Laboratory Interpretation and Special Studies

Laboratory tests turn a clinical suspicion into a number, but only a clinician who knows what each test measures, what moves it and how often it misleads can use that number well. Part II asks you to read a urinalysis, a CBC, a chemistry panel, a set of rheumatologic markers and a few special studies, and to decide what they mean for the patient in front of you. In practice, these results are often what tells a chiropractor that a "back pain" is a myeloma, a pyelonephritis or a spondyloarthropathy.

Section 1Urinalysis

The urinalysis is cheap, fast and informative about the kidneys, the urinary tract and systemic metabolism. A clean catch midstream specimen, examined within about an hour or refrigerated, avoids contamination and the breakdown of cells and casts. The exam has three parts: physical, chemical (dipstick) and microscopic.

Physical examination

Dipstick (chemical) findings

Microalbuminuria (moderately increased albuminuria), a urine albumin to creatinine ratio of 30 to 300 mg/g, is below the dipstick threshold but is the earliest marker of diabetic nephropathy and an independent cardiovascular risk factor; people with diabetes are screened annually.

Microscopic examination

The sediment is examined under low and high power. More than about 3 red cells per high power field is hematuria; more than about 5 white cells per field is pyuria. Many squamous epithelial cells indicate a contaminated sample, while renal tubular epithelial cells suggest acute tubular necrosis. Dysmorphic red cells (misshapen from passage through the glomerulus) point to glomerular bleeding; uniform cells point to the lower tract (stone, tumor, infection). Sterile pyuria (white cells without growth on culture) suggests tuberculosis, chlamydia or gonorrhea, interstitial nephritis or a stone.

Casts are cylinders of Tamm Horsfall mucoprotein formed in the distal tubule and collecting duct, so anything trapped in them came from the kidney itself. They are the most localizing finding in the sediment.

Section 2Hematology

The complete blood count

Anemia workup

Anemia is a sign, not a diagnosis. The first step is the MCV; the second is the reticulocyte count, which asks whether the marrow is responding (high: blood loss or hemolysis) or failing (low: deficiency, chronic disease, marrow disease).

Iron deficiency is the most common anemia worldwide. In a man or postmenopausal woman, iron deficiency means gastrointestinal blood loss until proven otherwise (colon cancer, ulcer, NSAID gastropathy), so it always calls for referral. Anemia of chronic disease (inflammation, infection, malignancy, rheumatoid arthritis) is driven by hepcidin, which traps iron in macrophages; it is usually normocytic but may become mildly microcytic. In thalassemia trait, the red cell count is normal or high despite microcytosis (a Mentzer index, MCV divided by RBC count, under 13 favors thalassemia); hemoglobin electrophoresis shows increased HbA2 in beta thalassemia trait.

Macrocytic anemia with hypersegmented neutrophils (six or more lobes) is megaloblastic. Vitamin B12 deficiency raises both methylmalonic acid and homocysteine, and can cause subacute combined degeneration of the dorsal columns and lateral corticospinal tracts (loss of vibration and position sense, ataxia, spasticity, paresthesias), sometimes before anemia appears. Folate deficiency raises homocysteine only and spares the nervous system. Pernicious anemia (antibodies to intrinsic factor and parietal cells), vegan diet, gastric or ileal surgery, metformin and proton pump inhibitors cause B12 deficiency.

Hemolysis is signaled by a high reticulocyte count, high LDH, high unconjugated (indirect) bilirubin and low haptoglobin. A positive direct Coombs (antiglobulin) test means antibody coated red cells: autoimmune hemolysis (lupus, CLL, drugs) or transfusion reaction.

White cell differential

Remember the order of normal frequency with "Never Let Monkeys Eat Bananas." Absolute neutrophil count under about 1,500/µL is neutropenia and under 500/µL carries severe infection risk. A very high count (over about 50,000) raises the question of leukemoid reaction versus leukemia; blasts in the peripheral blood suggest acute leukemia and require urgent referral.

