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LIFESTYLE AND FITNESS  RESEARCH
How Does a Ketogenic Diet Affect YOU? Part 3: C-Reactive Protein: A Marker
of Inflammation

BY FRIEDMANSPROUT
APRIL 1, 2015
COMMENT 1
by Katie Mark

The latest craze surrounding the ketogenic diet has us further investigating whether or not a
high-fat/low-carbohydrate lifestyle might be an appropriate dietary approach for some
people. In this 3-part series (click here for part 1 and part 2), we’re evaluating how the
ketogenic diet affects biomarkers.
The ketogenic diet is a very low-carbohydrate (<10% of total calories), moderate protein and
high-fat (>70% of total calories) diet. After at least two weeks of keto-adaptation, the body’s
energy source switches from glucose to fat.

In part one of “How Does a Ketogenic Diet Affect YOU?” we found studies suggesting that
nutritional ketosis lowers fasting glucose and insulin levels and possibly increases insulin
sensitivity. In part two, we investigated the impact of ketosis on cortisol. We found that a
high-fat, carbohydrate-restricted diet may increase certain forms of cortisol, but blood
cortisol levels are only half the story. Further research is needed to clarify the relationship
between ketosis and an increase in certain forms of cortisol: the active form (cortisol), the
inactive form (cortisone) and metabolites of cortisol from enzymatic breakdown.

Now let’s evaluate how the ketogenic diet affects C-reactive protein (CRP).

Increased CRP: Is there a need to worry?

C-Reactive Protein Model

CRP is considered a marker of inflammation. The liver makes CRP when inflammation in the
body is present. High levels of CRP are influenced by genetics, high stress, exposure to
environmental toxins and a sedentary lifestyle. Diet can also impact CRP levels, especially
diets high in refined and processed foods.

There are two blood tests to measure CRP. The non-specific test indicates acute CRP levels
that result from general inflammation in the body. The more sensitive measure is the highly
sensitive CRP (hs-CRP) test, which accurately measures basal levels of CRP by measuring
inflammation in blood vessels. The hs-CRP test is the accepted measure to determine the risk
for cardiovascular disease (CVD).

Higher CRP levels signify a higher risk for developing CVD and abdominal obesity. Weight
loss is known to decrease markers of inflammation such as CRP.

It is believed that a high saturated fat and very low carbohydrate diet (VLCARB) increases
the risk for CVD. A study published in Nutrition Metabolism (London) compared a VLCARB
diet to two low saturated fat, high carbohydrate diets to determine their effect on body
composition and CVD risk. The isocaloric (similar calorie composition) diets were: very low
fat (CHO:fat:protein; %SF 70:10:20), high unsaturated fat (50:30:20; 6%) and VLCARB
(4:61:35, 20%). The study concluded that weight loss resulted in a reduction of CRP
regardless of the dietary macronutrient composition. Yet, it is uncertain whether or not the
macronutrient composition of a diet influences inflammation.
A study published in The Journal of American College of Nutrition found an increase in CRP
in overweight women who followed a short-term low carbohydrate, high-fat weight loss diet.
The study reported that an increase in CRP might have resulted from the oxidative stress
caused by this type of diet.
Another study published in Obesity (Silver Spring) looked into the inflammatory response
caused by a high-fat, low-carbohydrate weight loss diet (HF) by randomly assigning 19
overweight men and women to either an antioxidant (AS) or placebo (P) supplement. The
objective was to see if the antioxidants vitamins C and E could decrease the inflammation
reported in a HF diet.
CRP decreased 32% in the AS group and increased 50% for the P group; however, this was
statistically insignificant. The HF diet did not decrease CRP within the short-term 7-day
study even though other markers of inflammation decreased.

The study could not confirm if oxidative stress was causing the inflammation. It was
concluded that further research is needed to determine the different CRP responses over the
long term, especially while using antioxidant supplements. This is important considering
most fruits and vegetables, which are low in fat, contain antioxidants.

