Figure 1. Microscopic view of a blood sample: erythrocytes (medium-sized, red , disc-shaped cells), leukocytes (large purple, nucleated bodies), and thrombocytes (small purple, irregular-shaped cells).
USING BLOOD TESTS AND URINALYSIS TO ASSESS SYSTEMIC CONDITIONS WITH OCULAR CONSEQUENCES
BY Alan G. Kabat, OD, FAAO
COPE Certificate 10644-PD, Expires December 1, 2006
Optometry is a continuously evolving profession. Although our roots are firmly entrenched in refractive care, over the years we have grown to incorporate more and more medical skills into our armamentarium. Today, we are not only responsible for the visual welfare of our patients, we also have the responsibility to detect and help manage systemic disorders that may be suggested by the ocular examination. Uveitis, retinopathy, optic neuropathy – these ocular manifestations often portend significant underlying health problems that can only be diagnosed by means of blood and other laboratory tests.
Unfortunately, the field of ancillary medical testing is vast and intimidating. Anyone who has ever reviewed their own blood work knows that there are countless tests, many with confusing acronyms and multiple subcategories. Yet, with a little education optometrists can begin to understand these laboratory tests and recognize the situations in which they might be useful.
In general, there are five types of laboratory tests that we as optometrists might need to order. These include:
1. Blood Analysis – "blood work," as we often call it, is the most common laboratory test performed by physicians. There are several elements that we can examine:
2. Urinalysis – evaluation of a patient’s urine is a quick and easy way to detect multiple disorders. Many common ailments including diabetes, renal disorders, and sexually transmitted diseases can be identified using simple urinalysis screening.
3. Lumbar Puncture – though more invasive, evaluation of the cerebrospinal fluid may yield helpful information about the brain and central nervous system. Meningitis, neurosyphilis, and pseudotumor cerebri are often diagnosed in this manner.
4. Microbiology Studies – by using various growth media and powerful viewing systems, laboratories can identify both foreign microbes and abnormal cells within tissues.
5. Radiology – radiologic testing helps to identify deep tissue structures that cannot otherwise be evaluated. Multiple modalities exist, each with their own benefits, drawbacks, and indications:
This course, the first of two on systemic diagnostic testing for the optometrist, focuses on understanding blood tests and urinalysis. The second course will discuss lumbar puncture, microbiological testing, and radiologic studies.
HEMATOLOGY
Hematology is the study of formed blood elements. As most of us know, there are primarily three cellular components of blood with which we are concerned (Figure 1).
The erythrocytes, or red blood cells (RBCs), are responsible for carrying and delivering oxygen to all vascularized bodily tissues, as well as removing waste (e.g., carbon dioxide) from those tissues.
Erythrocytes obtain their red color from a protein called hemoglobin, an iron-based molecule with a high affinity for oxygen.
Leukocytes, or white blood cells (WBCs), are another key element of the blood. Leukocytes are larger but less numerous than red blood cells. Their primary function is to provide immunity. There are multiple forms of leukocytes, although all serve in some capacity to defend the body against infecting organisms and foreign agents.
The final cellular components with which we are concerned in hematology are the thrombocytes, or platelet cells. These small, colorless, enucleated bodies play a vital role in the hemostatic process. When the endothelial lining of a blood vessel is traumatized, platelets migrate to the site of injury and help form a plug that reduces blood loss.
Figure 1. Microscopic view of a blood sample: erythrocytes (medium-sized, red , disc-shaped cells), leukocytes (large purple, nucleated bodies), and thrombocytes (small purple, irregular-shaped cells).
Hematologic testing essentially consists of ascertaining the relative number (or amount), size, and volume of the respective cellular elements in the blood. This seemingly simple information can yield critical information about disease states, such as anemia, leukemia, clotting disorders, infection, and autoimmune disease. The most important component of hematologic testing is the complete blood count, or CBC (Figure 2). The CBC encompasses a wide range of specific measurements, detailed below:
RBC – the RBC or "red cell count" may be expressed as the number of erythrocytes per cubic millimeter (mm3 or mL) of plasma. This measurement is made by examining a blood sample on a grid under a microscope and literally counting the number of cells over a given area. A typical, normal value for a healthy adult is anywhere between 4.1 million and 5.6 million cells/mL.
The RBC may be diminished or elevated in certain disease states. Obviously, if there are bleeding disorders or other loss of blood elements, the RBC will be reduced. This is referred to clinically as anemia. There are numerous etiologies in anemia; most commonly these include loss of blood (e.g. trauma, surgery), nutritional deficiencies, or bone marrow dysfunction. In cases where there is an excess of red blood cells, such as in certain malignant bone marrow disorders, the appropriate term is polycythemia. Both of these conditions can have ocular manifestations.
HgB – the HgB is a direct measurement of the hemoglobin in a sample of blood and is indicative of the overall volume of erythrocytes. To perform this test, the red blood cells in the sample are lysed and the liberated hemoglobin is measured spectrophotometrically.
Levels of hemoglobin are important in diagnosing certain anemias and polycythemias. Typically, the HgB value follows the RBC value, but it is possible for these to be inconsistent in certain hematologic disorders. Normal hemoglobin values are generally between 12 and 18 g/dL.
Hct – the hematocrit represents the proportion, by volume, of the blood that consists of erythrocytes. The word hematocrit translates literally as "to separate blood." Historically, this value was obtained by centrifuging a sample of blood, causing the red cells to accumulate at the bottom of the test tube where they were visually measured.
Today, the hematocrit is most commonly calculated by using the HgB level (Hct = HgB X 3).
Like the HgB, the hematocrit also typically mirrors the RBC, although values may be inconsistent in some conditions. Typically, a diminished Hct is indicative of anemia or sickling disorders, while elevated levels may be representative of polycythemia. The hematocrit is expressed as a percentage; normal values are 41-51% for males, 36-46% for females.
MCV – the mean corpuscular volume represents the average size of the red blood cells within a sample. Again, this is typically a calculated measurement today, rather than a direct observation [MCV = (Hct/RBC) X 1,000].
This test yields a great deal of information when taken in context with other hematologic findings. The MCV may be altered in various disorders. For example, it is elevated in folic acid deficiency, vitamin B12 deficiency, hemolytic anemia, cirrhosis of the liver, or chronic alcoholism. When the MCV is high, we say that the condition is "macrocytic", indicating larger-than-average erythrocytes.
