Optimal Ranges vs. Reference Ranges in Blood Tests

Reference ranges signify values considered normal within a population, though not necessarily optimal. They usually indicate a percentile within a population, covering around 80-95% of individuals. These ranges may be expressed as a single threshold value or a range. Test results can vary among laboratories due to different assays, thus requiring interpretation in relation to specific lab reference ranges.

While populational norms do not always reflect ideal health parameters, evaluating test results against standard reference ranges is essential. Additionally, optimization involves considering results with the aim of achieving optimal health. For example, in the case of apolipoprotein B (apoB), laboratories typically cite a reference range of <120 mg/dL for low or intermediate risk. However, due to strong evidence linking apoB to cardiovascular outcomes and available interventions for lowering it, aiming for the lowest possible level without side effects, typically around the 5th percentile (approximately 60 mg/dL), is advisable.

Optimization also entails considering other factors that may affect a metric. These factors include age, sex, symptoms, medications, and other clinical variables, all of which can influence the interpretation of results irrespective of their alignment with generic reference ranges.

Basic Lipid Panel

The lipid panel serves as a vital assessment tool for understanding cholesterol levels in the body. Cholesterol, a crucial lipid essential for bodily functions, primarily originates from hepatic synthesis and intestinal absorption. Interpretation of personal lab results necessitates comprehension of cholesterol’s role and genesis. Atherosclerotic cardiovascular disease (ASCVD) stands as a prominent global cause of mortality, primarily due to the accumulation of cholesterol particles within arteries.

Cholesterol, being insoluble in water, relies on lipoproteins for transportation in the bloodstream. Lipoproteins, categorized based on their separation in a centrifuge tube, include Very Low Density (VLDL), Intermediate Density (IDL), Low Density (LDL), and High Density (HDL). These lipoprotein particles facilitate cholesterol transport between tissues and the liver. Apolipoprotein B (apoB) on beta-lipoproteins (LDLs, VLDLs, and IDLs) and apolipoprotein A on HDLs define lipoprotein structure. ApoB serves as a crucial metric for estimating the atherogenic particle count in a sample.

ASCVD arises from the embedding of apoB particles in arterial walls, initiating plaque formation. Elevated levels of apoB particles heighten the risk of arterial deposition, underscoring their association with ASCVD development.

Components of a Standard Lipid Panel

The standard lipid panel comprises various components that report specific concentrations of cholesterol and triglycerides within lipoprotein particles present in a fixed volume of blood. These components include:

• Low-Density Lipoprotein-Cholesterol (LDL-C): This measures the concentration of cholesterol within LDL particles. Lowering LDL-C is a primary therapeutic goal in managing lipid disorders. Labs may report LDL-C through calculations or direct measurement, with the latter being more precise.

• High-Density Lipoprotein-Cholesterol (HDL-C): This indicates the concentration of cholesterol within HDL particles, which play roles in cholesterol transport. While high levels of HDL-C were previously viewed as protective, this notion has been revised. Low HDL-C may indicate insulin resistance, but its correlation with cardiovascular risk is limited.

• Triglycerides (TG): This reports the concentration of triglyceride molecules carried within lipoprotein particles, particularly VLDLs. Elevated TG levels can signify insulin resistance, and very high levels may lead to pancreatitis.

• Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C): This reflects the total concentration of cholesterol in non-HDL particles and is considered a better marker for atherosclerotic cardiovascular disease (ASCVD) risk than LDL-C.

• Very-Low Density Lipoprotein-Cholesterol (VLDL-C): This estimates cholesterol concentration within VLDL and IDL molecules. Elevated VLDL-C indicates increased circulation of cholesterol-rich VLDL remnants, associated with higher TG levels and ASCVD risk.

• Triglyceride/HDL-C Ratio: Once used as a marker for insulin resistance and metabolic syndrome, this ratio is now discouraged due to its dependence on race and ethnicity.

• Total Cholesterol (TC): This reports the mass of cholesterol molecules within all lipoprotein particles circulating in the blood and is typically listed at the top of the lipid panel.

Additional Lipid Concentration Tests

Tests focusing on lipid concentrations beyond cholesterol:

• Campesterol and Sitosterol are plant sterols, closely resembling cholesterol in structure. The measurement of their levels aids in estimating intestinal cholesterol absorption. These measurements play a role in guiding therapies aimed at reducing LDL-C or apoB levels. For instance, ezetimibe can lower cholesterol absorption, prompting the liver to increase apoB (LDL particles) clearance from the bloodstream.
• Lathosterol and Desmosterol represent intermediary products in the complex pathways of cholesterol synthesis. Their concentrations serve as indicators of cellular cholesterol production. Elevated levels, particularly when associated with increased apoB or LDL-C, signify heightened cholesterol synthesis. This synthesis can be mitigated by cholesterol synthesis inhibitors such as statins and bempedoic acid. Inhibiting sterol synthesis in the liver enhances the clearance of apoB (LDL) particles from the bloodstream.

