Clinical Laboratory and Special Studies in Cases

A laboratory value means nothing until it is attached to a patient: a sedimentation rate of 85 mm/h is a curiosity in a healthy 30 year old, and a reason for same week referral in a 74 year old with new headache and jaw pain. Part III tests whether you know which test to order for a given question, what pattern of results points to which disease, and what you do next when a result is dangerous. This chapter works through urinalysis, hematology, serology, chemistries, stool and joint fluid, electrophysiologic studies and the statistics that decide whether a test is worth ordering at all.

Section 1Urinalysis and hematology in cases

The dipstick

A routine urinalysis has three parts: physical (color, clarity, specific gravity), chemical (the dipstick) and microscopic (sediment). It is cheap, fast and screens for kidney disease, urinary infection, diabetes, liver and hemolytic disease, and it is the first test for flank pain that might be renal rather than spinal.

Microscopy: casts and crystals

Casts form in the renal tubules from Tamm Horsfall protein, so a cast localizes disease to the kidney itself. Red cell casts mean glomerulonephritis. White cell casts mean pyelonephritis or interstitial nephritis (they distinguish upper from lower urinary tract infection). Fatty casts and oval fat bodies ("Maltese cross" under polarized light) go with nephrotic syndrome. Muddy brown granular casts indicate acute tubular necrosis. Waxy casts and broad casts mean advanced chronic kidney disease. Hyaline casts are nonspecific and can follow exercise, fever or dehydration.

Crystals help in stone disease: calcium oxalate (envelope or dumbbell shaped) in the most common stones and in ethylene glycol poisoning; uric acid (rhomboid, yellow brown) with gout, high cell turnover and acid urine; struvite or magnesium ammonium phosphate ("coffin lid") with urease producing infection and staghorn calculi; cystine (hexagonal) in the inherited disorder cystinuria.

The complete blood count

Classifying anemia

The MCV divides anemia into three groups, and each group has a short list. In microcytic anemia (MCV below 80), iron deficiency is most common; in an adult man or a postmenopausal woman, iron deficiency means gastrointestinal blood loss (often colon cancer) until proven otherwise, and in a premenopausal woman heavy menses is the usual cause. Iron studies separate the causes: iron deficiency shows low ferritin (the single best test; below about 30 ng/mL is diagnostic in most settings), high TIBC and high RDW; anemia of chronic disease shows normal or high ferritin with low TIBC; thalassemia trait shows normal iron, a very low MCV out of proportion to mild anemia, a normal or high red cell count (Mentzer index MCV divided by RBC below 13) and target cells. Lead poisoning and sideroblastic anemia are rarer causes, with basophilic stippling and ringed sideroblasts.

In macrocytic anemia (MCV above 100), the megaloblastic causes are vitamin B12 and folate deficiency, recognized by hypersegmented neutrophils (6 or more lobes). B12 deficiency (pernicious anemia, metformin, long term proton pump inhibitors, vegan diet, gastric or ileal surgery) causes subacute combined degeneration: loss of vibration and position sense, ataxia and upper motor neuron signs, sometimes before anemia appears; methylmalonic acid and homocysteine are both elevated, whereas folate deficiency raises only homocysteine. Nonmegaloblastic macrocytosis comes from alcohol, liver disease, hypothyroidism, reticulocytosis and medications.

In normocytic anemia (80 to 100), the reticulocyte count decides the direction. High reticulocytes indicate blood loss or hemolysis (raised LDH and indirect bilirubin, low haptoglobin, schistocytes or spherocytes on smear). Low reticulocytes indicate underproduction: anemia of chronic disease, chronic kidney disease (low erythropoietin), early iron deficiency, or marrow infiltration by leukemia, myeloma or metastatic cancer, especially when other cell lines are also low.

White cells and platelets

For a chiropractor these results matter directly: patients on anticoagulants or with thrombocytopenia bruise and bleed more easily, so high velocity and deep soft tissue techniques are modified or avoided, and any unexplained bruising, petechiae, gum bleeding or hemarthrosis is a reason to check a CBC and coagulation profile rather than treat.

Section 2Serology and blood chemistries in cases

Inflammatory markers: ESR and CRP

The erythrocyte sedimentation rate (Westergren method) measures how far red cells fall in an hour; acute phase proteins, mainly fibrinogen and immunoglobulins, neutralize the negative surface charge of red cells so they stack (rouleaux) and settle faster. A common rule of thumb for the upper limit is age divided by 2 for men and age plus 10, divided by 2, for women. ESR rises slowly over days, falls slowly over weeks, and is raised by anemia, pregnancy, age and kidney disease; it is lowered by polycythemia, sickle cells and very high white counts. An ESR above 100 mm/h narrows the field to a few causes: infection (osteomyelitis, endocarditis), multiple myeloma and other malignancy, and giant cell arteritis or polymyalgia rheumatica.

C reactive protein is made by the liver under the influence of interleukin 6. It rises within 6 to 8 hours, peaks at about 48 hours and falls quickly when inflammation resolves, so it tracks response to treatment of infection better than ESR. A standard CRP below about 10 mg/L (1 mg/dL) is usually considered normal; high sensitivity CRP is a separate cardiovascular risk test with much lower cutoffs. Both ESR and CRP are nonspecific: their main value in a back pain patient is as a screen that, when normal, makes infection and many cancers less likely, and when high, demands an explanation.