The MCV may also be diminished in some patients – this is representative of a "microcytic" disorder, or a situation in which smaller-than-normal erythrocytes prevail. Conditions in which the MCV is decreased include chronic iron deficiency as well as some forms of thalassemia. Less commonly, a low MCV may be indicative of severe chronic infection, polycythemia, or lead poisoning. Occasionally, the MCV may be normal even though other findings (such as the RBC or HgB) are abnormal. This further helps to define "normocytic" anemia, such as is seen in renal failure or acute blood loss.
The MCV is a very small value, as one might imagine, and is measured in cubic micrometers or units called femtoliters (fL). Normal values are generally between 80-100 fL.
MCH – the mean corpuscular hemoglobin is an estimate of the amount of hemoglobin present in an average red blood cell. Like MCV, the MCH is calculated from other CBC values [MCH = (HgB X 10)/RBC].
Because the MCH tells us about the amount of hemoglobin pigment in the cells, it helps us to differentiate "hypochromic" anemias (i.e. those with low MCH values) from "normochromic" and "hyperchromic" disorders (i.e. those with high MCH values). Examples of hypochromic anemias include iron deficiency and thalassemia, while hyperchromic states are noted in folic acid or vitamin B12 deficiency. Hypochromic anemias are also often microcytic, whereas hyperchromic conditions are commonly macrocytic.
The MCH is measured in picograms, which is one trillionth (10-12) of a gram. Normal values for this test are roughly between 25 and 35, depending on the laboratory.
MCHC – the mean corpuscular hemoglobin concentration is very similar to the MCH, however the MCHC describes the proportion of hemoglobin in an average erythrocyte, rather than the absolute value. It is calculated by the following equation: [MCHC = (HgB X 100) / Hct]. The MCHC is expressed as a percentage, with normal values between 31 and 36%.
RDW – RDW stands for red cell distribution width. It is a measure of variability or non-uniformity in erythrocyte size across a given sample. The RDW is normally low (normal range 12-15%), but higher values may be indicative of significant heterogeneity in RBC size, a condition sometimes referred to as anisocytosis.
An elevated RDW is the first hematological manifestation of iron deficiency anemia, and hence a very sensitive screening test for that particular disorder.
Figure 2. Results of a typical CBC with differential.
Platelet Count – the platelet count represents the number of thrombocytes, or platelets, per cubic millimeter of blood plasma. There are normally between 150,000 and 450,000 platelets in each microliter of blood.
Low platelet counts denote a condition known as thrombocytopenia, which is typically associated with bleeding disorders.
High platelet counts define thrombocytosis, usually indicative of bone marrow disorders but sometimes secondary to infections, cancer, or splenectomy.
MPV – the mean platelet volume (MPV) is similar to the MCV; it represents the average size of the platelets within a blood sample. This is a relatively new test and not included in by all laboratories. Measured in cubic micrometers or femtoliters, normal values are generally between 7 and 11 fL.
A reduced MPV is indicative of small platelets, and may be consistent with disorders such as aplastic anemia. An elevated MPV is encountered when platelets are larger than average, such as in Idiopathic Thrombocytopenic Purpura.
Recently, researchers have found that altered MPV levels may be consistent with increased risk of certain systemic diseases. Specifically, a low MPV has been shown to be an important marker for inflammatory bowel disease such as ulcerative colitis or Crohn’s disease.1 In contradistinction, scientists have found markedly elevated MPV levels in patients at risk for stroke and heart attack.2,3
WBC – the WBC or "white cell count" is expressed as the number of leukocytes per cubic millimeter (mm3 or mL) of blood plasma. Most healthy adults have between 4,000 and 11,000 cells/mL. By convention, the WBC is expressed in units of 1,000. Therefore, doctors may refer to this value as (for example) "5.5," which is normal, or "16.2," which is elevated.
When the white cell count is elevated, we describe this clinically as leukocytosis. Leukocytosis may occur in a variety of disorders, however we generally think of infectious or autoimmune disease in patients with a high WBC. Leukemia, a malignant proliferation of white blood cells, also presents with a grossly elevated white count.
A diminished WBC is expressed clinically as leukopenia. Leukopenia generally results from immune deficiencies (e.g., AIDS) or from bone marrow disorders in which insufficient white cell production occurs. Aplastic anemia is one such condition (red cells and platelets are also reduced in this disorder).
Differential – most laboratories typically also perform a "Diff," or WBC differential count, as part of the CBC (some labs may however require that the ordering physician specify this on the Rx, e.g., "CBC w/ Diff"). This important test helps to identify the various types of white cells present in the blood. Two different measurements are reported in the Diff – a percentage (%) and an absolute value (cells/mm3).
In general, there are five distinct forms of white blood cells, each of which perform a different function and is implicated in different conditions. These include:
Several other studies also bear mention within a discussion of hematology.
SED Rate - The erythrocyte sedimentation rate, aka "sed rate" or ESR, is a simple test dating back to the ancient Greeks. A specific amount of diluted, unclotted blood is placed in a narrow tube and left undisturbed for exactly one hour. Naturally, over time the red cells accumulate at the bottom, while the plasma rises to the top (Figure 3).
The height (in millimeters) of the red cell column within this tube after one hour represents the ESR. Laboratories may use either the Westergren or the Wintrobe method, although the Westergren is more widely accepted. The premise of this test rests on the fact that certain inflammatory disorders yield abnormal proteins, which bind to red cells and make them "sticky." This causes the erythrocytes to clump together and settle out of the plasma more rapidly.
Hence, an elevated ESR serves as an indirect marker of inflammatory disease. This test is very important in the diagnosis of certain systemic conditions, particularly giant cell arteritis, systemic lupus, and rheumatoid arthritis.
Practitioners must remember however that, although the ESR boasts high sensitivity (i.e. it is very good for diagnosing inflammatory disease) it yields low specificity (i.e. it does not help identify the specific disease).
Although each laboratory report generally lists a normal range for the ESR, there is variability with regard to age and sex. In general, normal ESR values increase with age, and women tend to have higher rates than men. A good rule of thumb for calculating the "normal" ESR for a patient is as follows:
Normal maximum SED rate for a Male = Age/2
Normal maximum SED rate for a Female = (Age+10)/2
Figure 3. Sedimentation of a blood sample. Erythrocytes settle to the bottom of the tube at a rate which correlates with the level of systemic inflammation.
