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Lab Testing: The Basics Blair Lonsberry, MS, OD, MEd., FAAO Professor of Optometry Pacific University College of Optometry [email protected] . Case History • 49 WF presents with a complaint of blurry/fluctuating vision at distance and near • PMHx: – Hypertension 15 years – Review of Systems: • Joint pain • Seasonal allergies • Ocular: dryness, redness, burning, blurriness • POHx: no surgeries or trauma reported • Meds: HCTZ Entrance Skills • VA (corrected): – +1.00 – 0.50 x 180 20/25 – +1.00 – 0.50 x 180 20/25 • All other entrance skills unremarkable • Refraction: – +1.25 – 0.50 x 180 20/25 – +1.25- 0.75 x 180 20/25 • Patient notes vision “still not quite right” and “fluctuating” Rheumatoid Arthritis • Collagen vascular disorders: – most common form of inflammatory joint disease – lead to most common form of physical disability in the US • Average onset between 3550 • familial predisposition • 3x more females • Predominately Caucasian Rheumatoid Arthritis • Rheumatoid Arthritis (RA) is not a benign disease. • RA is associated with decreased life expectancy. – The risk of cardiovascular mortality is twice that of the general population. • Affecting approximately 1% of the adult population, RA is associated with considerable disability. Rheumatoid Arthritis Epidemiology-Systemic • Bilateral predilection for peripheral joints extending towards trunk – hands-elbows-ultimately shoulders • Chronic inflammation leads to erosion of bony surfaces and cartilaginous destruction – this leads to joint deformity and physical impairment Other Diagnostic Criteria for RA Cutaneous Ocular Pulmonary Cardiac Neurological Nodules Sicca Pleuritis Pericarditis Peripheral neuropathy Leukopenia Vasculitis Episcleritis Nodules Atherosclerosis Cervical myelopathy Anemia of chronic disease Scleritis Interstitial lung disease Myocardial infarction Fibrosis Hematological Lymphadenopathy Osteoarthritis (OA) vs. RA • Etiology of RA is inflammatory which improves with activity while osteo is mechanical and worsens with activity • Infl’n secondary to mechanical insults in osteo while no previous insult required in RA • Joint cartilage is primary site of articular involvement in osteo while its the bony surfaces of the joints in RA Diagnosis • Many patients have symptoms that are not exclusive to RA making diagnosis difficult – prodromal systemic symptoms of malaise, fever, weight loss, and morning stiffness • Lab tests and radiographic studies are necessary for initial diagnosis and are helpful in monitoring progression – no one single test is confirmatory of disease Criteria for Diagnosis of RA RA likely if: – Morning stiffness > 30 minutes – Painful swelling of 3 or more joints – Involvement of hands and feet (especially MCP and MTP joints) – Duration of 4 or more weeks – Differential diagnoses include: crystal arthropathy, psoriatic arthritis, lupus, reactive arthritis, spondyloarthropathies. Lab Testing for RA Tests Diagnostic Value Disease Activity Monitoring ESR or CRP Indicate only inflammatory process ESR elevated in many but not all - Very low specificity active inflammation. Maybe useful in monitoring disease activity and response to treatment RF RF has a low sensitivity and specificity for RA. Seropositive RA has worse prognosis. ANA Positive in severe RA, SLE, or other No value-do not repeat connective tissue disorders (CTD) X-rays Diagnostic erosions rarely seen in disease of <3 mo’s duration Joint aspiration Indicated if infection suspected No value Serial x-rays over many years may show disease progression and indicate med change Rheumatoid Factor (RF) • RF is an autoantibody directed against IgG • Most common lab testing are latex fixation and nephelometry • RF present in 70-90% of patients with RA – However RF is not specific for RA – Occurs in a wide range of autoimmune disorders – Prevalence of positive RF increases with age • As many as 25% of persons over age of 65 may test positive – High titer for RF almost always reflects an underlying disease Rheumatoid Factor (RF) • Indication: – RF should be ordered when there is clinical suspicion of RA • Interpretation – Positive test depends on pretest probability of the disease • If other clinical signs present can provide strong support for diagnosis of RA • Keep in mind that the combination of a positive test is not specific for RA – Negative test should not