Platelets and coagulation

Thrombocytopenia is a count under 150,000/µL. Surgical bleeding risk rises below about 50,000, and spontaneous bleeding (petechiae, purpura, mucosal bleeding) below about 10,000 to 20,000. Causes include immune thrombocytopenia, drugs (heparin induced thrombocytopenia, which paradoxically causes clotting), DIC, TTP, marrow failure and splenic sequestration. Thrombocytosis is usually reactive (iron deficiency, inflammation, after splenectomy) but can be a myeloproliferative neoplasm.

Factor VII has the shortest half life, so the PT is the first test to prolong with warfarin, vitamin K deficiency or early liver failure. DIC prolongs PT and aPTT, lowers platelets and fibrinogen, raises D dimer and produces schistocytes. A normal D dimer helps rule out DVT or PE when clinical probability is low; a positive one proves little.

Erythrocyte sedimentation rate

The ESR (Westergren method) measures how far red cells fall in a tube in one hour. Fibrinogen and immunoglobulins neutralize the negative surface charge of red cells, so they stack (rouleaux) and sink faster. A rough upper limit is age divided by 2 for men and (age plus 10) divided by 2 for women in mm/h. The ESR is a nonspecific marker of inflammation that rises slowly and stays up for weeks. It is elevated in infection (including osteomyelitis and discitis), inflammatory arthritis, malignancy, anemia, pregnancy, kidney disease and older age; it is very high (often over 100 mm/h) in multiple myeloma, giant cell arteritis, polymyalgia rheumatica and osteomyelitis. It is falsely low in polycythemia, sickle cell disease, spherocytosis and low fibrinogen states.

Section 3Clinical chemistry

The basic metabolic panel (electrolytes, glucose, BUN, creatinine, calcium) and the comprehensive panel (which adds the liver tests, albumin and total protein) are the most commonly ordered blood tests. Learn the reference ranges below as board values; individual laboratories vary slightly.

Electrolytes, glucose and renal function

The anion gap equals sodium minus (chloride plus bicarbonate), normally about 8 to 12. A high anion gap metabolic acidosis suggests unmeasured acids: ketoacidosis, lactic acidosis, uremia, or toxins (methanol, ethylene glycol, salicylates). A BUN to creatinine ratio over 20 suggests a prerenal cause (dehydration, heart failure) or upper GI bleeding; a ratio near 10 to 15 with both elevated suggests intrinsic renal disease.

The estimated GFR, calculated from creatinine, age and sex, stages chronic kidney disease, defined as eGFR under 60 mL/min/1.73 m2 or markers of kidney damage (such as albuminuria) for more than 3 months. Stages run from G1 (90 or more, with damage) through G3a (45 to 59), G3b (30 to 44) and G4 (15 to 29) to G5, under 15 (kidney failure). Because creatinine rises only after substantial nephron loss, a "normal" creatinine in a small elderly woman may hide a low GFR. eGFR matters for drug dosing, contrast imaging and NSAID advice.

Without unequivocal hyperglycemia, a diagnosis needs two abnormal results (the same test twice or two different tests). HbA1c reflects average glucose over the life span of the red cell, roughly the previous 2 to 3 months; it reads falsely low when red cell turnover is fast (hemolysis, blood loss, recent transfusion) and falsely high in iron deficiency. A common treatment target is under 7 percent. Fasting hypoglycemia is glucose under about 70 mg/dL; symptoms (sweating, tremor, confusion) usually appear under about 55.

Liver panel

Patterns matter more than single values. A hepatocellular pattern has transaminases raised out of proportion to ALP: viral hepatitis (ALT over AST, often in the hundreds to thousands), ischemic or acetaminophen injury (thousands), fatty liver disease (mild ALT elevation). An AST to ALT ratio over 2 suggests alcoholic liver disease. A cholestatic pattern has ALP and GGT raised out of proportion, with or without conjugated bilirubin: gallstones in the common duct, pancreatic head cancer, primary biliary cholangitis, drugs. An isolated high ALP with normal GGT points to bone.