C-reactive protein. The C-reactive protein (hs-CRP or CRP) is similar to the sed rate in that it serves as a marker for systemic inflammation. This protein is described as an acute phase reactant, released by the body in response to injury, infection, tissue necrosis or malignancy. The normal range is 0-1 mg/dL. A level between 1 and 10 mg/dL is considered a moderate elevation, and above 10 mg/dL is a marked elevation.
Like the ESR, the CRP is a highly sensitive but non-specific test; i.e., it is very helpful in establishing an inflammatory etiology, but not very helpful in identifying the specific disease (e.g. rheumatic fever, rheumatoid arthritis, hepatitis, etc.).
However, when the CRP is used in conjunction with the ESR and both tests are positive, there is a 98% specificity for giant cell arteritis.4 In addition to inflammatory disease, prospective epidemiological studies have demonstrated that higher CRP levels may also be associated with increased risk of cardiovascular disease.5, 6
Coagulation. Coagulation studies are also an important consideration in hematology. These tests evaluate those properties of the blood involved in clotting, which can be altered in certain disease states (e.g., hemophilia) or drug regimens (e.g., coumadin, heparin, or aspirin therapy).
The two most common tests utilized in this area of hematology are the prothrombin time ("protime" or PT) and the partial thromboplastin time (PTT or aPTT). Both tests are important and are typically ordered together. Usually a normal PT is 11-15 seconds; it is considered prolonged and cause for concern if it is greater than 24 seconds. There is some variation between the PTT and the aPTT, which stands for activated partial thromboplastin time. Results for these tests vary based on the method and activators used.
Normal aPTT results are usually between 25 to 40 seconds; PTT results are between 60 to 70 seconds. APTT results for a patient on heparin should be 1.5 to 2.5 times normal values. An aPTT longer than 100 seconds indicates spontaneous bleeding.
OCULAR INDICATIONS FOR HEMATOLOGIC TESTING
When is hematologic testing indicated within the realm of eye care? There are numerous instances where the aforementioned tests would be beneficial. Overall, we tend to employ hematology studies when there are hemorrhagic or ischemic conditions present, when there are severe, atypical or idiopathic inflammatory signs in one eye or both. Table 1 illustrates a sampling of specific ocular conditions in which CBC, ESR, CRP, or coagulation studies might be applicable.
Table 1. Ocular Indications for Hematologic Testing
|
Order CBC with Diff in cases of:
Order ESR and/or CRP in cases of:
Order PT, PTT in cases of:
|
BLOOD CHEMISTRY
Blood chemistry serves to evaluate non-cellular, essential elements of the blood. Serum electrolytes, liver enzymes, nitrogen elements, protein, glucose, lipids, thyroid hormones, and other components can be measured through this important form of testing.
Electrolytes - Electrolytes are chemical elements – ions, if you will – that carry a charge and can act osmotically in the blood and tissues. Electrolytes in proper concentration and balance are critical to normal physiologic function. When levels of these elements are disturbed or altered even slightly, impaired muscular or neurologic function can result, as well as severe stress on the heart. Extreme disruptions in normal electrolyte levels can result in metabolic alkalosis or acidosis, and death.
Certain conditions or disorders are known to result in altered electrolyte levels. These may include excessive salt or insufficient water intake (i.e., dehydration); overuse of diuretics (e.g., acetazolamide); prolonged diarrhea or vomiting; malnutrition; chronic alcoholism; and heart or kidney failure. Tumors of the adrenal gland (which is responsible for potassium and chloride secretion) can also render electrolyte levels altered or unbalanced.
The principal serum electrolytes include sodium (Na), Potassium (K), Chloride (Cl), Carbon Dioxide (CO2), Calcium (Ca), Phosphorus (P). Normal values for these elements are shown in Table 2.
Table 2. Normal Electrolyte Ranges for Adults
|
Sodium
|
135 to 148 mmol/L
|
|
Potassium
|
3.5 to 5.5 mmol/L
|
|
Chloride
|
96 to 109 mmol/L
|
|
Carbon Dioxide
|
20 to 32 mmol/L
|
|
Calcium
|
8.5 to 10.6 mg/dL
|
|
Phosphorus
|
2.5 to 4.5 mg/dL
|
Liver Enzymes / Liver Function Tests - The liver is the primary blood filter in the human body. Damage to this structure can occur in a number of systemic disorders, including alcohol or drug abuse, immunologic disorders, viral infection and cancer. When significant hepatic or biliary tract disease is present, liver enzymes in the blood can be markedly abnormal. Evaluation of these specific enzymes and a few other proteins are sometimes referred to as "liver function tests," or "LFTs."
There are generally five LFTs that are of note clinically. Many health care professionals are familiar with the AST (Aspartate Aminotransferase, sometimes also referred to as the Serum Glutamic-Oxoacetic Transaminate or SGOT) and the ALT (Alanine Aminotransferase, sometimes also referred to as the Serum Glutamic-Pyruvic Transaminase or SGPT).
AST and ALT are enzymes that are produced in the liver and leak into the general circulation when liver cells are injured. Hence, serum AST levels are elevated in liver damage, but also may be increased with heart, kidney, or pancreatic disease. The ALT is far more specific to the liver than to other organs, and elevated ALT levels are very indicative of hepatic inflammation. The AST and ALT are also used to monitor the course of chronic liver disease (e.g., hepatitis) and the response to treatment.
Alkaline Phosphatase is an enzyme that is associated with the biliary tract, as well as other organ systems (e.g., bone, intestine, and placenta). Serum alkaline phosphatase levels may be elevated when biliary tract damage, inflammation, or malignancy are present.
Low levels are sometimes found in hypoadrenia (atrophy or dysfunction of the adrenal glands), malnutrition, protein deficiency, and some vitamin deficiencies. Because alkaline phosphatase is not specific to the liver, it is best to consider this information in conjunction with several other liver function tests, such as the total bilirubin, serum albumin, GGT (gamma-glutamyl transpeptidase) and LDH (lactic dehydrogenase).
Bilirubin is a byproduct of hemoglobin breakdown in the liver. Therefore, bilirubin levels can be a good indicator of liver function. This protein is often elevated in liver disease as well as in mononucleosis, hemolytic anemia, deficient UV exposure, and drug toxicity. Decreased bilirubin may be indicative of an inefficient liver, excessive fat digestion, or a diet low in nitrogen bearing foods.
