Blood Chemistry Analytes: Liver, Gallbladder, Pancreas, … · ALT and AST analysis for...

Blood Chemistry Analytes: Liver, Gallbladder, Pancreas, Electrolytes and Minerals

Dr. Wayne L. Sodano, DC, DACBI, DACBN, CIHP, BCTNDirector of Clinical Support & Education for Evexia Diagnostics

Copyright © 2020 Evexia Diagnostics. All rights reserved. The content of this presentation is protected by both United States and International copyright laws and is provided solely for informational purposes. No part of this content may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by any

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The main functions of the liver include:•Filtration and storage of blood

•Metabolism of carbohydrates, proteins, fats, and hormone

•Detoxification of endogenous and exogenous substances

•Formation of bile

•Storage of vitamins and iron

•Formation of coagulation factors

The liver is the largest organ in the body, contributing about 2% of the total body weight, or about 1.5 kg in the average adult human.

Copyright © 2020 Evexia Diagnostics. All Rights Reserved

Most of the plasma proteins are synthesized in the liver, which includes albumin and globulin. The globulin fraction includes hundreds of serum proteins including carrier proteins, enzymes, complement, and immunoglobulins (synthesized by plasma cells).

Albumin is the major protein component of serum.


Liver studies (function) are roughly divided by the particular functions of the liver:

• Synthetic liver function

• Excretory liver function and gallbladder function

• Hepatocellular injury

• Detoxification


LiverFunctionAssessment AnalyteTestingConsiderations

Proteinsynthesis

• Albumin• Prealbumin• PT/INR(Notsensitivetolowlevelofliverdamage)

Excretionintobileduct

• Gamma-GlutamylTranspeptidase• Bilirubin• AlkalinePhosphatase• 5’- Nucleotidase

Hepatocellularinjury • AspartateAminotransferase• AlanineAminotransferase


Total serum protein

Albumin makes up about 60% of the total serum protein and has a half-life of 12 to 18 days.

Albumin maintains colloidal osmotic pressure in the blood and acts as a transport carrier for hormones, enzymes, and drugs.

Prealbumin is involved in the binding and transport of various solutes (e.g. thyroxin and retinol).

Globulins are used in the synthesis of antibodies. The sub-fractions of globulins include the alpha, beta, and gamma.

albumin, prealbumin, and globulins

=


The liver is required for the synthesis of most clotting factors and serves as a large reservoir for these factors.

Only substantial liver damage (> 80% loss of synthesis) will result in abnormal INR, albumin, and prealbumin values.


Total Serum Protein, Albumin, Globulin, A/G Ratio

Analyte Age ReferenceRangeg/dL(exceptprealbumin)

SIUnitsg/L(exceptprealbumin)

OptimalRangeg/dL

TotalProtein Adult 6– 8.5 60– 85 6.9– 7.4

Albumin Adult 4.0– 5.0 40– 50 4– 5

TotalGlobulins Adult 2.3– 3.4 23– 34 2.0– 3.5

A/GRatio Adult 1.4– 2.6 1.4– 2.6 1.5– 2.0


Total serum protein is a combination of pre-albumin, albumin, and globulins

Total serum protein that is in the normal reference range does not mean that the quantity of each analyte "is within" the normal reference range. The analytes must be viewed individually.

Increased: Dehydration; digestive dysfunction may cause an increase in total serum globulin.

Decreased: Protein malnutrition/need for digestive support (need for amino acids), digestive inflammation (i.e. enteropathies).


Pre-Albumin

Regarded as the best lab test of protein malnutrition.

Prealbumin can bind thyroxine, however, it is secondary to thyroid-binding globulin in transportation of T3 and T4. It also plays a role in transport and metabolism of vitamin A.

Increased: Hodgkin’s disease, pregnancy

Decreased: malnutrition, liver damage, burns, and inflammation (negative acute-phase reactant)


Albumin

Increased : Dehydration

Decreased : Chronic cachectic or wasting disease, chronic infections, inflammatory diseases, malnutrition, protein-losing enteropathies (e.g. Crohn disease), and digestive inflammation/malabsorption

Albumin can serve as a negative acute-phase reactant.


Total Globulins

The distribution of the globulin fractions must be taken into consideration when assessing an abnormal total globulin value.

Total globulin is useful with other tests for assessing degenerative, inflammatory, infectious processes, and a need for digestive support.


Albumin/Globulin Ratio

The value of the A/G ratio is limited due to the countless number of protein variables.

Increased: Generally of no clinical value.

Decreased: Indication of a rise in globulin, which can be attributed to a variety of causes such as cancer, inflammation, infection, and systemic diseases.


Excretion into the Bile Duct

• Gamma-Glutamyl Transpeptidase (GGT)

• Bilirubin (indirect and direct = total)

• Alkaline Phosphatase (ALP)

• 5’ - Nucleotidase


Analyte Age ReferenceRange SIUnits OptimalRange

GGT Adult 9- 58units/L Same 0- 30

TotalBilirubin Adult 0.3– 1.3mg/dL 5.13– 22.23umol/L 0.1– 1.2mg/dL

Unconjugated(Indirect,insoluble)Bilirubin

Adult 0.2– 0.9mg/dL 3.42– 15.39umol/L -----

Conjugated(Direct,watersoluble)Bilirubin

Adult 0.1– 0.4mg/dL 1.71– 6.84umol/L ------

AlkalinePhosphatase Adult 33– 96units/L Same 70- 96

5’- nucleotidase Adult 0.0– 1.6unitsat37° C Same ------


Bile

• Cells of the liver produce bile (about 600 to 1000 mg/day), which thenpasses through ducts in the liver to the gallbladder.