Lipid panel

LDL is often calculated with the Friedewald equation: LDL equals total cholesterol minus HDL minus triglycerides divided by 5 (in mg/dL), which is invalid when triglycerides exceed about 400. Non HDL cholesterol (total minus HDL) captures all atherogenic particles. Secondary causes of dyslipidemia include hypothyroidism, nephrotic syndrome, diabetes, cholestasis and drugs.

Calcium, phosphorus and alkaline phosphatase

Total serum calcium is about 8.5 to 10.5 mg/dL, of which roughly 40 percent is bound to albumin. Correct for a low albumin: corrected calcium equals measured calcium plus 0.8 times (4.0 minus albumin); ionized calcium is measured directly when precision matters. Phosphorus is about 2.5 to 4.5 mg/dL. Hypercalcemia causes "stones, bones, groans and psychiatric overtones" (kidney stones, bone pain, constipation and abdominal pain, confusion and depression) plus polyuria and a short QT. More than 90 percent of hypercalcemia is due to primary hyperparathyroidism (outpatients) or malignancy (inpatients).

Cardiac markers

Cardiac troponin (I or T) is the marker of choice for myocardial injury: it begins to rise about 3 to 4 hours after onset (within 1 to 3 hours with high sensitivity assays), peaks at about 24 to 48 hours and remains elevated for 7 to 10 days or longer. A rise or fall above the 99th percentile with symptoms or ECG changes of ischemia defines myocardial infarction. CK-MB rises at 4 to 6 hours, peaks near 24 hours and returns to normal in 2 to 3 days, so it is useful for detecting reinfarction. Myoglobin rises earliest (1 to 2 hours) but is not cardiac specific. Total CK also rises with skeletal muscle injury: intramuscular injections, strenuous exercise, trauma, statin myopathy, rhabdomyolysis and muscular dystrophy. BNP (or NT-proBNP) is released by stretched ventricles; a BNP under about 100 pg/mL makes heart failure unlikely as the cause of dyspnea.

Thyroid tests

TSH (about 0.4 to 4.0 mIU/L) is the best single screening test for primary thyroid disease because pituitary output changes logarithmically with small changes in free hormone. Free T4 (about 0.8 to 1.8 ng/dL) then defines the disorder.

Section 4Serology and inflammatory and rheumatologic markers

Serologic tests are most useful when the pretest probability is moderate and the clinical picture is suggestive. Ordered indiscriminately for vague aches, they generate false positives that mislead. Always pair a marker with the history and examination.

Acute phase reactants

C reactive protein (CRP) is made by the liver under the influence of interleukin 6. It rises within 6 to 8 hours of an inflammatory stimulus, peaks at about 48 hours and falls quickly as inflammation resolves, so it tracks disease activity and treatment response better than the ESR. A standard CRP under about 1.0 mg/dL (10 mg/L) is usually normal; very high levels (over 10 mg/dL) suggest bacterial infection. High sensitivity CRP measures low levels for cardiovascular risk: under 1 mg/L low, 1 to 3 average, over 3 mg/L high risk. In septic arthritis, osteomyelitis and postoperative spinal infection, CRP and ESR are both raised, and a normal CRP makes vertebral osteomyelitis unlikely.

Rheumatoid arthritis markers

Antinuclear antibodies

The ANA, done by indirect immunofluorescence on cultured cells, is the screening test for systemic lupus erythematosus. It is positive in about 95 percent or more of SLE, so a negative ANA makes SLE very unlikely, but it is also positive at low titer in many healthy people (especially older women), in other connective tissue diseases, and with some drugs, so a positive ANA alone does not diagnose anything. Titers of 1:160 or higher are more meaningful than 1:40 or 1:80. The fluorescence pattern hints at the antigen, and specific antibody tests follow.

In active lupus, complement (C3 and C4) falls as it is consumed by immune complexes.