completely rule out possibility of RA • From 10-30% of patients with long-standing disease are seronegative • The sensitivity of the test is lowest when the diagnosis is most likely to be in doubt Antibodies to Cyclic Citrullinated Peptides (anti-CCP) • Proteins that contain citrulline are the target of an AB response that is highly specific for RA • Anti-CCP detected using ELISA • Associated conditions: – Appears to be quite specific for RA • Specificity as high as 97% – Sensitivity in the range of 70-80% for established RA and 50% for early-onset – Has superior specificity and comparable sensitivity for diagnosis of RA as compared to RF Antibodies to Cyclic Citrullinated Peptides (anti-CCP) Indication: – Should be ordered when there is a clinical suspicion of RA Interpretation: – Presence provides strong support for the diagnosis of RA – In patients with early onset, undifferentiated, inflammatory arthritis positive results are a strong predictor of progression to RA and the development of joint erosion – Negative test does not exclude possibility of RA particularly at the time of initial presentation (apprx 50% of patients lack detectable antibodies) Diagnosis • Joint x-ray and radionucleotide evaluation of suspected inflamed joints are indicated Rheumatoid Arthritis: Treatment • Treatment must be started early to maximize the benefits of medications and prevent joint damage. • The use of traditional medications in combination and the new biologic therapies has revolutionized the paradigm of RA treatment in recent years. • The approach to care of patients with RA should be considered as falling into two groups. – Early RA (ERA) is defined as patients with symptoms of less than 3 months duration. – Patients with established disease who have symptoms due to inflammation and/or joint damage. Treatment and Management-Systemic • The treatment approach varies depending on whether the symptoms arise from inflammation or joint damage making the differentiation vital. • There is no curative treatment for RA – treatment is to minimize inflammation – minimize damage and – maximize patient functioning. • Pharmaceutical agents inhibit inflammatory responses – have traditionally been used in a stepwise approach from weakest to strongest. Treatment and Management-Systemic • Current Tx regimens utilize a step-down approach with initiation of one or more DMARD’s at time of diagnosis. • RA most destructive early in disease • “Easier” and more effective if Tx initiated early. • DMARD-disease modifying antirheumatic drug – these drugs not only reduce inflammation but also change the immune response in a long-term and more dramatically than NSAID’s – give chance of permanent remission Case • 48 yr old white female presents with acute loss of vision in her right eye and decreased vision in her left – She was scheduled 2 weeks previously for an eye exam on a referral from her PCP but had fallen and was unable to make that appointment – She reports that her vision in her right eye seems to be getting worse over the past several weeks. – Was diagnosed with diabetes 1.5 years ago • BS control has been erratic with range between between 6.713.3 (120-240) • Last A1C: 9.1 Blood Sugar • Hypoglycemia is typically defined as plasma glucose 3.9 mmol/L (70 mg/dL) or less – patients typically become symptomatic of hypoglycemia at 2.8 mmol/L (50 mg/dL) or less Entrance Skills/Health Assessment VA: OD: finger count OS: 6/12 (20/40) CVF: OD: unable to assess OS: temporal hemianopsia Pupils: sluggish reactivity with a 2+ RAPD OD SLE: corneal arcus noted, no other significant findings IOP: 16, 16 mmHG OD, OS DFE: see photos Note: not patient photos http://content.lib.utah.edu/cdm4/item_ viewer.php?CISOROOT=/EHSLWFH&CISOPTR=159 Physical Presentation • Upon entering the room I noted that her right hand was twitching – I asked her how long that had been going on and she said about 2-3 weeks – I asked her if she experienced headaches, to which she said she had bad headaches that even woke her up at night Referral • Contacted her PCP who reported that she had examined the patient 3 weeks prior and had not noted any of these findings • Referred the patient for an immediate MRI – wasn’t able to be scheduled until the next day Imaging/Surgery Referral • MRI revealed large mass in her brain – Patient was diagnosed with a Craniopharyngioma – She was referred for immediate surgery – Neurosurgeon