The purpose of this module is to provide an overview of the most common laboratory tests and guide the interpretation of results.
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g vigorous exercise, as well as in athletes who train at high altitudes or who take performance-enhancing drugs such as anabolic steroids, so it is crucial to obtain a detailed history. Table 3 lists the most common etiologies of increased hemoglobin and hematocrit levels (Cleveland Clinic, 2018).
While the CBC w/diff provides essential data regarding the presence of and features of anemia, a complete anemia workup requires an anemia panel (Longo, 2019). Anemia is a broad topic with variable classifications, presentations, and etiologies beyond the scope of this module. For a more detailed account outlining the various types of anemias, refer to the NursingCE.com course entitled, Anemia: Diagnosing, Classifying, and Managing Anemia in Adults.
WBCs
WBCs are also called leukocytes and are the essential cells of the immune system. While WBCs only make up about 1% of all blood cells in healthy adults, they serve critical functions in the fight against infection and mediate the inflammatory process. WBCs have variable lifespans, as some live for only 24 hours; the average WBC lifespan is 13 to 20 days. There are five specific subtypes of WBCs: neutrophils, lymphocytes, monocytes, basophils, and eosinophils. Each subtype serves a distinct function and collectively they comprise the "differential" component of the CBC. When the total WBC count is abnormally elevated, it is called leukocytosis. This is most commonly an indicator of an acute bacterial infection or an inflammatory process. However, a high WBC does not always indicate a pathologic process, as there can be physiological causes of leukocytosis such as stress, pregnancy, steroid therapy, or vigorous exercise. When leukocytosis occurs, the CBC's differential provides information about the relative percentage and the absolute number of each WBC subtype. A lower than normal WBC count is called leukopenia and increases the risk for acquiring an infection (Longo, 2019).
Neutrophils may also be referred to as segmented neutrophils (segs) or polymorphonuclear cells (polys or PMNs). They are the main WBC used for fighting and preventing infections, as they are primed to destroy and ingest any potential bacterial intruder. Neutrophils arrive first at the site of inflammation or injury. Therefore, elevations in neutrophils are usually seen early on in the course of an injury or illness. The absolute neutrophil count (ANC) measures the total number of neutrophils circulating in the blood, which correlates directly with the patient's risk level for acquiring an infection. This value is particularly important to monitor in patients undergoing myelosuppressive treatment for cancer. When the ANC drops below the normal range, the patient's risk for infection rises dramatically. Most laboratories designate an ANC level of less than 1500 as abnormal, or neutropenia. When a patient is neutropenic, they are at high risk for developing a serious illness, including life-threatening sepsis. Bands are immature neutrophils that are typically released following acute injury or inflammation. The presence of bands indicates that an inflammatory process is occurring, as the bone marrow has increased production of WBCs and is releasing them into circulation before they are fully mature. An increase in the number of bands is commonly referred to as a "left shift" or "shift to the left" (Pagana & Pagana, 2018).
Lymphocytes primarily fight viral infections, and there are two major types: B cells and T cells. B cells make antibodies in response to antigens (foreign substances) to provide future immunity to that specific antigen. T cells help to destroy cancer cells and also help to control the immune response against foreign substances. Monocytes are phagocytic cells that fight off viruses, fungi, and bacteria. Their job is to remove foreign materials such as dead or injured cells, microorganisms, and other particles from the site of injury to facilitate healing and prevent further injury or infection. Basophils help prevent blood from clotting within the microcirculation and are also involved in the inflammatory response, particularly with regards to modulating hypersensitivity reactions to allergens. In addition to their presence in the blood, basophils are also found within the gastrointestinal tract and skin, where they are referred to as mast cells. Mast cells contain heparin and histamine and are involved in allergic and stress responses. Eosinophils are also involved in mediating allergic and inflammatory reactions and serve an important role in fighting parasitic infections. Eosinophils are present in the respiratory tract and airway, serving similar functions in response to allergic reactions (Pagana & Pagana, 2018).