There are additional indicators of liver function, which may be ordered in cases of suspected hepatic or biliary disease, including the GGT, LDH and prothrombin time. However, these tests are not typically part of a normal comprehensive metabolic panel (CMP).
Normal values for the liver function tests are shown in Table 3.
Table 3. Normal Results for Liver Function Tests
|
AST (SGOT)
|
0 to 40 IU/L
|
|
ALT (SGPT)
|
0 to 40 IU/L
|
|
Alkaline Phosphatase
|
25 to 150 IU/L
|
|
Total Bilirubin
|
0.1 to 1.2 mg/dL
|
|
Serum Albumin
|
3.5 to 5.5 g/dL
|
Nitrogen Elements / Renal Function Tests – Like the liver, the kidneys are responsible for filtering blood and removing waste products. However, excretion is not their only job; they serve also in a regulatory and endocrinologic capacity as well. The kidneys, through their various processes and secretions, are responsible for helping to maintain normal blood pressure, stimulating red blood cell production, and inducing calcium absorption in the gut. Several blood chemistry tests are pertinent for renal function.
Blood Urea Nitrogen, or BUN, is simply the nitrogen component of urea and represents the end product of protein metabolism. It is produced in the liver and normally excreted by the kidneys, so the BUN may be elevated if renal function is impaired. Increased BUN levels may also be encountered with excessive protein intake (e.g., those patients who are strict proponents of the Atkin’s diet), low fluid intake, the use of certain drugs, intestinal bleeding, or heart failure. A reduced BUN is often due to a poor or low protein diet, intestinal malabsorption, liver damage, or the use of anabolic steroids.
Creatinine is a waste product of muscle metabolism. It is produced at a steady rate in direct proportion to the body’s overall muscle mass. The greater the amount of muscle tissue, the more creatinine is produced. Normal clearance of this substance occurs via the kidneys, so creatinine levels in the blood are an excellent indicator of whether or not the kidneys are functioning properly. Creatinine may be elevated in acute or chronic renal disease, degenerative muscle disorders, and drug toxicity. Low creatinine levels may indicate protein starvation or liver disease.
Normal values for the renal function tests are shown in Table 4.
Table 4. Normal Ranges for Renal Function Tests
|
BUN
|
5 to 26 mg/dL
|
|
Serum Creatinine
|
0.5 to 1.5 mg/dL
|
Proteins - Proteins are extremely abundant in serum, comprising enzymes, hormones, and antibodies. These soluble particles also exert osmotic pressure and help maintaining acid-base balance. The major serum proteins measured are albumin and globulin
Albumin is the major protein present within the blood, and is produced within the liver. Though the liver makes many other proteins as well, albumin is particularly easy to measure, making it a reliable and inexpensive laboratory test. Chronic liver disease such as cirrhosis causes diminished production of albumin and, subsequently, decreased serum albumin levels. Malnutrition, severe diarrhea, fever, infection, and inadequate iron intake can also cause low albumin (hypoalbuminemia) without associated liver disease. High levels are very uncommon, and are usually indicative of dehydration.
Globulins are somewhat larger than albumin and plays an important role in immunity (e.g., IgA, IgE, IgG, etc.). Chronic infection, liver disease, rheumatoid arthritis, and myeloma can lead to elevated globulin levels. Conversely, lower levels are often noted in immunocompromised patients, and those suffering from malnutrition.
Normal values for the serum proteins are shown in Table 5.
Table 5. Normal Ranges for Serum Proteins
|
Total Serum Protein
|
6 to 8.5 g/dL
|
|
Serum Albumin
|
3.5 to 5.5 g/dL
|
|
Total Globulin
|
1.5 to 4.5 g/dL
|
Glucose - Glucose is the body’s primary source of energy. All of the carbohydrates and much of the fat that we consume is ultimately broken down into glucose. The pancreas is responsible for directing the regulation of this critical compound via a delicate balance of two hormones, insulin and glucagon. Insulin helps to move glucose into cells where it can be used as fuel; it also directs excess glucose from the blood and into other organs where it can be stored for later utilization (either as glycogen in the liver or fat in the adipose tissue). Glucagon is secreted when blood glucose levels are low, helping to reconvert those stored fuel reserves back into glucose.
Diabetes is a primary disorder of glucose metabolism, essentially caused by underproduction of or cellular resistance to insulin. The major clinical indication of diabetes is elevation of serum glucose levels. The potentially sight-threatening ocular manifestations of diabetes are numerous and well known to most eye care professionals, so the significance of such a condition to optometry is easily understood.
Several tests can be utilized to detect or monitor the treatment of diabetes. Most clinicians prefer to utilize a fasting plasma glucose test (FPG, also known by the more antiquated term fasting blood sugar, or FBS). In order to perform the FPG, patients must refrain from eating or drinking for a minimum of eight hours prior to drawing the blood sample. Serum glucose may also be measured without fasting (random plasma glucose, or RPG), however these results are generally not as accurate because they may be influenced by the size, composition, and timing of the patient’s last meal. Different normal values are utilized for the fasting and random plasma glucose tests.
An older test that is sometimes seen in the literature, although rarely utilized clinically today, is the oral glucose tolerance test (OGTT). In this procedure, fasting patients must ingest a syrupy beverage containing the equivalent of 75 to 100 grams of glucose, after which their serum glucose levels are checked hourly for three hours. This allows physicians to monitor glucose metabolism and utilization over time. Unfortunately, it is somewhat unpleasant for the patient and time-consuming for both the patient and the physician/technician. Hence, it is generally reserved as a confirmatory investigation for pregnant women suspected of having gestational diabetes.
A final test utilized in diabetes is the glycosylated hemoglobin, also known as the HbA1c or simply A1c. This test is based on the principle that excess glucose in the blood binds to the hemoglobin aspect of red blood cells, a process known as glycosylation. The greater the level of serum glucose, the greater the percentage of glycosylated blood cells. Since the life span of a normal red blood cell is approximately 120 days, this test gives us a tool to evaluate not only the level of blood sugar but also the degree of glucose control over a three-month period. The HbA1c is generally not utilized as a diagnostic test but rather as a mechanism for monitoring patient compliance and the efficacy of the therapeutic regimen.