• Bile aids in the digestion of fats and fat-soluble vitamins.

• Bile also serves to export toxins.

• Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes or the obstruction of bile flow through intra-or extra-hepatic bile ducts.

• The effects of cholestasis are profound and widespread leading to worsening liver disease and systemic illness. The clinical presentation of cholestasis may include: scleral icterus, high level of conjugated bilirubin, cutaneous jaundice, pruritus, and xanthomas.


Gamma-Glutamyl Transpeptidase (GGT)

Transfer of amino acids and peptides across cellular membranes is responsible for extracellular metabolism of glutathione, the main antioxidant in cells.

The highest concentration found is in the liver and biliary tract. Used to diagnose and monitor hepatobiliary disease.

Elevated GGT helps to identify a higher demand for glutathione due to excessive exposure to toxins or lifelong accumulation of toxicants.


Research has shown that patients who are obese with higher levels of GGT (between 40 – 60) may be experiencing an increased toxic burden, resulting in an elevated demand placed on glutathione production.

Obese patients with elevated normal ranges of GGT levels have a higher association with diabetic risk.

Elevated GGT is also a risk factor for myocardial infarction and stroke. GGT activity can catalyze the oxidation of low-density lipoprotein, a process involved in the pathogenesis of arthrosclerosis.

Gamma-Glutamyl Transpeptidase (GGT) - continued


Increased GGT: Liver disease, alcohol abuse, primary biliary cirrhosis, fatty liver, cholestasis, pancreatitis, diabetes mellitus, hyperthyroidism, environmental toxin exposure and/or toxic body burden, oxidative stress, chronic inflammation, EBV, severe COPD, certain cancers, and RA

Decreased GGT: hypothyroidism

Gamma-Glutamyl Transpeptidase (GGT) - continued


Bilirubin (Total = Direct + Indirect)

Bilirubin is formed from the hemoglobin that is released after the breakdown of RBCs via the reticuloendothelial system (mainly in the spleen).

The heme portion is catabolized to form biliverdin and subsequently transformed to unconjugated (indirect/insoluble) bilirubin. The unconjugated bilirubin enters the liver where it is conjugated (made water soluble) by a glucuronide, resulting in the formation of conjugated (direct) bilirubin.


Bilirubin (total = direct + indirect)(direct = conjugated → water soluble)

(indirect = unconjugated → water insoluble)


Bilirubin (Total = Direct + Indirect)

Increased Total Bilirubin: Liver/biliary dysfunction

Increased Conjugated (direct, water soluble) bilirubin: gallstones, extra-hepatic duct obstruction (e.g. tumor, inflammation, scarring), drug induced cholestasis

Increased Unconjugated (indirect, insoluble) bilirubin: sickle cell anemia, hemolytic anemia, hepatitis, pernicious anemia, erythroblastosis fetalis, transfusion reaction, Gilbert syndrome

Gilbert syndrome is an inherited, benign trait present in 3 to 5 % of the population. It is caused by the reduced production of hepatic glucuronyl transferase enzymes and results in intermittent mild elevation of unconjugated (indirect) bilirubin.


Alkaline Phosphatase

Alkaline phosphatase (ALP) refers to a group of isoenzymes that are found mainly in the liver, bone, small intestines, kidneys, placenta, and leukocytes.

Serum ALP is of interest in the diagnosis of two main groups of conditions: hepatobiliary diseases and bone diseases associated with increased osteoblastic activity (e.g. Paget’s disease, malignant tumors, fractures and osteomalacia).

Moderate elevation in ALP is also seen in ulcerative colitis, regional enteritis, congestive heart failure, and Hodgkin’s disease.

A cofactor for these enzymes is zinc; therefore a zinc deficiency can cause low serum ALP.


Elevation of ALP due to liver disease does not distinguish between intra- and extra-hepatic diseases; therefore it must be interpreted in concert with other analytes.

Increased ALP: liver disease (primary or metastatic), diabetes mellitus, bone disease (healing fractures, osteomalacia, Paget disease, hyperparathyroidism, sarcoidosis, pregnancy about the 16th to 20th week), hyperthyroidism, and renal disease

Decreased ALP: hypothyroidism, vitamin B12 deficiency, excessive vitamin D ingestion, vitamin C, zinc, and magnesium deficiency, celiac disease, scurvy, and hypophosphatemia


5’ – Nucleotidase (5’ – NT)

An intrinsic membrane glycoprotein that catalyzes hydrolysis of 5 – nucleotides to their corresponding nucleosides.

5’ – NT was described in heart and skeletal muscle about 60 years ago.

Clinically useful for the differential diagnosis of hepatobiliary and osseous diseases; the enzyme activity being increased only in hepatobiliary disease.