The Verdict
A ketogenic diet may increase CRP levels, but weight loss reduces CRP levels. The reason
for the increase in CRP is unclear. One plausible explanation is that low intakes of
magnesium, vitamin C and other nutrients while on a ketogenic diet may lead to this effect.
When magnesium is low, CRP increases. It has been reported that increased vitamin C intake
may reduce high CRP levels.

An imbalance between anti-inflammatory fats (omega-3 fatty acids) and pro-inflammatory

fats (omega-6 fatty acids) is another possible explanation. Polyunsaturated vegetable oils
primarily contain the pro-inflammatory omega-6 fatty acids. Eating less grain-fed meats and
chicken and more grass-fed meats and free-range chicken is also important to consider.
Grain-fed animals have higher omega-6s whereas grass-fed animals have higher omega-3s.
Omega-3s are anti-inflammatory and important for normal body functions, including
regulating blood clotting and building cell membranes in the brain. Omega-3s are also
suggested to protect against heart disease.

An elevated CRP level is never a good thing. If you are opting for a ketogenic diet, increasing
magnesium and vitamin C intake as well as choosing grass-fed products may reduce CRP
levels.

ver the last decade, our research has demonstrated that nutritional ketosis is surprisingly

effective at reducing chronic inflammation. This observation helps to explain the prompt and

dramatic benefits seen with type 2 diabetes and may also demonstrate the potential to

improve a number of other chronic diseases.

An Overview of Inflammation and Nutritional Ketosis

Inflammation is a complex fabric of signals and cellular responses from our immune system

that enables our bodies to recognize and respond to infection and injury. Having too weak of

an inflammatory response leaves us prone to infection or impaired healing. But having too

great of a response, or one that remains over-active for too long, puts us at risk for a form of

chronic injury that underlies type 2 diabetes, coronary heart disease, many common cancers,

and Alzheimer’s disease.

This balance between too little and too much inflammation is exquisitely delicate, and it is

regulated by a number of circumstances including our genetic inheritance, toxins in the

environment, and by many components of our diet. One of the first purified drugs designated

for human use was an anti-inflammatory compound—aspirin. Currently, we have a host of

different drug classes designed to modulate inflammation, but safely managing their dose and

duration of use requires professional vigilance to avoid dangerous side effects.

In the past decade, nutritional ketosis has emerged as a potent modulator of inflammation.

And, unlike drugs that typically target just one aspect of the body’s immune response, keto-

immuno-modulation (KIM) seems to work evenly to balance the anti-inflammatory effect in a

safe, sustainable and surprisingly potent way. Using various blood tests that monitor various

inflammatory signals, nutritional ketosis has been shown to reduce these signals to a degree
comparable to the most powerful drugs currently available. Importantly, it appears to do so

without the serious side effects that characterize most pharmaceuticals. Herein we will

present some of the evidence behind KIM as a novel therapy that may allow us to prevent and

reverse what are currently regarded as chronic progressive diseases.

Measuring Inflammation Levels

Inflammation has been studied by doctors since the time of the Greeks, but those early

observations were for the more severe forms that cause obvious symptoms like redness,

fever, pain and swelling.

With the invention of the microscope, scientists discovered white blood cells, and saw that

they went up during fever and injury, but then came back down when the illness was over.

From this information they identified a ‘normal range’ where the white blood cell (WBC)

count of most apparently healthy people resided.

Beginning in the mid-1980s however, pioneering scientists initiated a process that is defining

a new normal range for the WBC count. Early reports have linked values that are chronically

in the upper half of the ‘old normal’ range with increased risk of heart attack, and this is true

even in people with normal cholesterol values²,³. In other words, a biomarker of inflammation

that is in a range predicting future disease cannot be considered normal.

But that was just the start. Since then, these high-normal WBC levels as well as another test

reflective of inflammation in the body called C-reactive protein (CRP) have been shown to

also predict the development of type 2 diabetes⁴, many common forms of cancer⁵,⁶, and

probably Alzheimer’s⁷.

Beyond the WBC count and CRP, there are many different cell types, proteins, and lipid-

derived molecules that participate in the modulation of inflammation and immune functions.