The normal and abnormal values for glucose testing are shown in Table 6. It is important to note that abnormally elevated results on two or more separate occasions is diagnostic of diabetes. More recently, a condition known as "pre-diabetes" has also been recognized as that range between 110 and 126 mg/dL. This condition has also been called "impaired glucose tolerance" and warrants consultation and management with a primary care physician.
Table 6. Glucose Test Values (Values must be obtained on two separate occasions to be diagnostic of pre-diabetes or diabetes.)
|
Fasting Plasma Glucose (FPG)
|
Normal Range: 65 to109 mg/dL
Pre-Diabetes: 110 to 126 mg/dL Diabetes: >126 mg/dL |
|
Random Plasma Glucose (RPG)
|
Normal Range: 65 to 200 mg/dL
Diabetes: >200 mg/dL |
|
Oral Glucose Tolerance Test (OGTT) With 100 gm Glucose Load (Normal Values)
|
Fasting: <105 mg/dL
1 hour: <190 mg/dL 2 hours: <165 mg/dL 3 hours: <145 mg/dL |
|
Glycosylated Hemoglobin (HbA1c). (Percentages assigned to each term can vary depending on testing procedures used.)
|
Excellent control: <7%
Good control: 7 to 9% Fair control: 9 to 11% Poor control: >11% |
Thyroid hormones / Thyroid function tests - Thyroid disease is an extremely common endocrine disorder, particularly in the United States. Both the hormones secreted by the thyroid and those that control the thyroid (secreted by the hypothalamus and pituitary glands) are detectable in the blood. The levels of these various hormones help to define thyroid dysfunction, both hyperthyroidism and hypothyroidism (Figure 4).
Figure 4. The thyroid hormone regulation cycle involves the hypothalamus, pituitary, and thyroid glands.
Triiodothyronine (T3) and thyroxine (T4) are hormones secreted by the thyroid gland. As the name implies, triiodothyronine contains three atoms of iodine per molecular chain, while thyroxine contains four atoms. Both of these hormones can be measured directly in the blood serum and are used to evaluate thyroid function. However, triiodothyronine is very short-lived and difficult to measure, hence the T3 test is more costly. For this reason, many clinicians and laboratories no longer perform the T3 as part of a routine thyroid screening, but rely upon the T4 and other tests to diagnose thyroid dysfunction.
Increased T3 and T4 levels are found in hyperthyroidism, acute thyroiditis, and hepatitis. Diminished T3 and T4 levels can be found in hypothyroidism as well as chronic thyroiditis, cretinism, cirrhosis, and malnutrition.
Thyroid-Stimulating Hormone (TSH) is produced by the anterior pituitary gland and is responsible for the release and circulation of thyroid hormones. TSH levels respond to high circulating T3 and T4 by decreasing. Conversely, when the T3 and T4 are low, TSH secretion increases.
T3-Uptake (T3U) is an indirect measurement of unsaturated thyroxine binding globulin in the blood. The T3U tends to follow T3 and T4 levels; it is elevated in hyperthyroidism, as well as some cases of hepatic disease, metastasis, and pulmonary insufficiency. Decreased T3U levels are noted in hypothyroidism, as well as in normal pregnancy.
Free T4 Index (FTI or T7) is a calculated value used to correct the estimated total thyroxine for the amount of thyroxine binding globulin present. It uses the T4 value and the T-uptake ratio. Essentially, it is the T4 value multiplied by the T3U value, i.e., T4 X T3U = T7. Hence, the T7 will also be elevated in hyperthyroidism, depressed in hypothyroidism.
The thyroid function tests, their normal ranges and implications regarding disease state are summarized in Table 7.
Table 7. Serum Thyroid Hormone and Other Thyroid Function Tests
|
Test
|
Normal Range
|
Hyperthyroid
|
Hypothyroid
|
| Triiodothyronine (T3) | 70 to 195 ng/dL | High | Normal or Low |
| Thyroxine (T4) | 5 to 12 ug/dL | Normal or High | Low |
| Thyroid Stimulating Hormone (TSH) | 0.3 to 5.0 mIU/L | Low | High |
| T3 Uptake (T3U) | 24 to 34% | High | Low |
| Free Thyroxine Index (FTI or T7) | 4 to 11 | High | Low |
Lipid profile - Lipids are fatty substances that are essential to normal human metabolism and homeostasis. While the American public sometimes views "fat" as a bad thing, it is only when lipid levels are significantly elevated that systemic damage can occur. Lipids consist primarily of cholesterol and triglycerides.
Cholesterol is a structural component of cell membranes and is important in the synthesis of certain hormones, glucocorticoids, and bile. It is normally produced in the liver, though additional cholesterol is absorbed from the diet, particularly from foods that are high in saturated fat content. Total serum cholesterol consists of essentially three components: high-density lipoproteins, low-density lipoproteins and very-low-density lipoproteins.
High-density lipoproteins, or HDLs, are desirable; they function to remove circulating cholesterol from peripheral tissues and transport it to the liver for metabolism. HDLs also do not bind to arterial walls, and hence are often referred to as "good cholesterol." Low-density lipoproteins, or LDLs, are known as the "bad cholesterol."
LDLs encourage cholesterol deposition within arteries, leading to atherosclerosis and hypertension. Very-low-density lipoproteins, or VLDLs, are the most dangerous form of cholesterol. Elevated VLDL levels are invariably an indicator of systemic disease, particularly arterial plaque formation.
LDL/HDL ratio. In healthy individuals, HDL values are relatively high while LDL and VLDL values are generally low. A ratio (LDL/HDL) is sometimes used to represent the relative health risk with regard to cholesterol. For example, it is estimated that an adult male with a LDL/HDL ratio of 1.0 possesses the average risk of developing heart disease, whereas an individual with a ratio of 8.0 has three times the average risk.7
Patients with high ratios are encouraged to improve their levels through a combination of aerobic exercise (which helps to raise HDL levels) and adopting a diet low in saturated fats (which helps to decrease LDL levels).
Triglycerides are soluble fats found within the blood plasma and adipose tissue. Serum triglyceride levels are often increased due to excessive consumption of fatty foods. However, a diet high in sugar and carbohydrates can also lead to elevated triglycerides, as excess glucose is ultimately converted to fat in the body.