Precise marker for early hepatic primary or secondary tumors1

1Hyder MA, Hasan M, Mohieledien. Comparative study of 5’-Nucleotidase Test in Various Liver Disease. J Clin Diagn Res. Feb 2016; 10(2): BC01 – BC03.


5’ – nucleotidase is an enzyme that is most often elevated in individuals with liver disease.

The presence of an elevated ALP with a normal 5’ – nucleotidase value suggests that ALP is elevated secondary to non-hepatic causes. In other words, if the 5’ – nucleotidase is normal in the face of an elevated ALP, the pathologic source is outside the liver (e.g. bone, kidney, or spleen).

Increased 5’ – nucleotidase: bile duct obstruction, cholestasis, hepatitis, hepatic necrosis, ischemia, and tumor, hepatotoxic drugs


Hepatocellular Injury Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)

Transaminases: metabolic links between carbohydrate and protein metabolism.

ALT is involved in the glucose-alanine cycle, interchanging alanine and pyruvate, thereby regenerating glucose consumed by the muscle.

AST is even more vital for aerobic glycolysis by allowing the NADH (nicotinamide adenine dinucleotide) that is generated in the cytoplasm to be effectively relocated within the mitochondria through the shuffling of malate (as well as α-ketoglutarate, aspartate, and glutamate).

Analyte Age ReferenceRangeUnits/L SIUnits

OptimalRange

ALT Adult 7-41 Same 6- 29AST Adult 12- 38 Same 10- 35


Both of these enzymes (ALT and AST) require the cofactor pyridoxal phosphate (B6) for activity.

Therefore a low serum level of both of these enzymes may be due to a B6 deficiency.


ALT and AST analysis for hepatocellular damage

ALT is found mainly in the hepatocytes, with lesser quantities found in the kidneys, heart, and skeletal muscle.

AST is found in very high concentration within highly metabolic tissue, such as the heart, liver cells, skeletal muscle, and to a lesser degree in the kidneys, pancreas, and RBCs.

Damage to the hepatocytes causes the release of these enzymes even with minor levels of liver damage.

AST and ALT have half-lives of 17 and 47 hours, respectively, so they reflect active hepatocyte damage.


Liver abnormality is one of the associated extra-intestinal manifestations with celiac disease.

Modest elevation of serum aminotransferase levels is common in untreated celiac disease.

Celiac disease is a multi-systemic disease and abnormal,unexplained, elevated liver enzymes are common in individuals with celiac disease.

Patients with unexplained elevations of liver enzymes should be screened for celiac disease, as nine percent of patients with abnormal liver chemistries are diagnosed with celiac disease.


Increased AST: liver diseases, skeletal and muscle diseases, acute hemolysis anemia, acute pancreatitis, celiac disease, and heart disease

Decreased AST: renal disease and vitamin B6 deficiency

Increased ALT: liver disease (high – hepatitis/ moderate –cirrhosis, cholestasis, obstructive jaundice, hepatotoxic drugs, hepatic tumor/ mild – pancreatitis, infectious mononucleosis)

Decreased ALT: vitamin B6 deficiency


FHR shows ELEVATED AST & ALT

FUN

CTIO

NAL

HEA

LTH

REP

ORT

TMThe Functional Health Report (FHR) highlights out-of-range analytes and then provides a summary of possible health conditions related to the results in multiple areas like, Health Improvement Plan, Functional Index Report and Clinical Dysfunctions Report.

Here is an example of the summary, from a report with Alarmingly High ALT and AST levels, provided in the Health Improvement Plan section of the FHR.


Guide for Interpreting Liver Enzymes

If the patient is taking medication, consider drug-induced toxic liver damage as a cause of elevated enzymes.

ALP GGT,5’-Nucleotidase ALTandAST Differential

Diagnosis

Mildlyelevated WNL WNL Pregnancy,non-hepaticcauses

Moderatelyelevated Markedlyelevated WNLofslightlyelevated Cholestaticsyndrome

Mildlyelevated Mildlyelevated Markedlyelevated Hepatocellulardisease


Isolated Abnormalities in Liver Function Test Results

Modest elevation on serum aminotransferase levels is common in untreated celiac disease.

Test Non-HepaticSource

Bilirubin Redbloodcells(e.g.hemolysis,intra-abdominalbleeding,hematoma)

AST Skeletalmuscle,cardiacmuscle,andredbloodcells

ALT Skeletalmuscle,cardiacmuscle,andkidneys

LDH Heart,redbloodcells(e.g.hemolysis)ALP Bone,firsttrimesterplacenta,kidneys,

GGTEnvironmentaltoxinexposureand/ortoxicbodyburden,oxidativestress,drugs,alcohol,chronicinflammation,EBV,severeCOPD,

certaincancers,andRA

Bilirubin Gilbert’ssyndrome(totaland/orunconjugated)


Endocrine-disrupting chemicals (EDC) may be linked to the obesityepidemic.

Can disrupt the hypothalamus, leading to dysregulation of the HPT and HPA axes, resulting in thyroid and adrenal dysfunction.

EDC's are chemicals that alter the normal functioning of hormonesand other signaling molecules in the body.

