Inflammation is the natural healthy reaction of the immune system as it responds to injury or infection, or flight or fright scenarios. See Box 3-2 for a classic description of inflammation.
The immune system’s response to physiologic and metabolic stress is to produce pro-inflammatory molecules such as adipokines and cytokines - cell-signaling molecules that aid cell-to-cell communication and stimulate the movement of cells toward sites of inflammation in conditions of infection and injury. Thus immune system responses and the resulting inflammation are intimately connected.
Inflammation is the complex biological response of vascu- lar tissue to harmful stimuli such as pathogens, damaged cells or irritants that consists of both vascular and cellular responses. Inflammation is a protective attempt by the or- ganism to remove the injurious stimuli and initiate the healing process and to restore both structure and function.
Inflammation may be local or systemic. It may be acute or chronic.
Undurti N. Das, MD Molecular Basis of Health and Disease (2011) Optimally, the immune system’s function is to keep the body healthy, responding appropriately with an inflammatory re- sponse to environmental influences, such as short-lived infection and injury, and then returning the body to an alert system of defense. This function depends on the body’s ability to recognize
“self” and “non-self.” When the immune response is successful, the tissue returns to a state of wellness, or metabolic stability described as allostasis. If many areas of the body’s defense sys- tem, such as the gastrointestinal barrier, stomach acidity, skin, or various orifices (e.g., eye, ear, nose, lung, vagina, uterus), are compromised, there is diminishing recognition of “self” and BOX 3-1 Nutrient and System Partner
Principles
Nutrient Partners
• Calcium – Zinc – Copper
• Omega 6 GLA/DGLA - Arachidonic Acid – Omega 3 EPA/DHA
• Sodium chloride – potassium - calcium
• B Complex (B1-B2-B3-B5-B6-B9 (folate)-B12-Biotin-Choline)
• Antioxidants – reactive oxygen species (ROS)
• Albumin – globulin
System Partners and Rhythm Cycles:
• Autonomic Nervous System: sympathetic – parasympathetic
• Circadian Rhythm: 24 hour balanced rhythm
• Acid-Base Balance
• Microbiome: oral, nasal, skin, lung, vaginal, gastrointestinal
• Hormones-biochemistry
• Cortisol - insulin - glucose
• Estrogen – progesterone -testosterone
• T4-T3 (total and free forms)
• HPTA axis – Hippocampus – Pituitary – Thyroid - Adrenal
BOX 3-2 The five classic signs of
inflammation, first described and documented by Aulus Cornelius Celsus (ca 25 BC-ca 50), a Roman physician and encyclopaedist
• Dolor - “pain”
• Calor - “heat”
• Rubor - “redness”
• Tumor - “swelling”
• Functio laesa - “injured function” or “loss of function”.
“non-self” until the body is repaired. The longer the physiologic injury continues, the greater the loss of the ability to recognize
“self” and “non-self” (Fasano, 2012; Wu et al, 2014).
If the underlying cause is not resolved, the immune response can get “stuck” in a state of prolonged inflammation. Locked into this state for a while, the immune system loses its ability to recognize “self ” and “non-self,” a critical survival skill and the core of immunology (Paul, 2010; Queen, 1998).
Prolonged Inflammation
Prolonged inflammation, known as chronic inflammation, sustained inflammation, or non-resolving inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Mul- tiple studies have suggested that prolonged inflammation plays a primary role in the pathogenesis of chronic diseases (e.g., arthritis), when the immune response is to increase the ratio of proinflammatory to antiinflammatory cytokines (Bauer et al, 2014; Franceschi and Campisi, 2014).
One of the most fundamental characteristics of all chronic diseases is the initiation and continuation of a prolonged in- flammation over all or part of the lifespan, leading to clinical chronic disease (Bauer et al, 2014). In the chronology of chronic disease progression, inflammation is at first subclinical, often referred to as “silent inflammation.” This insidious inflamma- tion remains below the threshold of clinical diagnosis. Cellular and tissue damage occurs in the body for years before being noticed. It is like a “smoldering” fire with a small whiff of smoke and heat being evident before it finally bursts into a flame.
Some refer to early chronic disease as a “smoldering disease”
(Noland, 2013). Chronic disease inflammation is described as:
Low-grade, chronic, systemic inflammation may be defined as a 2- to 3-fold elevation of circulating inflammatory mediators, usually associated with the innate arm of the
immune system. It is a state that develops slowly (in contrast to pathological acute inflammatory responses, to sepsis for example), and its origin cannot be easily identified (in con- trast to chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, where additional symptoms identify local dysregulated inflammation). This makes it difficult to develop appropriate therapeutic strate- gies that target both cause and symptom (inflammation) in a concerted fashion (Calcada et al, 2014).