Platelets
Platelets, or thrombocytes, are small blood cell fragments that serve a primary role in blood clotting. In response to an injury, laceration, or blunt trauma, platelets gather at the site of an injury to seal cuts or breaks in blood vessels in conjunction with proteins called clotting factors to control bleeding. Platelets have an average lifespan of 7 to 10 days (Longo, 2019). Thrombocytopenia occurs when the platelet count declines beneath the normal range, thereby heightening the patient's risk for bruising and acute bleeding events. Spontaneous hemorrhage and death can ensue in the most severe cases, particularly when the platelet count drops below 20,000 (Longo, 2019). Thrombocytopenia can have various etiologies; it can be idiopathic, due to destruction of platelets caused by medications such as chemotherapy and certain antibiotics, as a side effect of radiation therapy, or as a result of decreased production of platelets caused by a viral infection. Aplastic anemia and idiopathic thrombocytopenic purpura (ITP) are rare autoimmune bleeding disorders in which the platelet count is affected. In aplastic anemia, the body fails to produce platelets in sufficient quantities, whereas in ITP, the immune system attacks and destroys its platelets. Increased platelet level (thrombocytosis) can occur in splenomegaly, as a byproduct of inflammation, due to stress hormones, or from myeloproliferative bone marrow disorders such as polycythemia vera or chronic granulocytic leukemia (Pagana & Pagana, 2018).
Blood Chemistry/Comprehensive Metabolic Panel (CMP)
The CMP, otherwise referred to as the blood chemistry panel, provides information about several body systems and organ health. It measures the glucose levels, liver and kidney function, as well as the fluid and electrolyte balance. Table 4 provides a sample of a CMP results report highlighting the relevant components of the test and the accompanying normal reference ranges (Pagana & Pagana, 2018).
Electrolytes
Embedded within the CMP are five serum electrolytes, including sodium, potassium, calcium, chloride, and bicarbonate (Bakerman et al., 2014).
Sodium
Sodium helps regulate and maintain fluid balance within the body and serves a vital role in muscle contraction and nerve impulse. Hyponatremia occurs when sodium levels drop lower than the normal range and is a result of either water retention or sodium loss. Hyponatremia can occur due to fluid volume losses secondary to vomiting, diarrhea, or enforced diuresis from medication therapy. Alternatively, hyponatremia may be secondary to a more significant etiology, such as an underlying liver or renal disorder (chronic renal disease), hormonal abnormality (adrenal insufficiency), congestive heart failure, or excessive water intake. Hypernatremia occurs when the sodium level rises above the normal range and is typically due to water depletion secondary to insufficient water intake, excessive sweating, water loss, or excessive sodium intake. Hypernatremia may also be due to an underlying condition such as interstitial nephritis, diabetes insipidus, or excessive mineralocorticoid (hyperaldosteronism, Cushing's syndrome, or corticosteroids; Bakerman et al., 2014).
Potassium
Potassium helps regulate the communication channels between nerve fibers and muscles, serving an important role in heart contraction and muscle functioning. Hypokalemia results when the potassium level drops below the normal range. There are three main mechanisms to consider with regards to the etiology of hypokalemia: (a) urinary loss (usually drug-induced from diuretic medications), (b) gastrointestinal loss (usually due to diarrhea, vomiting, or malabsorption), or (c) movement of potassium from extracellular to intracellular fluid (in severe illness such as diabetic ketoacidosis). Hyperkalemia occurs when the potassium level is higher than the upper limit of normal and can be due to increased dietary potassium intake or impaired renal clearance secondary to either acute or chronic renal failure. Hyperkalemia can also be drug-induced by potassium-sparing diuretics such as aldosterone antagonists (i.e., spironolactone [Aldactone]). If a serum sample is hemolyzed (cells are ruptured) during sample collection or processing, hyperkalemia can be inaccurately reported on the lab results, thereby reinforcing the need to associate all laboratory data with the patient's clinical presentation. Because more than 90% of potassium is excreted in the urine, which is then filtered and reabsorbed proximally before being excreted by the distal tubules, it is not uncommon to see hyperkalemia in patients with severe renal disease. Therefore, confirmed hyperkalemia should warrant further evaluation of the patient's renal function (Bakerman et al., 2014).