Example: Bisphenol A (BPA) – PLASTICS - can increase mRNA expression and enzymatic activity of 11β-hydroxysteroid dehydrogenase type 1. This enzyme converts inactive cortisone to the active hormone cortisol in adipose tissues and promotes adipogenesis (esp. central obesity).

ENVIRONMENTAL TOXIN EXPOSURE AND OBESITY: ‘OBESOGENS’


▪ There is a global increase in incidence of obesity, diabetes, and metabolic disease.

▪ There is a global increase in childhood obesity and type 2 diabetes.

▪ While there are genes that play important roles in these diseases, like all complex diseases, there must be both genetic and environmental components.

▪ The increase in obesity and metabolic disease over the last 4 decades cannot be accounted for by classical genetic factors, and thus must be due to some aspect of the environment.

UNIVERSITY OF PARMA 2014: WE ARE CONFIDENT THAT….


▪ There is more to the environmental component of obesity, diabetes,and metabolic syndrome than simply overeating, poor nutrition, lack of exercise and changes in lifestyle. The environmental component is multifactorial and includes prescription drugs, stress, nutrition, microbiome, infections, sleep patterns, nocturnal illumination, and environmental chemicals.

▪ Obesity and metabolic syndrome are endocrine disease/dysfunctions,and thus sensitive to disruption by environmental agents that can interfere with hormone and neuroendocrine actions (e.g. EDCs).

▪ There are pharmaceutical obesogens – prescription drugs with the known effect of causing weight gain (Therefore, you need to know the medications your patients are taking!).


▪ Susceptibility to metabolic disorders, at least in part, ‘programmed’ in utero and early postnatal life by exposure to environmental factors including stress, drugs, nutrition, and environmental chemicals.

▪ Programming may alter brain appetite and/or satiety centers, as well as fat cell numbers and other aspects of metabolism; including effects on control of GI tract, muscle, pancreas, liver function, etc. (i.e. altering the sensitivity for gaining weight).


ENDOCRINE DISRUPTING CHEMICALS

The most common presentations of toxic damage to the endocrine systems include: sleep disturbances, changes in energy level or mood; alterations in weight, appetite, and bowel function; changes in sexual function and/or interest, any menstrual change; changes in temperature perception, sweating, or flushing; and alteration in hair growth and skin texture.

The most common endocrine diagnoses associated with xenobiotic burden include:

InfertilityHypothyroidismAdult-onset diabetes and obesity


EFFECTS OF ENVIRONMENTAL TOXINS ON THE HYPOTHALAMUS

The effect of toxins on the hypothalamus can lead to significant autonomic dysfunction, behavioral changes, and a host of down stream conditions.

MAJOR FUNCTIONS OF THE HYPOTHALAMUS

Blood pressure regulation

GI stimulationHunger and satiety regulationNeuroendocrine controlBody temp regulationWater regulationSweatingLimbic system


Pancreatic Enzymes

Analyte Age ReferenceRangeunits/L SIUnits Optimal

Range

Amylase Adult 5- 125 Same Same

Lipase Adult 0- 50 Same Same


Amylase

Amylases are a group of enzymes that breakdown (i.e. digests) starch into glucose. Most circulating amylase originates from the pancreas and salivary glands, accounting for 40 to 60 % of the total serum amylase.

The kidneys are responsible for clearing about 25% of the amylase from the blood; therefore kidney dysfunction can cause an elevation in serum amylase.

The main diagnostic use of serum amylase is to diagnose and monitor pancreatitis. This analyte, however, has a low sensitivity, with about 20% of patients with acute pancreatitis having normal levels.

Increased Serum Amylase: Pancreatic disease, biliary disease, renal failure, intestinal diseases (e.g. infarction, bowel obstruction), drugs, salivary gland inflammation


Lipase is an enzyme secreted by the pancreas into the duodenum to breakdown triglycerides into fatty acids and glycerol.

Most of the serum lipase is of pancreatic origin, which makes it more specific than amylase for pancreatic disease .

The most common cause of elevated serum lipase is acute pancreatitis.

Increased Serum Lipase: Pancreatic disease, biliary disease, renal failure, intestinal diseases (e.g. infarction, bowel obstruction), drugs, salivary gland inflammation


Lipase

Lactic Dehydrogenase (Isoenzymes)

Lactic dehydrogenase is an intracellular enzyme that exists in the cytoplasm of all cells and represents a group of enzymes (isoenzymes) involved in carbohydrate metabolism.

Catalyzes the inter-conversion of lactate and pyruvate.

Highest concentrations of LD are found in the heart, liver, RBCs, skeletal muscle, and kidneys; with lesser concentrations in the brain, lung, and smooth muscle.

Total serum LD can be elevated for a variety of pathological reasons. An isoenzyme study can help isolate the potential cause of the elevation.