Of grave concern is the initiation of prolonged inflamma- tion in utero from the maternal inflammatory environment, thereby programming the fetus for a lifetime of chronic disease (Barker, 1998; Delisle, 2002; European Foundation for the Care of Newborn Infants [EFCNI], 2015; Fisher et al, 2012; Fleisch et al, 2012; see Chapter 15).
Clinical elevations of inflammatory biomarkers, such as high-sensitivity C-reactive protein (CRP-hs) (plasma), sedi- mentation rate, interleukin-6 (IL-6), and TNF-alpha, repre- sent systemic markers of inflammation that are exacerbated by insulin resistance (IR) and hyperinsulinemia (Das, 2012, 2014; see Table 3-1). Diseases well characterized by these markers include heart disease, diabetes, autoimmune diseases, and possibly cancer and Alzheimer’s disease (Birch et al, 2014;
Wu, 2013).
There are other common physiologies shared by these inflammatory conditions that include changes in nutrient tis- sue pools, plasma, and RBC membrane composition of polyun- saturated fatty acids and antioxidants. This multifactorial syn- drome (often referred to as metabolic syndrome) is related to obesity, and more importantly, insulin resistance and central adiposity evidenced by the presence of visceral adipose tissue (VAT). (See Chapters 7 and 30 for discussion of the metabolic syndrome). However, the expression of the prolonged inflam- mation is individual, and all individuals need not necessarily have all the characteristics described above.
Test Reference Association
Blood Speciman
8-hydroxy-2-deoxyquanosine , 7.6 ng/ml DNA increased ROS and cell proliferation*
Asymmetric dimethylarginine (ADMA) ,18 years: not established
18 years: 63-137 ng/mL
Inhibitor of L-arginine (Arg)-derived nitric oxide (NO)
C-reactive protein hi sensitivity #3.0 mg/L Systemic inflammation related to bacterial infection, trauma, VAT, neoplastic activity
CA-125 0-35 U/mL Inflammation in abdomen
Ovarian cancer Uterine fibroids
CA 15-3/CA 27-29 ,32 U/mL Breast Cancer, advanced
CA-19-9
Carbohydrate Ag 19-9 (screening test)
,55 U/mL
Up to 20% of individuals do not express CA 19-9.
Pancreatic cancer
Infections in your liver, gallbladder, and pancreas.
CEA
(other specimens also) 12-100 years: 0-5.0 ng/mL Cancer
CD4 Lymphocyte
CD4 percent HIV infections, autoimmune
CD8 Count Infections
Lymphoma Ceruloplasmin
(bound copper/ acute phase reactant) 18-46 mg/dL Acute Phase Reactant Cancer (elevated) Wilson’s Disease (low) Menkes syndrome (low)
TABLE 3-1 Biomarkers of Prolonged Inflammation
Continued
32 PART I Nutrition Assessment
Test Reference Association
Eosinophils 1-4% Elevated inflammatory marker of Allergies/ sensitivities, helminthic,
parasites, autoimmune, neoplasms Ferritin (storage iron) Males 5 years: 24-150 ng/mL
Females 5 years: 12-150 ng/mL Acute Phase Reactant Hemochromatosis (genetic) Iron Toxicity
Fibrinogen / Platelets 150-450 mg/dL / 150-450 billion/L Disseminated intravascular coagulation (DC) Liver disease
Homocysteine (Hcy) 0-15 umol/L Block in homocysteine metabolism to cystothionine relate to B6, B12, folate, betaine co-factors
IgA Total or IgA specific 50-350 mg/dl Elevated in lymphoproliferative disorders; chronic infections;
autoimmune; celiac disease.
IgE Total or IgE specific 800-1500 mg/dl Elevated immediate-response inflammatory allergic disorders;
parasitic infections;
IgG Total or IgG specific 800-1500 mg/dl Elevated inflammation marker of delayed sensitivities; chronic infections.
Interleukin-1 (IL-1) ,3.9 pg/mL Bone formation, insulin secretion, appetite regulation, fever reduction, neuronal development
Interleukin 8 (IL-8) ,17.4 pg/mL
, or 5 5 pg/mL (2014) Neoplasms /promotes angiogenesis Obesity
Oxidative Stress
Insulin (Korkmaz 2014) 2.0-12.0 ulU/ml Elevated inflammatory insulin resistance.