These fall under a number of class names like cytokines, chemokines, eicosanoids, and
isoprostanes. While the details of these compounds- origins, functions, and interactions, are

way too complex for this overview, we need to understand the breadth and delicacy of this

web of interacting bioactive factors. And perhaps most importantly, their modulation either

‘up’ or ‘down’ is a delicate process in order to maintain the body’s essential immune and

repair functions.

Complexity of Inflammation at a Glance

The processes within the body that control growth, repair, defense against infection, and

recovery from injury are some of the most basic to our survival. And, given that they have

had over a billion years to evolve, it is understandable that the interlocking functions of

immunity and inflammation are multi-layered and extremely complex. Every organ in the
body, from the skin to the intestine, has its own characteristic defense that goes into action

when a threat is perceived. When any organ is damaged it releases signals into the circulation

to alert the rest of the body. This is how a local infection in a foot or a lung can cause the

whole body to develop a fever.

So, whether it is an acute local infection causing major inflammation and fever, or something

more subtle, like a dietary allergen irritating the intestine, these systemic immune and

inflammatory signals can be measured in the blood. Some of these measurable signals are cell

types called white blood cells, some are proteins that are made in different organs like

muscle, liver, or adipose tissue, and some are peroxidized fats released from cell membranes.

Through these circulating signals, the body’s various systems communicate, and the whole

process is elegantly choreographed to protect life and function without over-reacting (e.g.,

driving fever too high or making way too many white blood cells).

There are circumstances, however, when this delicate balance gets too much stimulation and

a class of disorders called auto-immune disease can occur. In this instance, the body’s

activated defenses attack some of its own organs, causing conditions like rheumatoid arthritis,

lupus, psoriasis, and type 1 diabetes. These immune disorders in turn can increase levels of

the circulating inflammatory signals, and over time these can affect additional organs. For
example, people with long lasting rheumatoid arthritis are at increased risk of heart disease,

as are people with type 2 diabetes.

Drugs that Reduce Inflammation

Starting with aspirin, managing inflammation and immune responses has been a favorite

target for drug development. In general, the older, established drugs tend to have more

general modes of action and a broader spectrum of side effects. Recent pharmaceutical

research has moved to target specific enzymes, bioactive molecules, or white blood cell types

involved in inflammation to try to reduce side effects, but this has turned out to be a double-

edged sword. By focusing on just one single step in the complex cascade of the
inflammation/immune system, there is a strong tendency to distort this system rather than

reduce the inflammatory effect in a balanced manner.

Table 1. Examples of anti-inflammatory drugs, their uses, and side effects.

The risks associated with chronic use of a variety of anti-inflammatory drugs are well known

and often outweigh the desired benefits. One example is chronic aspirin use, which has been

used to reduce heart attacks in people already diagnosed with coronary artery disease. When

used in this instance, (as ‘secondary prevention’), it is associated with reduced long-term

mortality. However, when aspirin is used routinely in people without known heart disease
(primary prevention), overall mortality—primarily due to fatal hemorrhage—is significantly

increased⁸.

In another example, a mono-clonal antibody that targets the cytokine IL-1beta and its

downstream product C-reactive protein (CRP) was administered to people with known heart

disease and elevated blood CRP levels. The purpose of this study was to see if a drug that

reduces CRP, without reducing LDL-cholesterol, could prevent heart attacks. After studying

10,000 people over 4 years, mortality from heart disease was significantly reduced by 15%;

but death from all causes was no different between the active drug and placebo groups. The

reason: the mono-clonal antibody reduced immune function to the extent that an increased

number of people died from infections⁹.

These two examples are characteristic of a host of studies indicating that the long-term side-

effects of current anti-inflammatory drugs can end up negating their beneficial effects. Thus,

this type of chronic treatment has been reserved for patients whose underlying inflammation

puts them at high risk—for example rheumatoid arthritis, severe asthma, or organ transplants.