Increased triglycerides levels also predispose the patient to atherosclerosis and hypertension. In addition to diet, high triglycerides may also occur secondary to hypothyroidism, liver disease, pancreatitis, myocardial infarction, and renal disease. Normal values for the serum lipids are shown in Table 8.
Table 8. Normal Values for Serum Lipid Profile
|
Total cholesterol
|
100 to 199 mg/dL
|
|
Triglycerides
|
0 to 149 mg/dL
|
|
HDL
|
40 to 59 mg/dL
|
|
LDL
|
0 to 99 mg/dL
|
|
VLDL
|
5 to 40 mg/dL
|
|
LDL/HDL ratio
|
Male: 0 to 3.6
Female: 0 to 3.2 |
OCULAR INDICATIONS FOR BLOOD CHEMISTRY TESTING
When is blood chemistry indicated within the realm of eye care? Again, there are numerous instances where these tests would be applicable. Many of the laboratory studies discussed above are part of something called a comprehensive metabolic panel (CMP), possibly the most common blood test ordered by physicians after the CBC (Figure 5). The CMP consists of fourteen specific studies including serum electrolytes, liver enzymes, renal function tests, specific proteins, and (fasting) plasma glucose. It is a quick and inexpensive screening tool to check for conditions such as diabetes, liver disease, and kidney disease, and can also be used to monitor complications of these diseases.
In general, there are few explicit indications for the primary care optometrist to check electrolytes. Patients with vision loss or retinal hemorrhages of unknown etiology, or a known history of chronic alcoholism might warrant such tests as part of the CMP. More than likely, however, the results of these tests would be of greater interest to the primary care physician or internist.
A few specific ocular conditions or findings can be indicative of underlying hepatic or renal disease. In these cases, liver or kidney function tests might be of particular value, as well as serum proteins (which help to confirm liver and/or kidney damage). These conditions are summarized in Table 9.
Table 9. Ocular Indications for Liver/Renal Function Tests and Serum Protein Assessment (CMP)
| Liver | Kayser-Fleischer ring (indicative of Wilson's disease)
Toxic/nutritional amblyopia (with a history of alcoholism) Choroidal melanoma (most common site of metastasis is the liver) |
| Kidney | "Dot and fleck" retinopathy (Alport syndrome)
Vortex keratopathy/corneal verticillata (Fabry's disease) Hypertensive retinopathy |
If, as optometrists, we do not see many patients with hepatic or renal disease, we see more than our share of individuals with diabetes and thyroid disease. Oft times, patients with vision problems are completely unaware that the difficulty stems from an as yet undiagnosed endocrine disorder. There are numerous, sometimes subtle, ocular indications of possible complications from diabetes and/or thyroid dysfunction. These findings are summarized in Tables 10 and 11.
Table 10. Ocular Indications for Blood Glucose Testing
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Table 11. Ocular Indications for Thyroid Studies
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Finally, with the prevalence of diabetes, hypertension, and hypercholesterolemia in American society today, abnormal lipid profiles are exceedingly commonplace, even in seemingly healthy individuals. Like diabetes, elevated serum lipids and cholesterol can be a "silent killer," leading to cerebrovascular and cardiovascular complications such as stroke and heart attack. Specific ocular findings warranting a lipid profile are detailed in Table 12.
Table 12. Ocular Indications for Lipid Profile
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SEROLOGY
Serology is that component of laboratory testing that seeks to identify antigens and/or antibodies within bodily fluids. Most often, when we order these tests we are specifically looking at blood serum, but many of the same analyses can be applied to cerebrospinal fluid following a lumbar puncture (this will be discussed in another course). Serology can help to identify markers for a wide variety of conditions, most of which are either infectious (e.g., syphilis, Lyme disease, HIV, and tuberculosis) or inflammatory/autoimmune in nature (e.g., sarcoidosis, lupus, rheumatoid arthritis, and ankylosing spondylitis).
Each serologic procedure consists of at several steps. The first step involves combining a known source of antigen with a source of antibody, and allowing these to bind. Once the antigen-antibody reaction has taken place, the patient’s sample is added to the mixture.
Then another agent, which specifically detects the bound complex is applied. This agent is "tagged" in some way so as to be detectable to the laboratory technician. For example, the agent may be bound to an enzyme, which specifically converts a colorless substrate to a colored product (hence the term "enzyme-linked immunosorbent assay"). If the reaction with the sample is positive, the enzyme is activated and the substrate changes color.
Another method utilizes an agent that has been labeled with a radioisotope; if the reaction is positive, the radioactivity is detectable in the final sample by means of a gamma counter (this test is known as a "radioimmunoassay").
The results of serologic testing are generally reported as simply "positive" or "negative." However, a more precise method, which is sometimes used to quantify the reaction, involves titration. Titration helps to determine the relative amount of antibody in the serum by utilizing serial dilutions of the original sample. A serologic test is applied to each dilution, and the results are reported as a "titer," which represents the lowest concentration of the serum that still yields a positive result.
ELISA test. There are a number of strategies and specific tests involved in serology. Possibly the most well known is the Enzyme-Linked Immunosorbent Assay, or ELISA test. This test is utilized for a variety of infectious conditions including HIV, Lyme disease, toxoplasmosis, toxocariasis, viral hepatitis, Cat scratch disease, and other less common disorders.
Syphilis is one example of a disorder that relies on serology for confirmatory diagnosis. There are a number of laboratory tests that help to detect syphilis. The oldest of these is the Venereal Disease Research Laboratory, or VDRL. This test evaluates serum antibodies that appear and rise following syphilitic infection, but are not absolutely specific to Treponema pallidum.
Another more recent test that is similar, though more sensitive than the VDRL is the Rapid Plasma Reagin, or RPR. Overall, the sensitivity of both these non-treponemal tests varies with the levels of antibodies present during the stages of the disease.8 The VDRL and RPR serve as excellent screening tests for suspected cases of syphilis, because they are comparatively easy, rapid, and inexpensive.
A positive response on either of these tests correlates with disease activity, i.e., active syphilis. However, the clinician should realize that a number of other disorders can yield a false-positive on these tests, including lupus, malaria, mononucleosis, hepatitis, leprosy, atypical pneumonia, tuberculosis, typhus, and pregnancy.