Lipid Peroxides ,2.60 nmol/ml Inflammatory elevation when risk of oxidative stress/ elevated
triglycerides.
Liver enzyme: ALT 0-35/U/L Inflammatory elevation in liver disease
Liver enzyme: AST 0-35 U/L Inflammatory elevation with liver, kidney, muscle infection or injury.
Liver enzymes: Alk Phos 30-120 U/L Inflammatory elevation related to liver, bone, placenta
Liver enzyme: GGT 0-30 U/L Elevated inflammatory marker of liver disease, neoplasms, toxicity
Liver enzyme: LDH 50-150 U/L
Prostate Specific Antigen (PSA) Total PSA #4.0 ng/mL
% Free PSA .25 % (calc)
Prostate inflammation Prostate cancer Rheumatoid factor (RF) Less than 40-60 u/mL
Less than 1:80 (1 to 80) titer Rheumatoid Arthritis Sjorgrens
Autoimmune disease Sedimentation Rate/ ESR
Westergren Male ,50 years old:,15 mm/hr
Male.50 years old:,20 mm/hr Female,50years old:,20 mm/hr Female .50 years old:,30 mm/hr
Systemic inflammation marker related to autoimmune; viral infec- tions; rouleaux; carcinoid influence.
Total Protein 60-80g/L. 6.0-8.0g/dl), Total Protein in serum
Albumin 35 - 50 g/L (3.5 - 5.0 g/dL)
(half-life , 20 days) Acute Phase Reactant
Globulin 2.6-4.6 g/dL. Chronic inflammation, low albumin levels and other disorders
TH17
Interlukin 17 (IL-17) 0.0 – 1.9 pg.ml Fungal, bacterial, viral infections, autoimmune conditions
TNF-a 1.2-15.3 pg/mL Systemic inflammation
Acute Phase Reactant
Alzheimer’s, infection, depression, IBD, cancer
Uric Acid 2-7 mg/dl Antioxidant, elevated in abnormal urate cycle exacerbated by
protein in diet, gout, other.
VEGF 31-86 pg/mL Cancer, angiogensis
White blood cell count 4.5- 11 x10E3/uL (elevated) Leukocytosis , bacterial infections, anemia, cigarette smoking
(Low) Cancer, radiation, severe infection Stool Specimen
Calprotectin 2–9 years 166 µg/g of feces
10–59 years 51 µg/g of feces
60 years 112 µg/g of feces
Inflammatory Bowel Disease Intestinal inflammation Neoplasms
Lactoferrin Negative Intestinal inflammation
Pancreatic elastase I . 200 mcg/g Exocrine pancreatic function
Urine
5-hydroxyindoleacetate (5-HIAA) 1.6-10.9 mcg/ml creatinine Elevated with inflammatory breakdown of serotonin.
p-hydroxyphenyllactate ( HPLA) ,1.45 mcg/ml creatinine Inverse relationship to depletion of ascorbic acid
TABLE 3-1 Biomarkers of Prolonged Inflammation—cont’d
*Normal value ranges may vary slightly among different labs
sleep, and immune stress, all of which drive increased inflam- mation. Of equal importance with increased body fat percent- age is the fat distribution. Central adiposity at all ages is the most serious health concern. Visceral adipose tissue (VAT) has been discovered to have endocrine functions with the secretion of several known inflammatory adipokines, such as resistin, leptin, and adiponectin, and tumor necrosis-factor-alpha (TNF-alpha)—all contributing to the systemic total inflamma- tory load (Hughes-Austin et al, 2014). Sarcopenia results from a wasting of lean body mass from the ongoing inflammatory burden and is exacerbated by decreased physical activity. Most often the sarcopenia is accompanied by increased body fat per- centage, especially the deposit of VAT with increasing waist circumference.
Body composition can be assessed (see Chapter 7), and if found to be abnormal based an individual’s lean body mass (LBM) and fat mass (FM), it should be considered a primary marker for monitoring prolonged inflammation (Biolo et al, 2015; Juby, 2014; Stenholm et al, 2008).
Obesity today stands at the intersection between inflamma- tion and metabolic disorders causing an aberration of im- mune activity, and resulting in increased risk for diabetes, atherosclerosis, fatty liver, and pulmonary inflammation to name a few.