reported that she removed a tangerine sized Craniopharyngioma – was the largest tumor she has ever removed Note: not patient MRI http://neurosurgery.ucla.edu/images/P ituitary%20Program/Craniopharyngio ma/Cranio_Sag_Preop_fullylabeled.jp g Craniopharyngioma • Presenting signs and symptoms of increased intracranial pressure (80%) – Headache – Vomiting – Papilledema – Loss of vision and visual field (60%) – Diabetes (15%) – Mental deterioration or personality change (26%) Craniopharyngioma • Treatment: – Therapy is often unsatisfactory – Total resection often results in major functional deficits – Partial resection followed by conventional radiation therapy as a more conservative approach has been recommended Diabetes Lab Testing • Comprehensive medical panel will include: – Serum glucose – Electrolytes – Liver enzymes – Kidney function: • BUN and creatinine – Elevated in renal failure • Glomelular filtration rate – Reduced in chronic kidney disease/renal failure Blood Sugar • Throughout a 24 hour period blood sugar typically maintained between 3.9-7.8 mmol/L (70-140 mg/dL) • [A1c (%) x 1.59] – 2.59 = average Blood Glucose (in mmol/L) Recommendations for Management Kidney function • Urinalysis can be used in conjunction with blood testing to help confirm systemic etiology of conditions – Urine Glucose • Any glucose in the urine is abnormal – Urine Protein • Proteinuria is an important indicator of renal disease – Urine Ketones • Ketones are byproducts of body fat metabolism formed in the liver • Ketonuria occurs in patients with diabetes Kidney Function Tests: Serum Creatinine: - waste product that comes from the normal wear and tear on muscles of the body. – Kidney impairment results in rise of creatinine level in the blood BUN (blood urea nitrogen): - If kidneys cannot filter wastes out of the blood due to disease or damage, then the level of urea in the blood will rise Kidney function • Kidney function is important to assess prior to MRIs with contrast – Gadolinium-containing contrast agents may increase the risk of a rare, but serious, disease called nephrogenic systemic fibrosis in people with severe kidney failure. – Nephrogenic systemic fibrosis triggers thickening of the skin, organs and other tissues. – There's no effective treatment for this serious, debilitating disease. Liver Tests • Liver tests (LTs) are blood tests used to reflect the presence of damage or inflammation. • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the most commonly used tests • These enzymes normally found in the blood when liver cells are injured. Liver Tests • The ALT is felt to be a more specific indicator of liver inflammation as AST is also found in other organs such as the heart and skeletal muscle. • In acute injury to the liver, as in viral hepatitis, the level of the ALT and AST may be used as a general measure of the degree of liver inflammation or damage. Liver Tests • Bilirubin is the main bile pigment in humans which, when elevated causes the yellow discoloration of the skin called jaundice. – the bilirubin may be elevated in many forms of liver or biliary disease, it is relatively non-specific • Allbumin is a major protein which is formed by the liver. – chronic liver disease causes a decrease in the amount of albumin produced Blood Chemistry: Lipid Profiles Consists of: – Serum lipids, – Cholesterol, • High density lipoproteins (HDL) – “good” cholesterol • Low density lipoproteins (LDL) – “bad” cholesterol • Very-low density lipoproteins (VLDL) – dangerous cholesterol – triglycerides Current Recommended Lipid Levels Case • 30 BF presents with eye pain in both eyes for the past several days – Severe pain (8/10) – Never had eye exam before • PMHx: – Has chronic bronchitis – Rash on legs – Has recently lost weight and has a fever – Taking aspirin for pain Ocular Health Assessment VA: 6/9 (20/30) OD, OS PERRL FTFC EOM”s: FROM with eye pain in all quadrants • SLE: – 3+ injection, – 3+ cells and trace flare, – deposits on endo (see photo) • IOP: 18, 18 mmHg • DFE: – see attached fundus image and fluorescein angiography. • • • • Sarcoid Diagnosis Lab Test Findings CBC with differential Anemia/thrombocytopenia/leukopenia Serum calcium/24 hour calcium Hypercalcemia Liver/Kidney function tests AST/ALT/BUN/Creatinine elevated in hepatic disease ACE (angiotensin converting enzyme) Elevated in 60% of patients Pulmonary x-rays Hilar adenopathy Blood