Calcium
Calcium is one of the body's essential minerals required for muscle contraction, nerve function, healthy bones, and teeth. Calcium also serves important roles in blood clotting and cellular division. The CMP reports only the total calcium level in the bloodstream. Low levels of calcium, or hypocalcemia, may be a manifestation of hypoparathyroidism, renal failure, vitamin D deficiency or insufficiency, magnesium deficiency, acute pancreatitis, or several other conditions. High calcium levels, or hypercalcemia, may be due to hyperparathyroidism or tuberculosis, but also raises suspicion for malignancy (especially metastatic breast or lung cancer or multiple myeloma). In its most severe form, hypercalcemia related to malignancy is considered a life-threatening medical emergency. Hypercalcemia can be drug-induced secondary to thiazide diuretics, calcium-containing antacids (calcium carbonate [Tums]), or excess vitamin D intake. Since calcium in the blood is bound to albumin, the total calcium level reported may be an inaccurate representation of the free (ionized) calcium in patients with high or low albumin levels. Therefore, before treating abnormally high or low calcium, it is essential to determine the accurate (corrected) calcium level by using the formula listed in Figure 1. Several online calculators are readily available to assist clinicians (Goltzman, 2020).
Chloride and Bicarbonate
Chloride helps to regulate fluid balance within the body, and bicarbonate provides information regarding the acid-base status. Due to their direct inverse relationship, the clinical significance of chloride and bicarbonate should always be interpreted together and in conjunction with the anion gap. The anion gap is a calculated result that measures how much acid is in the blood, which provides useful information for delineating the etiology of acid-base disturbances. These tests help to distinguish between respiratory alkalosis (acute versus chronic) and metabolic acidosis. They can also help to identify diabetes insipidus, renal tubular acidosis, Addison's disease, as well as several other conditions (Bakerman et al., 2014).
Renal Function
While the electrolyte panel provides important information regarding the renal function, three tests within the CMP are explicitly directed toward evaluating the health status and functioning of the renal system: blood urea nitrogen (BUN), creatinine, and estimated glomerular filtration rate (eGFR) (Bakerman et al., 2014).
BUN
Urea nitrogen is a waste product generated from the breakdown of dietary protein within the liver. It is released into the blood and circulates until it is filtered by the kidneys and excreted via the urine. The BUN is a measure of the amount of waste products in the blood. The BUN increases when the kidneys are not functioning properly. This can be due to easily correctable causes such as dehydration, diarrhea, high protein diet, or certain medications, including chemotherapy or steroids. Alternatively, an elevated BUN may be a sign of a more complex condition such as congestive heart failure, renal disease, tissue necrosis, shock, or severe burns. Low BUN levels are not as common and are generally due to inappropriate antidiuretic hormone, overhydration, malnutrition, or liver disease (Bakerman et al., 2014).
Creatinine
Creatinine is a chemical waste byproduct of creatinine phosphate that serves an essential role in creating muscle energy. Formed primarily in the liver, creatinine is transported to the muscles where it is phosphorylated into creatinine phosphate. Creatinine phosphate acts as a storage for muscle energy, until it is broken down and excreted by the kidneys. High creatinine levels are generally an indication of kidney dysfunction, which may be secondary to dehydration, starvation, acute trauma, infection, or burns (Bakerman et al., 2014).
eGFR
The eGFR is the most sensitive test to measure how well the kidneys are functioning and is used to stage existing kidney disease. The eGFR reflects the level of creatinine in the blood, utilizing a specific formula to calculate a result based on the patient's age, gender, and body size. The normal eGFR in adults is more than 90, but as demonstrated in Figure 2, a normal eGFR is commonly reported as >60 ml/min/1.73 m2. Chronic kidney disease (CKD) is staged based on the severity of impairment of the eGFR value. According to the National Kidney Foundation (NKF, 2018), an eGFR below 60 for at least three months or an eGFR above 60 with kidney damage (marked by high levels of albumin in the urine) indicates CKD. The NKF (2018) classifies the staging of CKD as follows:
- Stage 1: eGFR 90 or higher (the patient has 90% to 100% of kidney function)
- Stage 2: eGFR 89 to 60 (the patient has 89% to 60% of kidney function)
- Stage 3a: eGFR 59 to 45 (the patient has 59% to 45% of kidney function)
- Stage 3b: eGFR 44 to 30 (the patient has 44% to 30% of kidney function)
- Stage 4: eGFR 29 to 15 (the patient has 29% to 15% of kidney function)
- Stage 5: eGFR less than 15 (the patient has less than 15% of kidney function) (NKF, 2018).