Analyte ReferenceRangeunits/L SIUnits OptimalRange

units/L

LD(total) 110-240 Same 120- 190


Percentage of Activity of LD Isoenzymes in Tissue

Organ LD-1 LD-2 LD-3 LD-4 LD-5

Heart 60 30 5 3 2

Liver 0.2 0.8 1 4 94

Kidney 28 34 21 11 6

Cerebrum 28 32 19 16 5

Skeletalmuscle 3 4 8 9 76

Lung 10 18 28 23 21

Spleen 5 15 31 31 18

RBCs 40 30 15 10 5

Skin 0 0 4 17 79


LD Isoenzyme Patterns in Selected ConditionsCondition IncreasedLDIsoenzyme(s)

Acutemyocardialinfarction LD-1morethanLD-2Sicklecellcrisis LD-1andLD-2

Earlyhepatitis LD-5(maybecomenormal,evenwhenALTisstillrising)

Malignantlymphoma LD-3andLD-4(LD-2mayalsoincrease)Carcinomaoftheprostate LD5;LD-5toLD-1ratioisgreaterthan1

Dermatomyositis LD-5SLE LD-3andLD-4

Collagendisorders LD-2,LD-3andLD-4Congestiveheartfailure LD-2,LD-3andLD-4

Viralinfections LD-2,LD-3andLD-4Variousneoplasms LD-2,LD-3andLD-4

Strenuousphysicalexercise LD-4andLD-5Benignprostatichypertrophy

Uterinehypertrophy LD-4

Pancreatitis LD-4Asthma LD3andLD5

Infectiousmononucleosis LD-1,LD-2,LD3andLD-5Copyright © 2020 Evexia Diagnostics. All Rights Reserved

Electrolytes, Minerals, and Acid-Base

Laboratory tests for evaluation of disorders of renal, water, electrolyte, and acid-base are the most common procedures performed in clinical chemistry laboratories (The Metabolic Panel).

Proper interpretation of laboratory tests of renal, electrolyte, and acid-base disorders requires an understanding of the physiology and pathophysiology of these systems.


Minerals such as magnesium, calcium, and phosphate are frequently discussed in the context of the endocrine system because of the effects that vitamin D and parathyroid hormone have on the regulation of these minerals.

Acid-Base: The maintenance of normal body pH is required for the normal functioning of the organs.

- Acidic metabolites, if not buffered, lead to organ dysfunction.


Accumulation of Acid Substances in the Body

When the body’s internal environment becomes acidified, deleterious effects on the biochemical systems of the body can ensue:

• reduced enzyme activity

• mineral loss and demineralization of the bone

• inflammation and tissue irritability due to the corrosive nature of acids

– all of which lead to illness.


Electrolytes and Serum Anion Gap

Anion gap = (Na + K) – (Cl + HCO3) or Na – (Cl + HCO3)

Analyte Age ReferenceRange OptimalRange

Sodium(Na+) Adult 136– 142mEq/L Same

Potassium(K+) Adult 3.8– 5.0mEq/L 4– 4.6

Chloride(Cl-) Adult 95– 103mEq/L 99- 103

Carbondioxideasbicarbonate Adult 23– 30mEq/L 26- 31

AnionGap Adult

10– 20mEq/L(K+ used)

8– 16mEq/L(K+ notused)

8– 12mmol/L(K+ used)


Normal volumes and composition of electrolytes in various body fluid compartments are essential for maintenance of life.

The body fluid: the extracellular fluid compartment and the intracellular fluid compartment.

Each compartment normally contains a different amount of the same electrolytes.


Normal Volume of Body Fluid Distribution (73 kg male)

Intracellular Volume (normally, more fluid is in the cells) 24 liter (60%)

Total Extracellular Volume 16 liters (40%)

Extracellular (interstitial) 11.2 liters (28%)

Extracellular (plasma) 3.2 liters (8%)

Extracellular (*transcellular) 1.6 liters (4%)

* Transcellular fluid: lumen of GI; fluids in the CNS; eye fluid; serous fluid


Electrolyte Concentrations in Extracellular and Intracellular Fluids

Analyte Plasma (mEq/L) Interstitial (mEq/L)

Intracellular Water(mEq/L)

Na+ 140 145.3 13

K+ 4.5 4.7 140

Ca++ 5.0 2.8 1 x 10-7

Mg++ 1.7 1.0 7.0

Cl- 104 114.7 3

HCO3-

Bicarbonate 24 26.5 10

SO42-

Sulfate 1.0 1.2 ----

Phosphorus 2.1 2.3 107

Protein 1.5 8 40

Organic anions 5 5.6 ----


One of the major causes of an aberrant fluid distribution in the body is significant body burden of endogenous (metabolic waste) and exogenous (environmental toxins) toxins.

A toxic body burden leads to a reduction in intracellular fluid volume and an increase in extracellular fluid volume. This is the body’s attempt to dilute the toxins that have accumulated in the interstitial space.

Disturbances in Water Balance and

Electrolyte Balance

Disease and Dysfunction=


Many illnesses may be a function of the body’s attempt to manage the increased amount of toxins that have accumulated and/or sequestered in the body.

A reduced intracellular fluid volume leads to cellular dysfunction and an increase in extracellular fluid volume leads to edema, inflammation, and nervous tissue irritation.

Reduced Intracellular Fluid Volume = Cellular Dysfunction


Sodium: major cation in the extracellular fluid

• regulating water balance in the body

• maintaining electrical potential • nerve transmission• pH balance• osmotic pressure

Sodium


Sodium balance is regulated by many factors such as aldosterone (produced by the adrenal glands), atrial natriuretic hormone/peptide (right atrium of the heart), and antidiuretic hormone (posterior pituitary gland).