Khan et al, 2014a In addition to assessing those who are overweight, obese, and have VAT, it is important to assess those with normal or low BMIs. However, body composition phenotypes cannot be deter- mined based solely on BMI (Roubenoff, 2004). See Chapter 7 for assessment of body composition (see Clinical Insight: Sarco- penic Obesity).
For the nutritionist to incorporate the related factors of pro- longed inflammation into the nutrition assessment, it is useful to conceptualize an overview of a person’s total inflammatory load (see Figure 3-1). It is a compilation of every factor in the patient’s history or story that contributes to the inflammation that a person carries.
As various factors are identified within diet, lifestyle, envi- ronment, and genetics, the pattern of where the most inflam- matory risk is being generated becomes clear and gives a basis of how to intervene with a plan for medical nutrition therapy (MNT).
Antigens
Antigens are a source of inflammation that become chronic with chronic exposure (see Chapter 26). During assessment of the total inflammatory load of an individual, the “antigenic load” is important. Antigens usually are thought to come from foods to which one is either allergic or sensitive, but also can be derived from cosmetics, clothing, inhalants, furniture, house- hold building materials, and other substances in the environ- ment. Antigens from food are much more likely to be signifi- cant when a person has lost gut barrier integrity and a situation of intestinal permeability, sometimes referred to as “leaky gut”
exists (Fasano, 2012). This condition provides access of larger molecules into the internal microenvironment, setting off a cascade of immunologic responses (see Chapters 26 and 28).
Genomics
Predictive genomic testing, family history, and personal history are gathered as the practitioner hears the patient’s story during an assessment. This information helps to paint a picture of biochemical individuality (Williams, 1956), which influences the response to inflammation. Since the completion of the Human Genome Project (2003), the rapid development of genomic testing for clinical application has greatly enhanced the toolbox of the nutrition practitioner. Nutrigenomics, nutri- genetics, and epigenetics are new fields of study about the way the individual metabolically interacts with their environment (Dick, 2015; see Chapter 5).
Body Composition
Chronic diseases are related directly to increased body fat exac- erbated by physical inactivity, poor diet, lack of restorative
Total Inflammatory Load Infection
Trauma
Antigens
Autoimmune Immune
Total inflammatory
load Stress / Toxins
Lack of sleep Lifestyle poor habits
FIGURE 3-1 Total Inflammatory Load
Energy Dysregulation
Another underlying physiologic system involved in inflamma- tion is compromised mitochondrial production of adenosine triphosphate (ATP) (Cherry and Piantadosi, 2015). Assessment of mitochondrial function focuses on structure and function by considering co-nutrients such as coenzyme Q10 and alpha- lipoic acid (already produced by the body) and their protective effects against oxidative stress. Quelling systemic prolonged inflammation promotes a healthier microenvironment for improved mitochondrial function and energy production.
Mitochondrial disease or dysfunction is an energy produc- tion problem. Almost all cells in the body have mitochondria, which are tiny “power plants” that produce a body’s essential energy. Mitochondrial disease means the power plants in cells do not function properly. When that happens, some functions in the body do not work normally. It is as if the body has a power failure: there is a gradation of effects, like a “brown out”
or a “black out.”
The ratios of carbohydrate, fat, and protein affect mitochon- drial function, primarily affecting glucose-insulin regulation.
During each assessment, determination of the most favorable macronutrient ratios and individual nutrient requirements provides the foundation for the most effective interventions for restoring mitochondrial health and general wellness. The com- plaint of “fatigue” is the most common phenotypic expression of mitochondrial dysfunction (http://mitochondrialdiseases.
org/mitochondrial-disease/, 2013. Accessed 02.07.15.) (see New Directions: Inflammaging).
34 PART I Nutrition Assessment
tract, and nose/lung) and reveal data that exceed expecta- tions. The total number of genes in the human microbiome exceeds the human genome tenfold. When the delicate mi- crobiome community in and on the body is disturbed and altered from healthy baseline, it becomes a factor in promot- ing prolonged inflammation and affects the way food is used. The loss of microbiome diversity and the presence of specific undesirable or virulent bacteria appears to be a com- mon finding related to various diseases (Fasano, 2012;
Viladomiu, 2013).