Liver Function Tests (LFTs)
LFTs, often called the hepatic panel, is a group of tests that measures specific enzymes and proteins in the blood and provide information about the liver (Murali & Carey, 2017).
Bilirubin
Bilirubin is the typical byproduct of the breakdown of RBCs, and it is reported in three values: total, direct, and indirect. Total bilirubin is a combination of both direct and indirect bilirubin values. Indirect (unconjugated) bilirubin is the amount of bilirubin that is bound to albumin and circulating through the bloodstream. Indirect bilirubin is absorbed by the liver where it is conjugated with glucuronic acid. Direct (conjugated) bilirubin is then secreted into bile and transported through the gallbladder and digestive tract before being excreted. Hyperbilirubinemia occurs when indirect bilirubin builds up in the bloodstream. Since bilirubin is a yellowish substance, pathologic accumulation in the blood can lead to jaundice, or yellowing of the skin and eyes (scleral icterus). Hyperbilirubinemia can cause abdominal pain, fevers, chills, systemic pruritus, dark-colored urine, fatigue, weakness, nausea, or vomiting. The differential diagnosis of hyperbilirubinemia can vary widely, but most common etiologies of hyperbilirubinemia include liver disease, bile duct inflammation or blockage, gallstones, cholelithiasis, or hemolytic anemia. When interpreting bilirubin values, it is essential to consider the patient's age and other health conditions (Murali & Carey, 2017).
Indirect (unconjugated) Bilirubin. At least 90% of bilirubin should be unconjugated in healthy adults. Therefore, when the total bilirubin level is elevated, and the breakdown of the direct and indirect values reveals that at least 90% is unconjugated, liver disease can be excluded as the culprit. In these cases, hemolysis or Gilbert's syndrome are more likely etiologies; both conditions usually demonstrate normal direct bilirubin levels. Gilbert's syndrome is a genetic liver condition seen in approximately 5% of the population that impairs the liver's ability to process bilirubin correctly. It generally causes mild hyperbilirubinemia without any clinical symptoms (Murali & Carey, 2017).
Direct (conjugated) bilirubin. Direct bilirubin is considered the most sensitive test in the diagnosis of liver disease. Therefore, elevated levels of direct bilirubin are often accompanied by elevated liver enzymes. The most common etiologies include alcohol abuse, hepatocellular disease, infectious hepatitis, cirrhosis, drug reactions, and biliary tract obstruction (extrahepatic or intrahepatic). When direct bilirubin is elevated, it will spill over into the urine (Murali & Carey, 2017).
Liver Enzymes
The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) tests are used to further evaluate the function of the liver and to detect liver injury or disease.
ALT. ALT is an enzyme primarily produced by the liver that is found in high concentrations within the hepatocytes (liver cells). The ALT is considered the most specific test with regards to evaluating for liver injury, as it is a direct indication of hepatocellular injury (hepatic jaundice).
AST. AST is an enzyme found in RBCs and muscle tissue, as well as vital organs such as the heart, liver, kidneys, and pancreas. While elevations in AST can indicate liver damage, they can also be seen in cases of acute cardiac muscle injury (i.e., myocardial infarction) or skeletal muscle injury.
ALP. ALP is an enzyme that is concentrated within the liver, bile duct, and bone cells. Elevations in ALP can indicate liver damage or bone problems such as rickets, Paget's disease, or the presence of cancer in the bones (primary bone tumors or metastatic bone lesions). When ALP is elevated with regards to liver pathology, it is primarily in response to cholestasis (a decrease in bile flow due to post-hepatic or obstructive jaundice).
In addition, ALT, AST, and ALP elevations may be drug-induced due to lipid-lowering statin therapy (i.e., atorvastatin [Lipitor]), chemotherapy, or numerous other medications processed through the liver. Elevations may also be related to excess alcohol consumption, underlying cirrhosis, or fatty liver (Bakerman et al., 2014; Murali & Carey, 2017).