Dietary Anti-inflammatory Treatments

There are a number of foods or purified nutrients that claim to have anti-inflammatory

properties, however, most of those claims are based upon shaky, limited, or non-existent

human study data. Some of the popular anti-inflammatory nutrients that, when administered

as supplements, have not yet stood up to scrutiny are fish oil¹⁰ and green tea¹¹.

Another popular antioxidant with anti-inflammatory properties is vitamin E (in particular the

alpha-tocopherol form). It has been used in hundreds of studies with very mixed results. At a

very high dose (1200 mg/day) Vitamin E appears to reduce CRP in people with type 2

diabetes¹² but may come with other risks¹³. A different natural form of vitamin E—gamma-

tocopherol—has much more potent anti-inflammatory and oxidative stress lowering

properties when used alone¹⁴,¹⁵,¹⁶,¹⁷ or in combination with the omega-3 fatty acid DHA¹⁸.

This latter study suggests that potent anti-inflammatory effects can be achieved, with
apparent safety, by combining moderate doses of nutrients wherein each component acts on a

different aspect of the inflammation web.

Aside from supplementation, weight loss itself has been shown to reduce inflammation¹⁹, and

it appears that the greater the weight loss the larger the anti-inflammatory effect²⁰. This could

be attributable to a reduction in the amount of very inflammatory visceral (belly) fat, and/or a

result of some patients being in nutritional ketosis.

New evidence that BOHB has potent regulatory effects on inflammation

Among the many ‘nutritional factors’ with potential anti-inflammatory properties, the ketone

beta-hydroxybutyrate (BOHB) is emerging as both highly potent and uniquely safe as a long-

term treatment for inflammation. Long discounted as just a by-product of fat metabolism,

BOHB has recently been found to have significant gene signaling/regulating (i.e., epigenetic)

effects. In the physiologically normal range that is seen with nutritional ketosis, BOHB

activates a number of different genes that protect our cells from oxidative stress²¹ and

inflammation²².

We hear a lot about the dangers of free radicals and oxidative stress, but how does oxidative

stress cause inflammation? One possible way that reactive oxygen species (ROS), aka ‘free

radicals’ appear to be connected to inflammation is through the creation of compounds called

isoprostanes. Isoprostanes are created when ROS attack specific fatty acids in cell

membranes. These isoprostanes are structurally similar to some of the pro-inflammatory

prostaglandins made by cyclo-oxygenase (COX) enzymes—the compounds that are blocked

by NSAIDs. But in this case, because there is no enzyme involved in the formation of

isoprostanes, NSAIDs can’t block their formation. However, by enhancing the body’s ability

to stop ROS before they can attack membrane fatty acids, BOHB prevents this whole class of

pro-inflammatory compounds from being created in the first place.

Figure 1. Contrasting effects of diets containing carbohydrate-plus-protein totals above
30% (thus suppressing ketogenesis) and a ketogenic diet on down-stream inflammatory
pathways regulated by beta-hydroxybutyrate (BOHB).

The hypothesis that isoprostane production by ROS is an important contributor to chronic

inflammation, and thus influential independent of acute inflammation or injury, is hard to

prove. This is because there are many (perhaps dozens) of different isoprostane molecules

that result from the random attacks of ROS on membrane fatty acids. Many of these resultant

isoprostanes are themselves highly reactive, so they change or disappear quickly, making

them difficult to measure accurately. As a result, it is challenging to determine the variance

among individuals as well as the influence of factors like a ketogenic diet on isoprostane

production.

That said however, we have noticed and reported in multiple human studies that upon starting

a well-formulated ketogenic diet, the fatty acid most commonly attacked by ROS, called

arachidonic acid (AA), promptly increases²³,²⁴,²⁵; and when the ketogenic diet is stopped,

AA quickly goes back to the lower, baseline level²³ (Volk MEAL Study, unpublished). It is

important to note that at the same time that we see this ketogenic diet-associated rise in AA,

the level of its immediate precursor goes down sharply. A reduction in the precursor provides
an indication of how much AA the body is making. These ‘footprints in the sand’ strongly

suggest that much less AA is being destroyed by ROS when the body is in nutritional ketosis,

therefore less needs to be made in order to maintain optimum membrane levels of this

important essential fatty acid. (Figure 1) Intriguingly, the level of AA in muscle membrane is

strongly correlated with insulin sensitivity²⁶ thus offering a novel mechanism to explain the

heretofore mysteriously prompt improvement in insulin sensitivity upon initiation of a

ketogenic diet.