Tests that are considered to be "trep-specific" (i.e., specifically detect antibodies to Treponema pallidum) include the Fluorescent Treponemal Antibody Absorption (FTA-ABS) and the Microhemagglutination Assay for Treponema pallidum (MHA-TP). These tests detect antibodies from a syphilitic infection. However, they do not indicate whether the infection is currently active, and the results of these tests remain positive despite treatment. Hence, trep-specific tests do not correlate with disease activity; they merely tell us if the patient has had a syphilitic infection at some point in their lives. Fortunately, there is a lower incidence of false-positive results with trep-specific tests, yet false-positives can occur in cases of Lyme disease, genital herpes, mononucleosis, malaria, and leprosy.
In most cases where syphilis is suspected, physicians typically order a non-treponemal specific test such as the RPR first – this is because it is inexpensive and because we are usually dealing with active disease states. If the RPR is positive, a trep-specific test such as the FTA-ABS is then ordered. If both are positive, it is confirmatory for syphilitic infection. Of course, if we need to confirm an old syphilitic infection because of unusual examination findings, then trep-specific testing should be adequate. Some clinicians advise consistently ordering both tests simultaneously, although the usefulness of such an approach can be debated.
Rheumatologic and autoimmune tests A number of rheumatologic blood tests also fall within the broad category of serology. Some of these tests can be extremely useful in the practice of medical eye care. Rather than looking for antibodies to foreign organisms, rheumatologic tests identify "autoantibodies;" that is, antibodies that the body develops to itself. These autoimmunologic disorders are unfortunately all too common.
Three specific tests bear mention within this discussion. The first is the Antinuclear Antibody test, or ANA. Antinuclear antibodies are autoantibodies (i.e. antibodies that are directed against one's own bodily tissues) found in patients with autoimmune disease. Autoimmunity typically involves inflammation in various tissues of the body, including the eye. ANAs may be detected in patients with a variety of autoimmune diseases, as well as some conditions that are not considered classic autoimmune in nature, such as chronic infections and cancer.
The ANA test utilizes fluorescence techniques, similar to those used in the FTA-ABS, to detect the antibodies in the cells. Positive tests are titred to determine the significance of the reactivity, since not all ANAs are associated with illness. More than 95% of patients with lupus have a positive ANA.
Scleroderma yields a positive result 90% of the time. Other disorders with a positive ANA include Sjögren's disease (70%) and rheumatoid arthritis (40%).9 Approximately 5% of the normal population can display a positive ANA, however the titers in these patients are low. In general, only titers of greater than 1:40 are considered significant.
The second rheumatologic test of importance is the Rheumatoid Factor, or RF. Like the ANA, rheumatoid factor is actually an autoantibody that binds to immunoglobulin G (IgG), forming a large immune complex. This immune complex is implicated in numerous inflammatory processes. Despite the name, the RF is not 100% specific for rheumatoid arthritis (RA), although a positive result is typically present in about 80% of patients who have RA.
Other clinical conditions that may yield a positive result on the RF include Sjögren's syndrome, systemic lupus erythematosus, myositis, tuberculosis, syphilis, leukemia, and hepatitis C. Hence, a major shortcoming of this test is a high percentage of false positive results. It has even been argued by some that the RF, which is rather expensive, is not sufficiently predictive enough to be worthwhile in general clinical practice.10
However, a negative result on this test can be most helpful in ruling out disease, and this is the capacity in which most clinicians utilize the RF. Titers can also improve the accuracy of this test; in general, those greater than 1:80 are suggestive of rheumatoid arthritis and the other aforementioned disorders.
Finally, the Human Leukocyte Antigen (HLA) test can be of value in helping to diagnose autoimmune disease. HLAs are proteins that are present in high concentrations on the surface of white blood cells, and serve as the major histocompatibility antigens for tissue recognition. Numerous HLA antigens are known to exist (usually designated as HLA-A, -B, -C, or -D); however some are of special interest because of their proclivity toward particular autoimmune disorders.
Perhaps the most widely recognized is HLA-B27, which is found in as many as 95% of individuals with ankylosing spondylitis and 70% of those with Reiter's syndrome. About 50% of patients with inflammatory bowel disease also test positive for the HLA-B27. Another well-known antigen is HLA-DR5, which is associated with Hashimoto's thyroiditis. Like the RF, HLA typing can be extremely expensive. It should be considered only for confirmation when the clinical picture strongly indicates a particular diagnosis.
OCULAR INDICATIONS FOR SEROLOGIC TESTING
There are numerous indications within the realm of eye care for many of the serologic tests discussed above. Typically, these tests are ordered in cases of idiopathic ocular inflammation, particularly if the presentation is bilateral, chronic, recurrent, or atypically severe. Uveitis is the most common ocular disorder that may warrant serologic testing, but other conditions such as scleritis, neuroretinitis, focal retinitis or choroiditis, or even keratoconjunctivitis sicca. A list of those conditions that may warrant specific serologic testing is presented in Table 13.
Table 13. Ocular Indications for Serologic Testing
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Indications for syphilis studies (e.g., RPR, FTA-ABS):
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Indications for ELISA tests:
|
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Indications for ANA, RF, and/or HLA:
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ORDERING BLOOD TESTS
Those optometric physicians who do not order laboratory tests on a regular basis are sometimes reluctant to begin because they are unsure of precisely how to request such tests from a laboratory. In fact, ordering blood tests is quite easy. Most laboratories will honor a hand-written prescription for the test(s) in question (Figure 6).
Practices that order laboratory tests more routinely often utilize their own preprinted sheets, listing the desired tests with "checkboxes." Some laboratories may provide such sheets for clients who utilize their services. It is often a good idea to communicate with the local laboratory to determine their preferred method of ordering; this helps to alleviate any possible confusion about the desired tests.
Figure 6. Handwritten requests for laboratory testing on a standard prescription pad are honored by most labs, but the practitioner should contact the laboratory beforehand to be certain.
Some optometrists are certified to draw blood (e.g., Oregon licensed optometrists who have completed Advanced Ocular Therapeutics Certification) or have staff members who are certified. Others have made arrangements with local physicians to draw blood or refer patients to private testing laboratories that have phlebotomists on staff. Optometrists with hospital privileges can refer patients to the hospital lab for blood work.
A bit of checking in the local community usually reveals a relatively simple method for getting blood drawn and analyzed.