Sodium Regulation


Baroreceptors are located in the carotid sinus, aortic arch, cardiac atria, hypothalamus, and the kidneys.

Osmoreceptors are located in the hypothalamus, which when stimulated, cause the release of antidiuretic hormones, natriuretic peptides (atrial natriuretic peptide and brain natriuretic peptide), and the renin-angiotensin-aldosterone system.

Sodium and Water Regulation ReceptorsOsmoreceptors and Baroreceptors


• Regulates muscle and nerve excitability and is an important electrolyte for cardiac function

• Controls intracellular volume

• Contributes to protein synthesis, enzymatic reactions, and carbohydrate metabolism

In acidic states, potassium tends to shift to the extracellular fluid causing an increase in serum potassium. The opposite is true in the alkaline state.

Potassium: Major intracellular cation


Increased serum potassium (THINK acidic state): excessive dietary intake, acidosis, dehydration, infection hemolysis, renal disease, low insulin, potassium sparing diuretics, NSAIDs, adrenal hypofunction, and dehydration

Decreased serum potassium: decreased dietary intake, licorice ingestion, alkalosis, diuretics, adrenal hyperfunction, corticosteroids and folic acid deficiency

Signs and Symptoms of Abnormal Serum Potassium

Symptoms of hyperkalemia Irritability, nausea, vomiting, intestinal colic, diarrhea

Symptoms of hypokalemia

Hypotension, weakness, cramps, loss of smooth muscle function, decreased insulin

release, abnormal ECG findings (deceased T-wave amplitude, widening QRS complex, and

a depressed ST segment)


Chloride maintains electrical neutrality mostly as a salt with sodium.

Primarily a passive physiological role balancing out the positive charges in the extracellular fluid and, by passively following sodium, helps to maintain extracellular osmolality.

Increased serum chloride: adrenal hyperfunction, Cushing syndrome, metabolic acidosis, and dehydration

Decreased serum chloride: metabolic alkalosis, adrenal hypofunction, Addison disease diuretic therapy, vomiting, and diarrhea

Chloride: Major Extracellular Anion


Total carbon dioxide: (CO2) in solution or bound to proteins, bicarbonate (HCO3-), carbonate (CO32-), and carbonic acid (H2CO3).

In practice, 80 – 90% is present as bicarbonate, and is a general guide to the body’s buffering capacity. Essentially, CO2 is primarily used as a rough guide for acid-base balance.

Increased carbon dioxide: severe vomiting, metabolic alkalosis, COPD, renal disorders, and alcoholism

Decreased carbon dioxide: metabolic acidosis, dehydration, diabetic ketoacidosis, chronic diarrhea, malabsorption syndrome, and starvation

Carbon Dioxide

CO2 + H2O H2CO3 HCO3- + H+


Increased acidosis: increase in hydrogen ion concentration and decreased HCO3 concentration.

Anion Gap = Na+ - (Cl- +HCO3-) or (Na+ + K+) - (Cl-+HCO3-) Used to determine metabolic acidosis

Na + unmeasured cations = Cl + HCO3 + unmeasured anions

Major unmeasured cations

• Calcium• Magnesium• Potassium• Gamma globulins

Major unmeasured anions

• Plasma proteins (albumin)• Sulphate• Phosphates• Lactate • Other organic anions


Although the term gap implies that there is a gap between cation and anion concentrations, the concentration of total cations in the serum is exactly equal to the concentration of total anions.

If anion gap is increased; then there is an increase in other anions (acids) – not HCO3.

AG = Na+ - (Cl- +HCO3-) The two sides must balance.


Increased Anion Gap: Thiamine deficiency (has been associated with metabolic acidosis)

Nearly all metabolic acidosis results from a reduction in bicarbonate content of the body.

Causes of metabolic acidosis include renal acidosis and extra-renal acidosis (e.g. gastrointestinal loss of bicarbonate, organic acidosis such as lactic acidosis, diabetic ketoacidosis, starvation, alcoholic ketoacidosis, acids precursors or toxins such as salicylate and acetaminophen).

Decreased Anion Gap: multiple myeloma, lithium toxicity


Serum Calcium, Phosphorous, Magnesium and RBC Magnesium

Analyte Age ReferenceRange OptimalRange

TotalCalcium(boundandunbound)

Adult 9.2– 10.5mg/dL 9.4– 10mg/dL2.35– 2.5mmol/L

Calcium,Ionized Adult 4.6– 5.3mg/dL

Phosphorous(P)

Phosphate(PO4)Adult 2.3– 4.7mg/dL

3.4– 4.0mg/dL1.10– 1.30mmol/L

SerumMagnesium Adult 1.6– 2.4mg/dL1.3– 2.1mEq/L

.82– 1.23mmol/L2.0– 3.0mg/dL

RBC-Mg Adult 4.2– 6.8mg/dL3.6- 5.6mEq/L

4.2– 6.8mg/dL1.72– 2.8mmol/L


Serum calcium three forms:

• Protein-bound calcium - about 41%

• Ionized calcium- free fraction - about 50% - which is diffusible through the capillary membrane

• Calcium complexed to anions, such as citrate, phosphate, and bicarbonate - about 9%- which is not non-ionized is diffusible through the capillary membrane

The ionic form of calcium is the physiologically active form,which is involved with bone formation and the functioning of the heart and nervous system.