HLA-B27

HLA-B27 is an MHC class I allele present in about 90 percent of white patients with ankylosing spondylitis and in a majority of those with reactive arthritis, and less often in psoriatic and enteropathic axial disease. But it is also carried by roughly 6 to 8 percent of the general white population, and most carriers never develop spondyloarthritis. Its positive predictive value is therefore low in unselected patients; it is useful only when inflammatory back pain (onset before 45, insidious, morning stiffness, improvement with exercise but not rest, night pain in the second half of the night) already makes the diagnosis plausible. A negative result lowers, but does not exclude, the probability.

Uric acid and synovial fluid

Serum urate is supersaturated above about 6.8 mg/dL. Hyperuricemia is common and usually asymptomatic, and the level may be normal during an acute gout attack; the diagnosis rests on finding needle shaped, negatively birefringent monosodium urate crystals in joint fluid. Calcium pyrophosphate crystals (pseudogout) are rhomboid and weakly positively birefringent. Long term urate lowering aims for under 6 mg/dL.

PSA and tumor markers

Prostate specific antigen is organ specific but not cancer specific. A traditional cutoff is 4.0 ng/mL, with age adjusted values. PSA rises with prostate cancer, benign prostatic hyperplasia, prostatitis, urinary retention, ejaculation and instrumentation (a digital rectal exam raises it only slightly). A low percent free PSA (under about 10 percent) and a rapid rise over time favor cancer. Screening for men about 55 to 69 is an individual decision after discussion of benefits and harms. A man with a raised PSA and new low back pain needs evaluation for osteoblastic spinal metastases.

Most other tumor markers are too insensitive and nonspecific for screening and are used to support a diagnosis and monitor treatment or recurrence.

Infectious serology

The heterophile antibody (Monospot) test detects infectious mononucleosis (EBV) but may be negative in the first week and in young children; EBV viral capsid antigen IgM confirms acute infection. The antistreptolysin O titer supports recent streptococcal infection (rheumatic fever, poststreptococcal glomerulonephritis). HIV screening uses a fourth generation antigen and antibody combination test (detects p24 antigen earlier than antibody alone), confirmed by a differentiation assay. Syphilis uses a nontreponemal test (RPR or VDRL), whose titer falls with treatment and which has false positives in lupus, antiphospholipid syndrome and pregnancy, and a treponemal test (FTA-ABS or TP-PA), which stays positive for life. Lyme disease uses a two tier approach (immunoassay, then confirmation). For tuberculosis infection, the tuberculin skin test is read as induration at 48 to 72 hours (positive at 5 mm or more in HIV, close contacts and the immunosuppressed; 10 mm or more in health care workers, recent immigrants and injection drug users; 15 mm or more in people without risk factors); interferon gamma release assays are not affected by prior BCG vaccination.

Hepatitis C is screened with an antibody test; a positive result is followed by HCV RNA, since antibody persists after cleared infection.

Section 5Special studies and test logic

Reference ranges

A reference range is usually the central 95 percent of results in a healthy population (the mean plus or minus 2 standard deviations). By definition, 5 percent of healthy people fall outside it. Order 20 independent tests on a healthy person and the chance that at least one is "abnormal" is about 1 minus 0.95 to the 20th power, roughly 64 percent. Results just outside the range, in a patient without matching symptoms, are often noise; repeat or follow the trend before acting. Ranges also differ by age, sex, pregnancy, laboratory and method. A critical (panic) value is one that signals immediate danger and is phoned to the clinician.

Sensitivity, specificity and predictive values

Test performance is described with a 2 by 2 table comparing the test result with the true disease state (the reference or "gold" standard).

Two mnemonics capture the clinical use. SnNout: a highly Sensitive test, when Negative, rules out disease (few false negatives), which makes sensitive tests good for screening (D dimer, ANA, the straight leg raise for disc herniation). SpPin: a highly Specific test, when Positive, rules in disease (few false positives), which makes specific tests good for confirmation (anti-CCP, anti-Smith, the crossed straight leg raise).