Lactate Dehydrogenase (LDH)
LDH, also known as lactic acid dehydrogenase, is an enzyme in the blood that plays an essential role in generating energy within the body. LDH is widespread throughout nearly all body tissues; when tissues become damaged, they release LDH into the blood, making it a nonspecific marker of tissue damage and inflammation. Patients with metastatic cancer often have elevated LDH levels due to the spread of cancer or damage to the liver from cancer treatments. LDH can be elevated in a wide range of conditions such as acute myocardial infarction, skeletal muscle disease, tissue necrosis, shock, congestive heart disease, systemic infections, liver disease, and beyond (MedLinePlus, 2020b).
Total Protein
Protein is necessary for cellular growth, development, and overall health. The total protein is the sum of two circulating proteins in the blood: albumin and globulin. Therefore, the total protein is difficult to interpret without the albumin and globulin values, which are also reported within the CMP.
Albumin. Albumin is produced within the liver and is the predominant protein within the bloodstream, accounting for approximately 60% of the total protein. The albumin provides important information about nutritional status; hypoalbuminemia (decreased albumin level) is commonly seen in malnutrition and malabsorptive disorders. The albumin also serves as a marker of liver and kidney damage, as albumin production within the liver is decreased in the presence of severe liver disease or inflammation. Typically, the only clinically significant cause of increased albumin levels is dehydration.
Globulins. Globulins comprise the remaining 40% of the protein in the bloodstream; they assist the immune system with fighting infection and transporting nutrients. Globulins may increase in the presence of infection, chronic inflammation, and some types of cancers, particularly plasma cell tumors and lymphomas.
A-G ratio. The A-G ratio refers to the ratio of albumin in relation to the amount of globulin present in the blood. It is calculated automatically by many labs and reported in CMP results. In healthy adults, the A-G- ratio should be slightly higher than 1. It can provide insight into the etiology of changes in the total serum protein value. Higher than normal A-G ratios are often due to the underproduction of globulins and can be caused by hypothyroidism, glucocorticoid excess, certain types of blood cancers such as leukemia, as well as some genetic disorders. Low A-G ratios may be a sign of an autoimmune disorder, cirrhosis, or kidney disease (Bakerman et al., 2014; Murali & Carey, 2017).
Lipid Panel
A lipid panel (or lipid profile) measures the amount of cholesterol and triglycerides within the blood. Lipids are fats and fatty substances within the blood that serve as sources of energy and are required by the body to maintain the health of cells and specific cellular functions. When cholesterol is present in excess, it can lead to atherosclerosis or the buildup of fatty plaque within the arteries. Plaque growth within the arteries leads to damage, narrowing, or blockage of the arteries and blood vessels, which can develop into coronary artery disease (CAD) and serious cardiovascular consequences including myocardial infarction (heart attack) and stroke (Mayo Clinic, 2018b). Hyperlipidemia, or high cholesterol levels, is considered a significant risk factor for cardiovascular and blood vessel disease, but this usually do not cause any warning signs or symptoms. Therefore, the lipid panel provides valuable information regarding a patient's risk for atherosclerosis and is also performed when monitoring response to lipid-lowering therapy. As demonstrated in Table 5, a standard lipid panel includes total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides. Dietary intake can impact the lipid panel results, so patients are advised to fast for at least eight hours before the test is performed. The reference ranges listed in Table 5 are values based on fasting.
HDL-C is referred to as the good cholesterol, as high levels are considered cardioprotective and associated with a reduced risk of cardiovascular and blood vessel disease. Since HDL-C takes up excess cholesterol and carries it to the liver for removal, the higher the HDL-C, the better. Alternatively, decreased levels of HDL-C are associated with an increased risk of cardiovascular disease, especially in males. The LDL-C is considered the bad cholesterol, as high levels are linked to increased cardiovascular damage, atherosclerosis, and associated morbidity and mortality. LDL-C deposits excess cholesterol in the walls of blood vessels. In general, the higher the LDL-C, the greater the risk for fatty plaque buildup within the arteries. The basis for cholesterol management is centered on lipid-lowering agents and diets targeting a reduction in the LDL-C level. Similar to LDL-C, high triglyceride levels are associated with an increased risk of cardiovascular and blood vessel disease (Bakerman et al., 2014).