Chemistry • Angiotensin-Converting Enzyme (ACE) – Found mainly in lung and liver – Serum elevations are found in patients with sarcoidosis, and significant levels are achieved in pulmonary sarcoid – Cirrhosis of the liver may produce elevated ACE levels – Active tuberculosis infection of the lung does NOT produce elevated ACE levels Diagnosis: Radiographic • Radiographic involvement is seen in almost 90% of patients. • Chest radiography is used in staging the disease: – Stage I disease shows bilateral hilar lymphadenopathy (BHL). – Stage II disease shows BHL plus pulmonary infiltrates. – Stage III disease shows pulmonary infiltrates without BHL – Stage IV disease shows pulmonary fibrosis. Diagnosis: Radiographic • CT and MRI scans may be useful in finding granulomas in other organ systems • Gallium scangallium 67 has been found to accumulate in active sarcoidal tissue Gallium Scan: Lacrimal/parotid gland, Hilar glands Stages of Syphilis Syphilis Diagnosis • Typical diagnosis is with blood tests using nontreponemal and/or treponemal tests. – Nontreponemal test are used initially and include: • venereal disease research laboratory (VDRL) • rapid plasma reagin (RPR) • chemiluminescent microparticle immunoassay (CMIA)*** *** primary screening test for patients suspected of being exposed to syphilis Syphilis Diagnosis • False positives can occur with some viral infections such as (varicella and measles), as well as with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, pregnancy – confirmation is required with a treponemal test such as: • treponemal pallidum particle agglutination (TPPA) or • fluorescent treponemal antibody absorption test (FTA-Abs) • The FTA-ABS test checks for antibodies to the bacteria that cause syphilis and can be used to detect syphilis except during the first 3 to 4 weeks after exposure to syphilis bacteria.. Tuberculosis • Difficult to culture the slow-growing organism in the laboratory (it may take 4 to 12 weeks for blood or sputum culture). • A complete medical evaluation for TB must include: – a medical history, – a physical examination, – a chest X-ray, – microbiological smears, – and cultures. • It may also include a tuberculin skin test, a serological test. – The interpretation of the tuberculin skin test depends upon the person's risk factors for infection and progression to TB disease, such as exposure to other cases of TB or immunosuppression Tuberculosis • Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to an extract made from M. tuberculosis. • Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection, so the test must be used with caution, particularly with regard to persons from countries where TB immunization is common Tuberculosis • The newer interferon release assays (IGRAs) overcome many of these problems. – IGRAs are in vitro blood tests that are more specific than the skin test. – IGRAs detect the release of interferon gamma in response to mycobacterial proteins – These are not affected by immunization or environmental mycobacteria, so generate fewer false positive results. Erythrocyte Sedimentation Rate This measures the height of RBC’s settling out of plasma per hour ESR Males: Age/2 Good sensitivity but poor specificity. Takes time for the levels to become detectable Females: (Age + 10)/2 High: Indicative of giant cell arteritis but normal levels do not exclude GCA as a diagnosis Giant Cell Arteritis • vessels most often involved are the arteries over the temples, – GCA = "temporal arteritis.” • symptoms, such as fatigue, loss of appetite, weight loss or a flu-like feeling – pain in the jaw with chewing (jaw claudication). – Sometimes the only sign of GCA is unexplained fever. – Less common symptoms include pains in the face, tongue or throat. Giant Cell Arteritis • GCA is a clinical diagnosis! • If patient meets criteria of clinical symptoms then treatment will be started regardless of whether lab test or biopsy are positive • Treatment should be started before lab results are back. Hemogram • C-Reactive Protein – Normal = no CRP – Abnormal serum glycoprotein produced by liver during acute inflammation – Disappears rapidly once inflammation subsides – 4 hour fast from food/fluids – Alternative to ESR – More informative • ESR high in most elderly • Elevated in conditions such as: temporal arteritis, preseptal cellulitis, endophthalmitis, HLA-B27 related iritis conditions. Superior Limbic