Sensitivity and specificity are relatively stable properties of a test, but predictive values change with prevalence. As prevalence (pretest probability) falls, PPV falls and NPV rises; as prevalence rises, PPV rises. This is why screening a low risk population produces many false positives, and why the same positive result means more in a patient whose history already points to the disease. Moving the cutoff trades one property for the other: lowering the cutoff for a positive result raises sensitivity and lowers specificity. The receiver operating characteristic (ROC) curve plots sensitivity against 1 minus specificity across cutoffs; the larger the area under it, the better the test discriminates.

Related terms: accuracy (closeness to the true value), precision or reliability (reproducibility on repeated measurement; interexaminer reliability is often expressed as the kappa statistic), and validity (whether the test measures what it claims to). A test can be precise but inaccurate if it is consistently biased.

ECG basics

Standard ECG paper runs at 25 mm/s: one small (1 mm) box is 0.04 s and one large (5 mm) box is 0.20 s; 10 mm vertically equals 1 mV. Heart rate equals 300 divided by the number of large boxes between R waves (or 1,500 divided by small boxes); for irregular rhythms count the QRS complexes in a 6 second strip and multiply by 10.

Pulmonary function tests

Spirometry measures forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and their ratio. Lung volumes (total lung capacity, residual volume) need body plethysmography or gas dilution, and the diffusing capacity (DLCO) measures gas transfer across the alveolar capillary membrane.

Asthma shows reversibility: an increase in FEV1 of at least 12 percent and 200 mL after a bronchodilator; COPD is not fully reversible. COPD severity is graded by FEV1 percent predicted (80 or more mild, 50 to 79 moderate, 30 to 49 severe, under 30 very severe). A peak flow meter allows home monitoring of asthma.

Bone density

Dual energy x-ray absorptiometry (DXA) of the lumbar spine and hip is the standard for diagnosing osteoporosis. The T score compares the patient with the peak bone mass of young healthy adults of the same sex, in standard deviations; the Z score compares with people of the same age.

A fragility fracture of the hip or spine establishes osteoporosis regardless of T score. The Z score is used in premenopausal women, men under 50 and children; a Z score of -2.0 or lower is "below the expected range for age" and should prompt a search for secondary causes (glucocorticoids, hyperparathyroidism, hyperthyroidism, malabsorption, myeloma, hypogonadism). Lumbar DXA can be falsely elevated by osteophytes, facet arthrosis, aortic calcification and compression fractures, which is why the hip is also measured. Screening is recommended for women 65 and older and for younger postmenopausal women at increased risk; the FRAX tool estimates 10 year fracture probability to guide treatment.

Nerve conduction studies and electromyography

Nerve conduction studies (NCS) stimulate a nerve and record the response, measuring latency, amplitude (number of functioning axons) and conduction velocity (myelin), normally about 50 to 60 m/s in the arms and 40 to 50 m/s in the legs. Demyelination slows velocity, prolongs latency and may cause conduction block (carpal tunnel syndrome with prolonged median distal latency, Guillain Barré syndrome). Axonal loss reduces amplitude with near normal velocity (diabetic and toxic neuropathies). Late responses test proximal segments: the H reflex is the electrical analog of the ankle jerk and is delayed or absent in S1 radiculopathy; F waves assess motor roots.

Needle electromyography (EMG) records muscle activity at rest and with contraction. Normal resting muscle is silent. After denervation, fibrillation potentials and positive sharp waves appear, but only after about 2 to 3 weeks (earlier in paraspinal muscles, later in distal limb muscles), so EMG is usually deferred until about 3 weeks after onset. Chronic reinnervation produces large, long, polyphasic motor unit potentials with reduced recruitment; myopathy produces small, short, polyphasic potentials with early recruitment.

When to order and when to refer

Order a test when its result will change management. Testing helps most when the pretest probability is intermediate: at very low probability a positive result is likely false, and at very high probability a negative result is unlikely to dissuade you. Before ordering, ask what you will do with a positive and with a negative result. Scope of practice for ordering laboratory tests and special studies varies by jurisdiction; where it allows, the chiropractor orders tests to screen for conditions outside the scope of chiropractic care and refers when results indicate.

Communicate referrals in writing, with the findings, the reason and the urgency, and document the referral and the patient's response in the record.

Words worth knowing