The cause of these changes in the patterns of microbiota from “healthy” to dysfunctional appears to be influenced by genetics, diet, exposure to environmental toxins, and antibiotic use (National Institutes of Health [NIH], 2014). After pathol- ogy has been determined, the systems biology-based practitio- ner often uses the functional Comprehensive Digestive Stool Analysis (CDSA) testing to provide more quantitative and spe- cific information regarding the condition of the gut environ- ment and microbiology. The CDSA tests for inflammatory markers such as calprotectin, lactoferrin, and pancreatic elas- tase 1 in the gut, much like sedimentation rate or C-reactive protein-ultra sensitive (CRPus) and IgA are markers of inflam- mation in the blood (Gommerman, 2014). Because the GI tract contains about 70% of the immune system, it is important to assess the condition of the GI tract—from the mouth to the anus—as part of the total inflammatory load of an individual (Underwood, 2014). A new field of study regarding diseases that are related to disturbances in the gut environment and the immune system is called enteroimmunology (Lewis, 2014; see Figure 3–2).
Hypercoagulation
With inflammation comes an increasingly unhealthy degree of coagulation within body fluids. At some point, the microenvi- ronment becomes too sluggish and congested, facilitating the development of chronic diseases such as cancer, cardiovascular disease, and infectious diseases (Karabudak et al, 2008). This increase in body fluid viscosity promotes secretion of more pro-inflammatory immune cytokines and chemokines that can set the stage for any of the chronic disease conditions. Autoph- agy is the normal response to raise the level of proteolytic en- zymes to “clean up” the cell debris and prepare it for recycling or elimination (Gottleib and Mentzer, 2010; Gurkar et al, 2013;
Wallace et al, 2014).
Dietary factors helping to maintain healthy fluid viscosity are hydration, vitamin E with significant gamma-tocopherol, polyunsaturated fatty acids (PUFAs), monounsaturated fats (MUFAs), and avoidance of any chronic subclinical infec- tions and foods or substances that may act as antigens (see Chapter 26). Common biomarkers of increased body fluid viscosity are blood fibrinogen with platelets, and urinalysis measurements of specific gravity and the presence of “cloud- iness” or mucus.
Infection
Acute infections are easily recognized and diagnosed because of their blatant signs and symptoms such as fever, leukocytosis, pus, and tachycardia. Subclinical infection processes, on the contrary, may go unnoticed for years or decades while promot- ing a “smoldering,” under-the-radar, inflammatory condition CLINICAL INSIGHT
Sarcopenic Obesity
Clinical Insight: Sarcopenic Obesity
FMI (kg/m2)
Body composition Phenotypes
Low adiposity - high muscle mass
(LA-HM)
Low adiposity - low muscle mass
(LA-LM)
High adiposity - low muscle mass
(HA-LM) High adiposity - high muscle mass
(HA-HM)
ASMI (kg/m2)
In this figure, body composition is depicted by a spectrum of ASMI and FMI (low to high). On the basis of the Baumgartner model (Waters and Baumgartner, 2011), these phenotypes can be depicted as follows:
LA-HM 5 low adiposity with high muscle mass (individuals with low FMI and high ASMI)
HA-HM5 high adiposity with high muscle mass (individuals with high FMI and ASMI)
LA-LM 5 low adiposity with low muscle mass (individuals with low ASMI and FMI)
HA- LM 5 high adiposity with low muscle mass (individuals with high FMI and low ASMI).
Those with LA-HM would be the least healthiest.
Cutoffs were defined according to the following deciles:
LA-HM (ASMI: 50–100; FMI: 0–49.99) HA-HM (ASMI: 50–100; FMI: 50–100) LA-LM (ASMI: 0–49.99; FMI: 0–49.99) HA-LM (ASMI: 0–49.99; FMI: 50–100).
ASMI, appendicular skeletal muscle mass index; FMI, fat mass index A population-based approach to define body-composition phenotypes Carla MM Prado et. al: Am J Clin Nutr, 99:1369, 2014.
NEW DIRECTIONS Inflammaging
Aging is a ubiquitous complex phenomenon that results from environ- mental, stochastic, genetic, and epigenetic events in different cell types and tissues and their interactions throughout life. A pervasive feature of aging tissues and most if not all age-related diseases is chronic inflam- mation. “Inflammaging” describes the low-grade, chronic, systemic inflammation in aging, in the absence of overt infection (“sterile” inflam- mation) and is a highly significant risk factor for morbidity and mortality in the elderly (Franceschi and Campisi, 2014).
Microbiome
After the Human Genome Project, the National Institutes of Health (NIH) launched studies for genomic identification and characterization of the microorganisms associated with healthy and diseased humans. The exciting findings focus on five body sites (mouth, skin, vagina, gastrointestinal (GI)