Keratoconjunctivitis (SLK) • inflammation of the superior bulbar conjunctiva with predominant involvement of the superior limbus • adjacent epithelial keratitis and a papillary hypertrophy of the upper tarsal conjunctiva. • association between thyroid abnormalities and SLK Superior Limbic Keratoconjunctivitis (SLK) • mimicking disorder has been encountered in soft contact lens (SCL) wearers, typically with exposure to thimerosal-preserved solutions • middle-aged people and women are predominantly affected • Much higher prevalence in Graves patients than normal population Thyroid Gland • T4 is the major hormone produced but has low activity in stimulating metabolism – T4 has a longer half-life, much higher levels of T4 than T3 are in the circulation – T4 considered a prohormone and is metabolized primarily in liver (87% of T3 in circulation is formed from T4) • T3 is 3-4 times metabolically more active than T4 Testing recommendations? Patients with no symptoms of thyroid disease and no obvious risk factors have a low likelihood of thyroid disease. In most situations, TSH is the more sensitive indicator of thyroid status. If further thyroid function tests are indicated they can be subsequently added by the laboratory, or the GP usually without the need to retest the patient. Thyroid Testing Algorithm Key points about Grave’s disease: Most common cause of eyelid retraction Most common cause of bilateral or unilateral proptosis. More common in women Associated with hyperthyroidism in 90% of patients; 6% are euthyroid Smoking is associated with increased risk and severity of ophthalmopathy. The course of ophthalmopathy does not necessarily parallel the activity of the thyroid gland or the treatment of thyroid abnormalities. Grave’s disease/Thyroid Ophthalmopathy Clinical signs • Eyelid retraction- most common sign • Lid lag • Proptosis • Restrictive extraocular myopathy • Optic neuropathy Other clinical features: • Most frequent ocular symptom is pain or discomfort (30%)- often the result of dry eyes • Diplopia- 17% • Lacrimation/photophobia- 15-20% • Blurring of vision- 7.5% CBC with Differential • Red blood cell count (RBC). RBC count is simply the number of erythrocytes (in millions) per cubic millimeter (mm3) or micro-liter (µL). It does not give the detailed information necessary to determine how well RBCs are functioning. • Hemoglobin (Hb). This represents the amount of oxygen-carrying protein (hemoglobin) in a sample and reflects the number of RBCs present. • Hematocrit. Provides a value related to the percentage of total blood volume that is comprised of red blood cells. It is closely related to hemoglobin levels. CBC with Differential • Red blood cell indices. Helpful in classifying anemias, these indices provide information such as RBC size, weight and hemoglobin concentration. • White blood cell count (WBC) and differential. A WBC count reflects the number of WBCs per µL. The differential provides detailed information about the types of WBCs present, along with percentages. This information is useful in the differential diagnosis of certain disease states. • Platelet count. This represents the number of platelets per µL and is useful in the diagnosis and management of blood clotting disorders and other diseases. Why Order a CBC Diff • helpful for patients with persistent infections, recurrent inflammation, or in those who exhibit signs of anemia or leukemia • part of a battery of tests performed prior to surgery • monitor patients for negative side effects associated with certain medications – E.g. acetazolamide (Diamox) Why Order a CBC Diff • cases of recurrent or bilateral uveitis, may be useful in identifying a possible non-specific systemic etiology – an elevated WBC count (leukocytosis) may be present with underlying bacterial infections – elevated lymphocyte count (lymphocytosis) may be present with viral infections – Parasitic causes of uveitis may reveal elevated eosinophils (eosinophilia) Why Order a CBC Diff • presence of cotton-wool spots and/or retinal hemorrhages of unknown etiology in a patient without a documented history of diabetes mellitus or hypertension should prompt eye care providers to order a CBC to rule out anemia • CBC could detect polycythemia (elevated RBC count), which is present in serious diseases such as leukemia Blood Components • Blood volume averages approximately 5 L in adults – This consists of a suspension of