Serum Calcium


Calcium’s actions include:

• Neuronal excitation

• Hormonal secretion (pancreatic insulin release and gastric hydrogen secretion)

• Blood coagulation

• Neurotransmitter release

• Innate immunity

• Muscle tone of smooth muscle cells of the vasculature, airways, uterus, gastrointestinal tract, and urinary bladder


Standard laboratory tests typically measure total serum calcium (bound and unbound/free), and do not report on ionized calcium unless ordered.

The measured value of total calcium is affected by total protein concentration, particularly albumin.

Low albumin levels frequently correspond to low calcium levels.Therefore, albumin testing should be included with serum calcium measurements since ionized calcium may be increased.

In general, low serum albumin (e.g. nephrotic syndrome, compromised liver function) will cause a drop in total serum calcium level.

Corrected Ca = [0.8 x (normal albumin - patient's albumin)] + serum Ca level


Increased Total Serum Calcium (hypercalcemia): Malignant tumors and hyperparathyroidism (the most common cause), osteomalacia associated with malabsorption, drugs (e.g. diuretics, estrogens, androgens, progestins, tamoxifen, and thyroid medication), renal disease, vitamin D and vitamin A intoxication, sarcoidosis (vitamin D effect produced by granulomatous infection)

Decreased Total Serum Calcium (hypocalcemia): low serum proteins (most common cause) malabsorption, hypoparathyroidism, gross vitamin D deficiency, low magnesium, and dietary deficiency


Phosphate is a major intracellular anion that is involved in the metabolism of proteins, lipids, and carbohydrates;and is a major component in phospholipid membranes, nucleic acids, nicotinamide diphosphate (an enzyme cofactor), cyclic adenine and guanine (second messengers), and phosphoproteins.

Phosphate also acts as an acid-base buffer and is involved in the production of ATP.

Serum Phosphorous (Phosphate)


Phosphate absorption is diminished when large amounts of calcium or aluminum (e.g. aluminum containing antacids) are present in the intestine due to the formation of insoluble phosphate compounds.

Phosphorus levels are determined by calcium metabolism, parathyroid hormone, vitamin D, renal excretion, and intestinal absorption.

Increased Phosphorous (hyperphosphatemia): renal disease (decreased renal excretion – most common cause), vitamin D toxicity, sarcoidosis, bone metastasis, acidosis, and hypoparathyroidism

Decreased Phosphorous (hypophosphatemia): hypercalcemia, chronic antacid ingestion, alcoholism, vitamin D deficiency, and alkalosis

Serum Phosphorous (Phosphate)


Magnesium is involved in more than 300 - 350 essential metabolic reactions.

• Required for energy production (ATP), numerous steps in the synthesis of nucleic acids and proteins, as well as carbohydrate and lipid metabolism.

• The Δ-6 desaturase enzyme required in the metabolism of fatty acids depends on magnesium.

• A key cofactor in both methylation and sulfur amino acid metabolism; also involved in the production of glutathione (important antioxidant) and S-adenosylmethionine.

Serum Magnesium


Magnesium depletion is commonly associated with both type 1 and type 2 diabetes mellitus. Between 25 and 38% of people with diabetes have been found to have hypomagnesemia.

Since only 1 to 2% of magnesium is present in the extracellular fluid, a better index of whole-body magnesium nutriture is assessing the intracellular content in red blood cells.

Increased Magnesium (hypermagnesemia): renal insufficiency (decreased excretion), ingestion of magnesium-containing antacids, and Addison disease

Decreased Magnesium (hypomagnesemia): malabsorption, malnutrition, alcoholism, and loop diuretics

Serum Magnesium: RBC-Mg the Better Test


FHR shows LOW LEVELS OF MAGNESIUM

FUN

CTIO

NAL

HEA

LTH

REP

ORT

TMThe Functional Health Report highlights out-of-range analytes and then provides a summary of possible health conditions related to the results in multiple areas like, Health Improvement Plan, Functional Index Report and Clinical Dysfunctions Report.

Here is an example of the summary, from a report with Low Magnesium levels, provided in the Health Improvement Plan section of the FHR.


Maintaining normal pH (i.e. acid-base balance) in the body is necessary for normal organ function.

The main organs involved in regulating and maintaining this balance are the lungs - CO2 excretion - and the kidneys - regulation of blood concentration of bicarbonate.

Bicarbonate and CO2 are considered the main buffers of the body, and their ratio is used to determine pH.

Acid-Base and Acid-Base Disorders: Bicarbonate and CO2 Buffer System


Acid-base physiology centers around maintaining the narrow range of the blood pH, which a pH of 7.38 to 7.44.

Deviations of blood pH, either above or below the set range, are termed alkalosis and acidosis, respectively.

Both alkalosis and acidosis can be categorized further in respiratory and metabolic components.