Elevated LDL-C and triglycerides levels are closely linked to unhealthy lifestyle choices such as a poor diet (excess intake of fatty foods and simple sugar), a sedentary lifestyle (lack of physical activity), obesity and excess weight, smoking or exposure to tobacco smoke, and excessive alcohol intake (American Heart Association [AHA], 2017). Further, hyperlipidemia and type 2 diabetes mellitus (T2DM) commonly occur together, as lipid abnormalities affect up to 70% of patients with diabetes. Patients with T2DM have a higher prevalence of lipid abnormalities in the peripheral venous circulation, increased amounts of atherosclerotic plaque accumulation, and smaller coronary artery lumen diameter than those without T2DM (Janus et al., 2016). The American Diabetes Association (ADA) recommends patients with T2DM strive for lower target cholesterol levels than those listed in Table 3. Optimal cholesterol values for patients with T2DM include:
- LDL-C: < 100 mg/dL,
- HDL-C: > 40 mg/dL (men) or > 50 mg/dL (women), and
- Triglycerides < 150 mg/dL (ADA, 2020).
Triglycerides can also be elevated in certain disease processes, including acute pancreatitis, acute alcoholism, gout, and in patients taking oral contraceptives. Lipid levels can also be elevated due to a strong family history, and in some cases, due to a genetic condition known as familial hypercholesterolemia (FH). Patients with FH have a genetic mutation that impairs the body's ability to remove excess LDL cholesterol from the bloodstream, thereby causing high LDL-C levels. Over time, the high levels of LDL-C build up within the arteries, amplifying the risk for early onset of cardiovascular disease and vessel blockage. To reduce cardiac damage and FH-induced morbidity and mortality, treatment for FH should begin early in life. Therefore, it is important to obtain a detailed family history to ensure patients are monitored appropriately (The FH Foundation, n.d.).
When interpreting the lipid panel values, it is important to evaluate all the components before drawing conclusions. The total cholesterol measures all the cholesterol in all the subtypes of lipoprotein particles. Therefore, a marked elevation in the HDL-C level can cause the total cholesterol to exceed the upper limit of normal, but this does not equate to increased atherosclerosis risk since HDL-C is a cardioprotective factor. It is essential to evaluate all aspects of the lipid panel, and not just the total cholesterol value (Pagana & Pagana, 2018).
Thyroid Function Tests (TFT)
TFTs are performed to determine if the appropriate amount of thyroid hormone is present within the bloodstream. TFTs may be ordered individually or collectively as a group (thyroid panel) to help diagnose or monitor thyroid disorders. The thyroid gland has several important functions and is responsible for maintaining various aspects of homeostasis within the body, including regulating body temperature, metabolism, and calcitonin. It also impacts the way tissues outside the thyroid are functioning. There are two primary hormones generated by the thyroid gland: thyroxine (T4) and triiodothyronine (T3). T4 contains four iodine atoms and is converted to T3, which contains three iodine atoms and has a stronger and more rapid metabolic action than T4. The amounts of T4 and T3 secreted into the blood are regulated by the pituitary gland (American Thyroid Association [ATA], n.d.).
Interpreting TFTs can be a daunting task and requires a rudimentary understanding of how the thyroid hormones are produced and released. As demonstrated in Figure 2, the release rate of T3 and T4 is controlled by the anterior pituitary gland and hypothalamus, which acts as a sensory controller. The process is initiated by the hypothalamus, which releases thyrotropin-releasing hormone (TRH). TRH is essentially the first thyroid messenger signal, as it is responsible for stimulating the release of thyroid-stimulating hormone (TSH) from the anterior pituitary gland. TSH is critical in modulating the release of T4, which is then converted to T3. The amount of TSH that the pituitary releases into the bloodstream depends on the amount of T4 that the pituitary perceives, as it functions on a negative feedback system. The pituitary is constantly measuring the amount of T3/4 and responding to changes to maintain an appropriate balance. If the pituitary senses that there is not enough T4, it will ramp up the TSH production, signaling the thyroid gland to produce more T4. Once the level of T4 reaches a specific level within the blood, TSH production decreases (ATA, n.d.).
