “better” to trickle down vertically, and slog its way to the masses. Just because it’s arrogant to insist on a narrative that isn’t working too well, doesn’t mean it’s going to change. The status quo, the accepted standard of doing things is beyond criticism. It meets spec and is very tempting. Normalization creates a culture. Culture drives the market. And America’s culture is sick. The twin towers of Obesity and Diabetes dragging all of us, afflicted or not, down like an anchor. Change your own status quo first, because you and you alone will endure dis-ease. And a place to start is to realize that there are better ways of looking at disease risk. With this knowledge, horizontal spread can occur. Demand for a new breed of medical provider increases. Change occurs. The status quo shifts because culture changes. YOU are the micro-market.

 

Back to Endurance News Weekly