Condition pH Analyte Causes

Metabolic Acidosis

↓ ↓HCO3-

Renal Acidosis: reduction in acid excretionExtra-renal acidosis: increase in net acid production • GI loss of bicarbonate• Organic acidosis – lactic acidosis (e.g. bowel dysbiosis)

ketoacidosis (e.g. diabetes)• Ingestion of acid precursors/toxins – salicylate, acetaminophen

Metabolic Alkalosis

↑ ↑HCO3-

Loss of HCl from stomach – vomitingIngestion of bicarbonateIncreased renal excretion of acid – diuretic therapy, potassium depletion, secondary hypoparathyroidism

Respiratory Acidosis

↓

↑CO2

(PCO2=arterialbloodgas– partialpressureof

CO2)

Lung disease• COPD• Advanced interstitial lung diseaseThoracicdeformityorairwayobstructionDiseasesofrespiratorymuscleandnervesDepressionofrespiratorycenter

Respiratory Alkalosis

↑ ↓CO2

PneumoniaPulmonary fibrosisPulmonary congestionCNS lesionsDrugs: salicylate, progesterone


Monitoring Urinary pH


Partnership


Evexia Diagnostics is proud to be a partner of The Integrative and Functional Nutrition Academy (IFNA). This partnership will allow any IFNA student and alumni (excluding those located in NY, NJ, and RI) to order lab testing directly from the extensive menu offered by Evexia Diagnostics.

By becoming a client of Evexia Diagnostics you will have access to:• Conventional AND functional lab testing all at discounted rates.• Customized blood panels• Functional Health Reports with each qualifying panel ordered.• Practice Management Solutions• Monthly Educational Webinars• "Ask the Doctor" clinical support and education with Dr. Wayne Sodano

To further support our partnership, Evexia Diagnostics will waive the new client set up fee for all IFNA students ($250.00 value) and only charge the annual client participation fee of $50.00. Use the coupon code IFNA250 to take advantage of this special offer.

Evexia Diagnostics is committed to making this a smooth and seamless process for all IFNA students wanting to become a client; we look forward to your participation and many successes ahead!

ReNew Metabolic Detoxification Program The ReNew Metabolic Detoxification program focuses on relieving the toxic burden on the body. In concert with a baseline and a customized blood panel for diagnostic application, this easy-to-follow detox program is a clear and effective tool for optimal wellness.

Program provides comprehensive support for phase I and phase II detoxification aiding the body in elimination of harmful substances from environmental exposure and those naturally produced by the body. The ReNew kit contains:

• Revive, a functional food powder made from pea protein that contains an easy to digest, low-allergen formula, free of dairy, gluten, and lactose.

• DigestPro Enzymes is a synergistic blend of enzymes important for the digestion of proteins, fats, and carbohydrates.

• Detox Essentials, prepares the liver for both phases of detoxification by helping to conjugate toxins for safe elimination.

• The ReNew kit also comes with easy to follow instructions, a program guide with schedule, and a shaker bottle.

Special Offer for IFNA Students:

Normally $175 (Retail Price)

Become an Evexia Client and get the Detox Program for

$101.49Copyright © 2020 Evexia Diagnostics. All Rights Reserved

Ask the Doctor

A FREE service available to all Evexia clients, accessed via your Evexia Clinician Portal. Dr. Wayne Sodano, Director of Clinical Support and Education will review test results, clinical conditions, further test recommendations or answer any other questions you may have via email. In addition our clients have the option of scheduling either a telephone or video conference for a fee.


Test Preparation and Reminders

EvexiaLink™Evexia Diagnostics easy-to-use EvexiaLink™ platform allows for the ordering ALL available conventional and specialty lab tests. EvexiaLink will also allow you to order testing on patients in any state (excluding NJ, NY & RI), throughout Canada and in Puerto Rico using our Evexia Internal Physician Network (EIPN). EvexiaLink is available to all EDI clients on the EDI website (www.EvexiaDiagnostics.com) and accessed via your Clinician portal.


Test Preparation and Reminders

STEP 1: Register new or select existing patient.

STEP 2: Select panel / test(s) & submit order.

STEP 3: Electronic requisition form will be ready within 5 minutes.

Lab Order Fee: Evexia Diagnostics charges $15 for each order placed by non-licensed practitioners or licensed practitioners ordering for out-of-state patients.

Restrictions: (1) Patients must be 6 years old or older for test(s) that require any blood draws. Patients under the age of 18 require the parental/guardian consent form to be completed electronically. (2) We do not support lab ordering for patients in NY, NJ, and RI.

*Note: Certain tests can only be ordered by licensed clinicians –contact Customer Success Team for details on specific test eligibility at (888) 852-2723, Monday-Friday, 8AM – 8PM EST Copyright © 2020 Evexia Diagnostics. All Rights Reserved

www.evexiadiagnostics.com

18 Titus Road / PO Box 1272Washington, CT 06793

(888) 852-2723

[email protected]

Office HoursMonday - Friday, 8am - 8pm EDT

Live chat is available at www.evexiadiagnostics.com


Next Session:Part 1: Anemia; Part 2: Functional

Blood Chemistry Interpretation

Dr. Wayne L. SodanoDC, DABCI, DACBN, CFMP, CIHP, BCTN


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