Thyroid disease is most commonly characterized as overactive (hyperthyroidism) or underactive (hypothyroidism). Hypothyroidism is classified as primary or secondary; primary is much more common. Hashimoto's thyroiditis, an autoimmune disease that causes the body to attack the thyroid gland, is the most common cause of primary hypothyroidism in the US. Secondary hypothyroidism is caused by the failure of the pituitary gland or hypothalamic disease, whereby the body does not make adequate amounts of TSH to stimulate the release of T3/4. The differential diagnosis for hyperthyroidism is a bit more complex and includes thyrotoxicosis, Grave's disease and subacute thyroiditis. The main distinction between hyperthyroidism and thyrotoxicosis is in the underlying pathophysiology of the hormones. Hyperthyroidism is characterized by the increased production and secretion of T3/4 from the thyroid gland. Thyrotoxicosis signifies a clinical disorder in which there is excess circulating T3/4, irrespective of the source (Yani, 2019). Graves' disease is an autoimmune disorder that leads to hyperthyroidism, as the body attacks the thyroid gland, inducing overactivity. While it carries many of the same symptoms of hyperthyroidism as outlined in Table 4, Grave's disease has characteristic physical signs including exophthalmos, prominence of the eyes, and extraocular muscle weakness (DeGroot, 2016). Table 6 outlines some of the most common clinical features of hypothyroidism and hyperthyroidism.
A thyroid panel is typically comprised of three main tests: free T4 (thyroxine [FT4]), free T3 or total T3 (triiodothyronine), and TSH, which are described in Table 7.
TSH
According to the US Preventative Services Task Force (USPSTF, 2015), TSH is considered the first-line screening test for patients with suspected thyroid dysfunction. The level of circulating TSH in the blood is used to determine if the thyroid is functioning normally, or if it is overactive or underactive. The USPSTF recommends that multiple tests over three to six months should be performed to confirm abnormal results (USPSTF, 2015). If the TSH is high, it indicates that the thyroid gland is not producing enough T3/4, which would raise the clinical suspicion for primary hypothyroidism. Conversely, if the TSH is low, it usually suggests that the thyroid is producing too much T3/4, raising clinical suspicion for hyperthyroidism. Less commonly, a low TSH level may be caused by an abnormality in the pituitary gland or hypothalamic disease, preventing the body from making adequate amounts of TSH to stimulate the release of T3/4. This condition is referred to as secondary hypothyroidism (ATA, 2019).
T4 Tests
T4 can be measured as total T4 or FT4. Total T4 measures both the free and the bound hormone available, whereas FT4 is a measure of the T4 hormone that is freely circulating in the blood and available to be used. FT4 is more commonly performed as it provides the most useful insight into the severity of an abnormal TSH level. FT4 is most accurate when performed in conjunction with the TSH level, and therefore these tests are usually ordered together (ATA, 2019). When interpreting the FT4, the APRN must exclude conditions that are commonly associated with transient elevations of the FT4, such as:
- Amphetamine abuse
- High altitude exposure
- Selenium deficiency
- Hyperemesis gravidarum
- Acute psychosis
- Estrogen withdrawal (DeGroot, 2016).
T3 Tests
T3 can be evaluated as either total T3 or free T3; however, free T3 is less reliable and typically not clinically indicated in suspected thyroid disease. The total T3 test is reserved for evaluating for hyperthyroidism or determining its severity, as patients with an overactive thyroid have elevated T3 levels. T3 testing is not clinically useful in hypothyroidism, as both the TSH and FT4 are typically abnormal earlier on in the course of the condition than the T3 level. Even patients with severe hypothyroidism may present with a T3 that is within normal limits. Reverse T3 is another thyroid test that is less commonly performed. It is a measure of the inactive thyroid hormone, and it is also only indicated in the evaluation of patients with suspected hyperthyroidism (ATA, 2019). According to the ATA (n.d.), when interpreting TFTs individually, clinicians are advised to first evaluate the TSH. If the TSH is normal, then no further testing is indicated. If the TSH is high, hypothyroidism is suspected, and the FT4 should be evaluated to determine the degree of hypothyroidism. If the TSH is low, FT4 and T3 should be added to determine the degree of hyperthyroidism. Figure 3 demonstrates a clinical algorithm for thyroid function testing for suspected thyroid disease and follow-up monitoring recommendations in non-pregnant adults. The most common thyroid conditions classified by TSH and FT4 values are demonstrated in Table 8 (ATA, n.d.).