Clinical Studies Demonstrating Reduced Inflammation

These newly discovered actions of BOHB are exciting, but how potent is its anti-

inflammatory activity? In a randomized trial comparing two weight loss diets—one ketogenic

and the other low fat, high carbohydrate—the ketogenic diet demonstrated much greater anti-

inflammatory effects after 12 weeks; and these reductions were seen in multiple inflammation

biomarkers, implying a broad-spectrum rather than focused mechanism of action²⁴.

Additionally, in our Virta/IUH study of patients with type 2 diabetes, both WBC count and

CRP were dramatically reduced in the ketogenic diet group compared to the usual care group

at 1 and 2-year follow-up²⁷,²⁸. In particular, the reduction in CRP in the ketogenic diet group

at 1 year was comparable in magnitude (35-40%) to what is seen with the most potent statin
drug. But unlike the statin, which appears to be primarily focused on CRP and has no effect

on WBC count, nutritional ketosis addresses both, providing a more balanced effect on the

network of interacting bioactive components influencing inflammation.

Summary: Nutritional Ketosis for Chronic Inflammatory Diseases

Nutritional ketosis has anti-inflammatory and immune-modulating effects that are as potent

as the most powerful drugs, but with a more balanced effect across the complex spectrum of

bioactive compounds and physiological functions. This explains in part the unique initial, as

well as lasting effects, of a well-formulated ketogenic diet in reversing type 2 diabetes, pre-

diabetes, and metabolic syndrome.

In addition to improved insulin sensitivity associated with less membrane damage from ROS,

the anti-inflammatory properties of nutritional ketosis could be beneficial in other diseases or

conditions beyond type 2 diabetes. There are an increasing number of case reports describing

improvements in auto-immune diseases such as rheumatoid arthritis and psoriasis, as well as

improvements in conditions like polycystic ovary syndrome²⁹,³⁰. These present additional

opportunities to understand the underlying processes of certain chronic diseases and explore

the potential for potent and sustainable non-pharmaceutical treatment options.

And finally, for almost a century, measurable ketones in one’s blood or urine was considered

abnormal. But as we see more and more benefits associated with blood BOHB levels in the

range identified in nutritional ketosis, one has to wonder which metabolic state is most

beneficial—BOHB of 0.1 to 0.2, or 1.0 to 2.0—particularly in individuals with type 2

diabetes or metabolic syndrome. For example, is someone who is eating a ketosis-suppressing

diet containing 300 g/d of ‘healthy carbohydrates’ and exercising 5 hours per week, but still

has metabolic syndrome, in a “normal” metabolic state? From an alternative perspective,

since reversal of metabolic dysfunction—including metabolic syndrome or type 2 diabetes—

can be achieved by eating protein in moderation and total carbohydrate under 50 g/day,

perhaps nutritional ketosis should be considered the new metabolic normal for people with
diseases associated with or caused by chronic inflammation.

The information we provide at virtahealth.com and blog.virtahealth.com is not medical

advice, nor is it intended to replace a consultation with a medical professional. Please

inform your physician of any changes you make to your diet or lifestyle and discuss these

changes with them. If you have questions or concerns about any medical conditions you may

have, please contact your physician.

CHANGES REQUIRED IN LIFE STYLE

1.Nutritional suppliments :
To decrease CRP level:
 1. Vit C n mgnesium
2. Omega 3 fatty acids: Anti inflammatory, nomal body function,
decrease heart risk, proper functioning of brain cell, regulates blood
clotting
3. Protein
4. Vit E
5. Multivitamin or nutrilite Daily

2. Change in Oil
Stop refined oil—more omega 6 fatty acids
Start olive oil, coconut virgin oil, Ghee(preferred cow’s)