Lipoprotein Testing

Lipoprotein testing assesses the concentration of various lipoproteins rather than their lipid content.

Apolipoprotein B (apoB) represents the concentration of all circulating apoB-carrying particles, including LDLs, VLDLs, and IDLs. LDL particles constitute over 90% of apoB levels due to their longer serum residence times. ApoB plays a causal role in ASCVD and is a crucial metric for estimating ASCVD risk and guiding therapy.

Apolipoprotein E is a lipoprotein present on VLDLs and HDL particles in both serum and brain tissues. The APOE gene exists in three isoforms (e2, e3, and e4), inherited from each parent, resulting in six possible combinations. APOE, heavily studied in relation to Alzheimer’s disease risk, also influences cardiovascular disease. Different apoE isoforms exhibit subtle structural variations leading to altered functions. ApoE4 is linked to higher LDL-C, apoB, and ASCVD risk, while ApoE2 is associated with lower levels of these parameters.

Possessing a single APOE4 allele doubles the risk of Alzheimer’s disease, while having two e4 alleles increases the risk approximately tenfold compared to e3/e3 carriers. Although genetic factors are unchangeable, appropriate therapies can mitigate the risk of dementia and cardiovascular disease regardless of APOE status.

While most physicians may recognize APOE’s significance in Alzheimer’s disease, its importance in cardiovascular disease might not be universally acknowledged. APOE testing may or may not be covered by insurance but typically requires only one test. If a physician is unfamiliar with APOE or hesitant to order the test, referring them to relevant articles may be beneficial.

Lipoprotein(a) consists of an LDL particle with an additional apoprotein(a) attachment, increasing its atherogenicity and potential damage to the aortic valve. Lp(a) concentrations vary depending on genetics, with approximately 1 in 5 individuals (1 in 3 African Americans) exhibiting elevated levels, making it a prevalent genetic disorder contributing to ASCVD. Lp(a) levels are assessed either by mass or particle number, with no standardized conversion formula due to variable molecular weights of apoprotein(a).

Screening for elevated Lp(a) levels is recommended for everyone due to its significant cardiovascular risk, as levels remain stable over time and are genetically determined. Currently, there is no FDA-approved therapy specifically targeting Lp(a), but PCSK-9 inhibitors, effective in lowering LDL-C/apoB, can also reduce Lp(a) levels by 25%, potentially offering additional protective benefits.

Inflammatory Markers Analysis

C-reactive Protein (CRP) serves as an acute-phase protein produced by the liver, demonstrating increased presence in the bloodstream during instances of bodily inflammation. A conventional CRP examination identifies elevated protein levels correlated with significant inflammatory conditions (>8 mg/L). However, the highly sensitive CRP (hs-CRP) blood test surpasses the standard CRP assay in its ability to detect minor increments in CRP indicative of cardiometabolic ailments (1.0-3.0 mg/L). CRP, while not particularly specific, may signal a need for further investigation into potential sources of chronic inflammation if consistently elevated.

Homocysteine, measured in micromoles/L (µmol/L), is an amino acid formed during the digestion of cellular nuclear proteins. It subsequently undergoes the “methylation cycle,” heavily reliant on various B vitamin concentrations, converting homocysteine into other essential amino acids. Elevated homocysteine levels stem from either overproduction or reduced catabolism of nuclear proteins, leading to endothelial dysfunction. Consequently, homocysteine stands as a significant metabolic indicator and risk factor for atherosclerotic cardiovascular disease (ASCVD) and contributes to the risk of Alzheimer’s disease.

Uric Acid results from the breakdown of purine molecules by xanthine oxidase enzyme activity. Elevated serum and joint concentrations of uric acid may trigger conditions such as gout or kidney stones, and heightened levels could elevate the risk for ASCVD. Additionally, excess uric acid correlates with insulin resistance and increased triglyceride levels.

Addressing elevated uric acid levels can involve various FDA-approved medications designed to lower uric acid, with allopurinol being the most commonly prescribed. Dietary adjustments favoring metabolic health and relatively low fructose intake represent the primary means of managing uric acid levels.

Metabolic Health and Insulin Resistance

Metabolic health and insulin resistance, encompassing conditions such as prediabetes and type 2 diabetes, are influenced by both genetic predispositions and lifestyle choices such as diet, physical activity, sleep patterns, and stress levels. The correction of metabolic health issues typically commences with lifestyle adjustments, potentially complemented by medication targeting specific concerns.