Thyroid Antibody Tests
Thyroid antibody tests are a separate subtype of TFTs that measure the level of the blood's thyroid antibodies. Thyroid peroxidase antibody, otherwise called antithyroid peroxidase antibodies (TPO), is one of the most common antibody tests currently used in clinical practice. It is performed to determine if hyperthyroidism is autoimmune, such as in Grave's disease or Hashimoto disease. Once a patient is known to be TPO antibody positive, repeat analysis is not indicated. In patients with suspected Hashimoto disease, antithyroglobulin antibody (Tg) testing may also be performed to confirm the diagnosis, as these patients typically have high levels of TPO and Tg (MedlinePlus, 2020c). The presence of thyroid- stimulating immunoglobulin (TSI) or TSH-receptor-thyrotropin receptor antibody (TRAb) strongly supports a diagnosis of Grave's disease (DeGroot, 2016).
Fasting Blood Glucose (FBG) and Glycated Hemoglobin (HbA1C)
FBG and HgbA1C are used to diagnose and monitor diabetes. The FBG is one of the most common routine tests. The test can be performed by drawing a blood sample or as a simple fingerstick with a glucometer machine. The normal FBG should range between 70–99 mg/dL. According to the ADA (n.d.), diabetes is diagnosed when the FBG is 126 mg/dL or higher, whereas an FBG of 100 mg/dL to 125 mg/dL is considered prediabetes. Prediabetes is the precursor to diabetes, in which the blood glucose levels are higher than normal but not high enough to meet the diagnostic classification of diabetes. The HbA1C is a measure of the average blood glucose levels over the past three months and does not require the patient to fast before testing. The normal HbA1C for non-diabetic adults should be less than 5.7%. Diabetes is diagnosed when the HbA1C is 6.5% or higher, whereas an HbA1C of 5.7% to 6.4% is considered prediabetes (ADA, n.d.).
Coagulation Profile
A coagulation profile measures the blood's clotting capacity and typically includes the prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), platelets, and fibrinogen. The normal values for a coagulation profile are listed in Table 9. PT is measured in seconds and refers to the amount of time it takes for the plasma portion of the blood to clot. The INR is a standardized number that is calculated from the PT result. Usually, the INR is reported and monitored in patients treated with anticoagulant therapy (blood-thinning medications). One of the most common reasons for performing PT/INR testing is to monitor warfarin (Coumadin) levels. Higher than normal PT/INR levels indicate a higher risk for bleeding events due to the body's impaired ability to clot blood. While on warfarin (Coumadin), it is essential that the PT/INR does not exceed therapeutic thresholds, otherwise the risk for bleeding heightens. The aPTT test is commonly performed alongside the PT/INR when evaluating patients with suspected bleeding or blood clotting disorders. While the PT test assesses how well all of the coagulation factors in the extrinsic and common pathways of the coagulation cascade are functioning collectively, the aPTT evaluates the clotting factors within the intrinsic and common pathways (American Association of Clinical Chemistry [AACC], 2019).
Fibrinogen is a protein synthesized within the liver and helps control bleeding by assisting with blood clot formation. An abnormal fibrinogen level may be due to various etiologies, such as fibrinolysis (the breakdown of fibrin), congenital or acquired fibrinogen deficiency, or may be the results of a severe infection or life-threatening condition in which the body uses up too much fibrinogen (disseminated intravascular coagulation [DIC]). An imbalance of these components poses a risk for acute bleeding, hemorrhage, and death (MedlinePlus, 2019).
References
American Association of Clinical Chemistry. (2019). Prothrombin time and international normalized ratio (PT/INR). https://labtestsonline.org/tests/prothrombin-time-and-international-normalized-ratio-ptinr
American Board of Internal Medicine. (2019). ABIM laboratory test reference ranges - January 2019. https://www.abim.org/~/media/ABIM%20Public/Files/pdf/exam/laboratory-reference-ranges.pdf
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