the formed elements (red blood cells, white cells and platelets) in plasma – Plasma comprises ~55% of the total blood volume (about 3 Liters) Blood • Centrifuged (spun) to separate • Clinically important hematocrit – % of blood volume consisting of erythrocytes (red blood cells) – Male average 47; female average 42 • Plasma at top: water with many ions, molecules, and 3 types of important proteins: – Albumin – Globulins – Fibrinogen 73 Blood Components • Erythrocytes (Red Blood Cells) – Multiple functions; most importantly – O2 delivery • O2 is bound by haemoglobin within the cell – Accounts for 97% of the normal O2 carrying capacity • Normal haemoglobin values are in the range of: – Men = 14 – 16 g/dL – Women = 12 – 14 g/dL • Low haemoglobin concentration = anemia Blood Components • Erythrocytes (Red Blood Cells) – Red blood cell production (erythropoiesis) occurs in the bone marrow • The kidney controls RBC production via a hormone called erythropoitin – The amount released depends on the O2 delivery to the renal cells » Note it is O2 delivery, not haemoglobin concentration – Aging erytrhrocytes are destroyed, often in the spleen, after an average life span of 120 days Blood Components • Erythrocytes (Red Blood Cells) – RBC production and haemoglobin syntheses require adequate supply of vitamins B12 and folic acid, as well as the mineral iron. • Deficiencies in these may cause anemia Blood Components • Erythrocytes (Red Blood Cells) – Erythrocyte sedimentation rate (ESR) • In an undisturbed vertical column of anticoagulated blood, erythrocytes slowly settle out, leaving plasma above • The normal values lie in the range of 5 – 10 mm/hr • This rate of sedimentation increases in certain diseases • High ESR values are often associate with an increase in immunoglobulins __RBC Leukocytes neutrophil eosinophil basophil small lymphocyte AKA WBCs: white blood cells Are complete cells Function outside the blood Note the size difference compared to erythrocytes monocyte 78 Blood Components • Leucocytes (White Blood Cells) – WBC’s are vitally important for: • Disposal of damaged and aging tissue • Immune responses which protect us from infections and cancer cell proliferation Hemogram • Eight components of the Hemogram (Complete Blood Count): – – – – – – – – Hematocrit Hemoglobin (Hb) Mean Corpuscular Volume (MCV) Mean Corpuscular Hemoglobin (MCH) Platelet Count Mean Platelet Volume Red Blood Cell Count (RBC) White Blood Cell Count Hematocrit • Hematocrit is a measure of the percentage of the total blood volume that is made up by the red blood cells • The hematocrit can be determined directly by centrifugation (“spun hematocrit”) – The height of the red blood cell column is measured and compared to the column of the whole blood Hematocrit (HCT) HCT Males: 40-54% Low: anemia Females: 34-51% High: fluid loss due to diarrhea, dehydration or burns Hemoglobin (Hgb) Hb Males: 140 – 174 g/L Low: anemia Females: 123 – 157 g/L High polycythemia, living at higher altitudes, smokers Mean Corpuscular Volume • The MCV is a measure of the average volume, or size, of an RBC • It is determined by the distribution of the red blood cell histogram – The mean of the red blood cell distribution histogram is the MCV Use of MCV Result • The MCV is important in classifying anemias – Normal MCV = normocytic anemia – Decreased MCV = microcytic anemia – Increased MCV = macrocytic anemia Mean Corpuscular Volume MCV Normal: 80 – 100 fL Low: iron deficiency anemia, thalassemia High living at higher altitudes, vitamin B12 or folate deficiency, recent blood loss Platelet Count Necessary for clotting and repairing damaged blood vessels PLT Normal: 130 – 400 x 109 / L Low: autoimmune disease, blood loss, anticoagulant medications, High: smokers, chronic bleeding and leukemia Hemogram • Red Blood Cell Count (RBC) 2,3,4 – Female = 4.0 – 5.2 x 1012 / L – Male = 4.4 – 5.7 x 1012 / L – Tells the clinician the number of erythrocytes – Below normal = anemia – Above normal = polycythemia – Abnormal RBC can lead to cotton-wool spots, hemes, Roth Spots, mid-peripheral or peripheral retinal hemes Hemogram • White Blood Cell Count (WBC) 2,3,4 – Normal = 4 – 10 x 109 / L – – – – – – – With differential : Segmented neutrophils = 2 – 7 x 109 / L Band neutrophils = <0.7 x 109 / L Basophils = <0.10 x 109 / L Eosinophils = <0.45 x 109 / L Lymphocytes = 1.5 – 3.4 x 109 / L Monocytes = 0.14 – 0.86 x 109 / L