Several tests serve to evaluate glucose disposal and insulin sensitivity, each presenting distinct advantages and drawbacks. Common assessments like Hemoglobin A1c and fasting glucose are readily accessible through insurance coverage, while tests like fasting insulin and the Oral Glucose Tolerance test may not be covered.

Fasting Glucose quantifies serum glucose concentration following an 8-12 hour fast. Elevated levels often signify inadequate glucose disposal and potential insulin resistance. However, it may not effectively detect early-stage insulin resistance, as fasting glucose remains within normal ranges initially before escalating to diagnostic thresholds for prediabetes or type 2 diabetes.

Hemoglobin A1c (HbA1c) reflects average blood sugar levels over a few months by measuring glycosylated hemoglobin. While valuable for diagnosing prediabetes or diabetes and assessing glucose control, it, like fasting glucose, lacks sensitivity in detecting early insulin resistance.

Fasting Insulin measures serum insulin levels after fasting, with high levels suggesting insulin resistance due to increased insulin requirements for maintaining normal blood glucose. Typically, insulin levels elevate years before fasting glucose levels rise.

The Oral Glucose Tolerance Test (OGTT) offers a comprehensive assessment of glucose disposal and insulin sensitivity. By administering a glucose solution and monitoring blood glucose and insulin levels at intervals, this test provides insights into metabolic function. Elevated blood glucose levels or significant insulin requirements during the test may indicate metabolic dysfunction.

Thyroid Tests

Maintaining proper thyroid function is crucial for overall bodily health, as thyroid hormones play a significant role in various physiological processes. Regulation of thyroid levels involves a feedback mechanism between the brain and the thyroid gland. The hypothalamus secretes Thyrotropin Releasing Hormone (TRH), which stimulates the anterior pituitary gland to release Thyroid Stimulating Hormone (TSH). TSH then prompts the thyroid gland to produce triiodothyronine (T3) and thyroxine (T4). These hormones, particularly T3 and T4, modulate bodily functions, including metabolic rate, through feedback mechanisms.

While T4 predominates in the bloodstream with a longer half-life, T3 is the more biologically active form. Together, they regulate numerous physiological processes.

• TSH Test: This is typically the initial thyroid test administered. It serves as a fundamental screening tool for thyroid dysfunction, commonly ordered for individuals showing potential symptoms. Abnormal TSH levels indicate either excessive (hyperthyroidism) or inadequate (hypothyroidism) thyroid hormone production. This test is readily available and often covered by insurance.
• Free T4 Test: This evaluates the concentration of unbound T4 in the bloodstream, offering insights into thyroid function. It is frequently conducted alongside TSH testing if there are indications of thyroid dysfunction or if TSH levels are abnormal.
• Free T3 Test: This assesses the concentration of unbound T3 in the bloodstream. Although it is the most biologically active thyroid hormone, its levels can fluctuate, necessitating consideration alongside TSH and Free T4 results.

Sex Hormones

Sex hormones are integral to maintaining overall health, warranting careful consideration in any comprehensive health regimen. Both high and low levels of these hormones can pose health risks and merit investigation.

• Estradiol, a primary estrogen steroid hormone, serves essential functions in both genders. In men, it influences body composition, indicating potential testosterone conversion to estrogen. Additionally, estradiol impacts brain function, bone density, sexual health, and vascular well-being. In women, it offers insights into menopausal transitions and overall hormonal balance, playing vital roles in bone health, cognitive function, sexual wellness, and vascular integrity.
• Testosterone, the principal male sex hormone, operates as an anabolic steroid in both sexes, albeit at lower levels in women. Its evaluation aids in identifying testosterone deficiency and assessing metabolic disease risks in men. In women, low testosterone levels may affect libido and muscle mass.
• Free testosterone, the unbound and active testosterone in circulation, provides functional insights into hormonal status. Its assessment, considering sex hormone binding globulin (SHBG) and albumin levels, offers a more accurate indication of bioactive hormone availability. Suboptimal free testosterone levels, despite total testosterone falling within normal range, may manifest symptoms of low testosterone.
• Follicle Stimulating Hormone (FSH), secreted by the pituitary gland, regulates reproductive processes in both sexes. In men, FSH levels reflect responses to exogenous hormones and distinguish between primary and secondary hypogonadism. In women, FSH levels vary across menstrual phases, serving as markers for menopausal stages and guiding hormone replacement therapy.
• Luteinizing Hormone (LH), also originating from the pituitary gland, stimulates testosterone production in men and contributes to the reproductive cycle in women.