URINALYSIS
The medical evaluation of urine is truly of historical significance, dating back to Ancient Greece. The urine provides a substrate for testing a wide array of medical disorders. Advantages to urinalysis over blood testing are numerous – specimens may be obtained easily and painlessly, and without the use of expensive equipment or the risk of infection. On the downside, urinalysis does not provide the extensive range or offer the precision accuracy of blood testing, but it nonetheless offers a quick and easy method of screening patients for systemic disease.
There are several components to urine specimen evaluation when performed by a laboratory. These are listed below, along with the normal and abnormal results.
General appearance – Normal urine is generally a clear fluid. Its color, clarity, and odor often yield information about the general state of health of the individual.
Contents – Normal urine may contain some crystals, tissue cells, or casts, but it should not contain blood, protein, sugars, ketones, bacteria, or parasitic organisms.
Acidity – The pH of urine generally ranges from an acidic 4.5 to a slightly alkaline 8.0. A more acidic pH may be the result of fever, phenylketonuria, alkaptonuria, or metabolic acidosis. Alkaline urine may occur in Fanconi's syndrome, urinary tract infections, or metabolic or respiratory alkalosis.
Specific gravity – The specific gravity refers to the overall concentration of particles within the urine. Greater concentrations are reflected in higher specific gravity values, while more dilute urine shows a lower specific gravity. The normal range is between 1.005 and 1.035, but this value can be impacted by a variety of disorders.
High specific gravity may be encountered in cases of diabetes mellitus, dehydration, renal disease, congestive heart failure, liver failure or shock. Low specific gravity is associated with diabetes insipidus, acute tubular necrosis, excessive hydration, and pyelonephritis.
Macroscopic urinalysis - In order to perform comprehensive urinalysis, several techniques must be utilized. Gross observation of the quantity, color, clarity, odor, etc. is referred to as macroscopic urinalysis. "Dipstick" urinalysis is another important component that allows the technician to evaluate numerous aspects of the urine specimen by use of reagents on a plastic strip (Figure 7).
Figure 7. Urine dipsticks are commercially available for patients and practitioners under various tradenames.
Each of these reagents contains a chromatophore, which changes color as it reacts with its specific substrate. A legend, usually on the outside of container, helps the technician to quickly identify abnormal findings (Figure 8). The dipstick method is extremely quick (i.e. less than 60 seconds) and can yield qualitative and semi-quantitative information about up to ten components of the urine.
Figure 8. Color coding makes dipstick urinalysis relatively quick and straightforward.
Microscopic urinalysis - Finally, microscopic urinalysis involves viewing a small sample of urine sediment under the microscope in order to identify crystals, casts, and tissue cells, including red and white blood cells.
Laboratory versus in-office urinalysis - Urinalysis is perhaps the most common ancillary medical test performed, and physicians often order this test as part of a general examination. Often, the samples are sent to a laboratory, much in the same fashion as is done for blood work. Independent laboratories generally utilize automated urinalysis techniques, incorporating highly calibrated instrumentation to detect the various components of urine with exquisite precision. Optometrists may order automated urinalysis by utilizing the same techniques as were discussed for blood work. That is, the request may be written on a standard prescription pad (Figure 6), or a preprinted laboratory test checklist may be utilized.
In some cases, dipstick urinalysis may be utilized as a quick screening unto itself, since it serves to identify abnormalities in the main areas of interest. This technique can be extremely helpful to the medical optometrist in various settings, by allowing him or her to rapidly ascertain a patient’s general status regarding diabetes, renal disease, infection, and other conditions that may impact ocular health.
Unlike blood testing, there is no special training necessary for dipstick urinalysis, and there is also no need for barrier precautions or specialized disposal of samples, because urine is not considered a potential biohazard.
Urine test strips are available to consumers under the trade names Chemstrip® (Roche Diagnostics), Multistix® (Bayer Diagnostics), Diascreen® (Chronimed), and UriScan™ (Biosys Laboratories).
OCULAR INDICATIONS FOR URINALYSIS
Under what circumstances might the eye examination indicate the need for urinalysis? In general, this is most helpful when there is suspicion of diabetes, or a question regarding the level of diabetic control. While blood plasma testing is more accurate (and certainly necessary for definitive diagnosis), urinalysis can provide a good indication of high blood sugar, as well as the presence of any ketones. Other circumstances in which urinalysis might be helpful include suspected genital infection (such as chlamydia or gonorrhea), in which case elevated leukocytes might be detected.
CONCLUSIONS
Optometrists, as integral members of the health care team, have the privilege and responsibility of caring for patients beyond simple refractive and ocular health. Numerous systemic conditions may impact ocular health, or be reflected in ocular findings. By achieving and maintaining a knowledge of basic clinical medicine and the use of diagnostic testing, optometrists provide better and more comprehensive care to their patients and the community.
REFERENCES
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3. Endler G, Klimesch A, Sunder-Plassmann H, et al. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2002; 117(2):399-404.
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7. Panagiotakos DB, Pitsavos C, Skoumas J, et al. Importance of LDL/HDL cholesterol ratio as a predictor for coronary heart disease events in patients with heterozygous familial hypercholesterolaemia: a 15-year follow-up (1987-2002). Curr Med Res Opin 2003; 19(2):89-94.
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ADDITIONAL INTERNET RESOURCES:
AMERICAN SOCIETY FOR CLINICAL LABORATORY SCIENCE – http://www.ascls.org
BLOODBOOK.COM – http://www.bloodbook.com
EMEDICINE.COM – http://www.emedicine.com
FAMILY PRACTICE NOTEBOOK.COM – http://www.fpnotebook.com
LAB TESTS ONLINE – http://www.labtestsonline.org
UPCMD DISEASE DIAGNOSIS SEARCH PAGE – upcmd.com/dot/search.html
VIRTUAL HOSPITAL – http://www.vh.org
WEBPATH: THE INTERNET PATHOLOGY LABORATORY – medlib.med.utah.edu/WebPath/webpath.html
Contact the Author:
Alan G. Kabat, OD, FAAO Nova Southeastern University College of Optometry 3200 South University Drive Fort Lauderdale, Florida 33328Pacific University College of Optometry provides On-Line CE as a service to optometrists. The college does not endorse or recommend any products, equipment, or services that might be discussed in the courses. Courses are prepared by individuals believed to be experts in their areas of specialization who are compensated for their efforts. The College relies on their expertise to produce accurate and timely courses. Questions or concerns about courses should be directed to the individual authors and/or the Continuing Education Department at the College of Optometry at kundart@pacificu.edu .
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