Prostate Test

Prostate Specific Antigen (PSA) is an enzyme naturally produced by the prostate gland, typically found in low concentrations within the serum of men with healthy prostates. Elevated levels of PSA may indicate a potential risk of prostate cancer, prompting the need for further investigation. PSA levels tend to rise gradually with age in most men. It’s important to note that certain medications, such as 5-alpha reductase inhibitors like Finasteride and Dutasteride, can artificially reduce PSA levels. Therefore, adjustments may be necessary for men taking these medications when interpreting PSA test results.

Liver Function Tests

The liver, a vital organ responsible for various metabolic processes, plays a crucial role in synthesizing essential molecules and eliminating toxins from the body. However, like any organ, it is susceptible to diseases, with fatty liver disease being the most prevalent, whether induced by alcohol consumption or other non-alcoholic factors. To assess liver health, several laboratory tests are utilized, primarily focusing on bilirubin and transaminase levels, namely AST and ALT.

• ALT and AST, enzymes synthesized in the liver, serve as indicators of liver function when present in the bloodstream. Elevated levels of these enzymes can signify liver dysfunction, potentially indicating the presence of a liver-related ailment. While minor elevations may not raise significant concerns, persistent increases often suggest chronic conditions such as fatty liver disease or other pathologies. Extreme elevations may point to acute liver injury.
• Total Bilirubin, a byproduct of blood breakdown processed by the liver, also plays a crucial role in assessing liver function. Impaired liver function can lead to elevated bilirubin levels, causing jaundice characterized by yellowing of the skin and eyes. However, certain individuals with Gilbert syndrome, a hereditary condition, may exhibit benign elevations in total bilirubin levels alongside normal direct bilirubin levels due to impaired bilirubin processing by the liver.

Kidney Function Test

Assessing kidney function is crucial for maintaining overall health. Impaired kidney function ranks among the leading causes of mortality and disability on a global scale. Chronic hypertension and metabolic disorders are primary factors contributing to the deterioration of kidney function.

• Cystatin C, a naturally occurring molecule in the body, serves as a marker for kidney health. Elevated levels of Cystatin C may suggest compromised kidney function.
• The Estimated Glomerular Filtration Rate (eGFR), derived from Cystatin C levels, offers insight into the kidneys’ ability to filter blood effectively, removing toxins and waste products. An eGFR below 90 mL/min/1.73 m² may signal kidney dysfunction, necessitating further assessment and management.

Hemoglobin

Hemoglobin serves as the crucial protein within red blood cells, facilitating the transportation of oxygen to bodily tissues. A decrease in hemoglobin levels suggests the presence of anemia, while an increase suggests erythrocytosis. Such deviations in hemoglobin levels necessitate additional laboratory analysis to ascertain their underlying causes.

Ferritin

Ferritin, a protein present in the blood, stores iron and acts as an indicator of the body’s iron reserves. Levels below 30 ng/mL suggest a deficiency in iron, while elevated levels may signify either an excess of iron or inflammation.

Omega-3 Index (Omega Quant)

The Omega-3 Index, facilitated by Omega Quant, evaluates the presence of EPA and DHA, essential fatty acids vital for cell composition and various physiological functions. It gauges the concentration of these fatty acids within red blood cell membranes, offering insight into overall omega-3 status. Research suggests that an Omega-3 Index below 4% correlates with an elevated likelihood of sudden cardiac death. Introducing supplements containing EPA and DHA omega-3 fatty acids can effectively elevate the Omega-3 Index to optimal levels.

Vitamin D

Vitamin D, classified as a hormone, plays a pivotal role in various bodily functions, notably in regulating calcium and magnesium levels. Its significance spans across brain and bone health, immune function, and potentially influences sleep and cognitive processes. A considerable portion of the population exhibits suboptimal levels of vitamin D, necessitating exposure to sunlight or dietary supplementation for adequate intake.

In conclusion, while reference ranges provide a framework for understanding where an individual’s test results fall within a population, they may not always signify optimal health. It’s imperative to interpret results in light of specific clinical circumstances and consider the potential for optimization beyond mere conformity to these ranges. This involves aiming for values associated with better health outcomes, as exemplified by the case of apolipoprotein B (apoB), where targeting lower levels than standard reference ranges may be advisable. Moreover, optimization extends beyond numerical values to encompass individual characteristics such as age, sex, symptoms, medications, and other clinical variables, all of which can influence health outcomes. By considering these factors and striving for personalized health goals, individuals can navigate towards optimal well-being, transcending the limitations of generic reference ranges. Therefore, a comprehensive approach that integrates clinical expertise with patient-specific considerations is essential for achieving and maintaining optimal health.