Autoantibodies and HLA B27

The rule for autoantibodies is that they are ordered to confirm a disease the clinical picture already suggests, not to screen people with nonspecific aches. An ANA ordered for fatigue and diffuse pain without objective findings will be positive in a meaningful number of healthy people and usually leads to more testing and anxiety rather than a diagnosis. Seronegative spondyloarthropathies (ankylosing spondylitis, psoriatic, reactive and enteropathic arthritis) are "seronegative" because RF and anti CCP are negative; HLA B27 and imaging are the relevant tests.

Uric acid

Urate saturates body fluids at about 6.8 mg/dL. Hyperuricemia is far more common than gout and is not treated by itself in an asymptomatic patient. During an acute gout flare the serum urate can be normal (urate shifts into crystals and inflammatory cytokines increase excretion), so a normal level does not exclude gout; the diagnostic test is crystals in joint fluid. Causes of high urate include underexcretion (kidney disease, thiazide and loop diuretics, low dose aspirin, alcohol, especially beer), overproduction (myeloproliferative disease, tumor lysis, psoriasis) and diet (purine rich meat and seafood, fructose sweetened drinks).

Calcium, phosphorus, alkaline phosphatase and the bone pattern

Serum calcium (about 8.5 to 10.5 mg/dL) should be interpreted with albumin, because about 40 percent is protein bound: corrected calcium = measured calcium + 0.8 x (4.0 minus albumin). Hypercalcemia in outpatients is usually primary hyperparathyroidism (high or inappropriately normal PTH); in sick or hospitalized patients it is usually malignancy (PTH suppressed: PTH related peptide from squamous cancers, lytic bone metastasis, myeloma). Symptoms follow "stones, bones, abdominal groans and psychic moans": kidney stones, bone pain, constipation and abdominal pain, fatigue, confusion and depression, plus polyuria.

Alkaline phosphatase (about 40 to 130 U/L in adults) comes mainly from liver and bone. A raised ALP with a raised GGT points to the liver (cholestasis); a raised ALP with a normal GGT points to bone, where it reflects osteoblast activity: growth in adolescents, healing fracture, Paget disease (often very high), osteoblastic metastasis (prostate, breast), osteomalacia and hyperparathyroidism. A bone specific ALP or ALP isoenzymes can confirm the source. ALP is typically normal in multiple myeloma, because myeloma suppresses osteoblasts.

PSA, glucose, kidney and liver tests

• PSA: a prostate specific (not cancer specific) protein. A level above about 4 ng/mL has traditionally prompted evaluation, with age adjusted ranges also in use. It rises with prostate cancer, benign prostatic hyperplasia, prostatitis, urinary retention, recent ejaculation and instrumentation. Screening men 55 to 69 is an individual decision after shared discussion. In a man with back pain and an osteoblastic lesion or a raised ALP, PSA is a targeted diagnostic test, not screening.
• Glucose: diabetes is diagnosed by fasting plasma glucose 126 mg/dL or higher, HbA1c 6.5 percent or higher, a 2 hour oral glucose tolerance value of 200 mg/dL or higher, or a random glucose of 200 mg/dL or higher with classic symptoms. Prediabetes is a fasting glucose of 100 to 125 mg/dL or HbA1c of 5.7 to 6.4 percent. Diabetes matters musculoskeletally because of adhesive capsulitis, peripheral neuropathy, Charcot joints, diffuse idiopathic skeletal hyperostosis and infection risk.
• Kidney panel: BUN (about 7 to 20 mg/dL) and creatinine (about 0.6 to 1.2 mg/dL), with eGFR calculated from creatinine, age and sex. A BUN to creatinine ratio above 20 suggests prerenal azotemia (dehydration, heart failure, GI bleeding). Chronic NSAID use, dehydration and diuretics can all injure the kidney; an eGFR below about 30 changes the choice of anti inflammatory drug and contrast agent.
• Liver panel: ALT is more liver specific than AST; AST to ALT ratio above 2 suggests alcoholic liver disease; very high aminotransferases (in the thousands) suggest acute viral, toxic (acetaminophen) or ischemic hepatitis. A cholestatic pattern raises ALP, GGT and conjugated bilirubin. Low albumin and a prolonged PT indicate reduced synthetic function.
• Creatine kinase: raised in muscle injury, inflammatory myopathy (polymyositis, dermatomyositis), statin myopathy, hypothyroidism and rhabdomyolysis (very high CK with dark urine that is dipstick positive for blood but shows few red cells).
• TSH: the first test for thyroid function; hypothyroidism causes myalgia, carpal tunnel syndrome, fatigue and raised CK.

Section 3Stool analysis and joint fluid analysis

Occult blood and colorectal cancer screening

Stool tests appear on Part III mainly through colorectal cancer screening, iron deficiency anemia and inflammatory bowel disease that travels with spondyloarthritis. Average risk adults are screened from age 45 to 75. Options include colonoscopy every 10 years, an annual fecal immunochemical test (FIT), a multitarget stool DNA test with FIT every 1 to 3 years, or CT colonography or flexible sigmoidoscopy every 5 years. Any positive stool test requires a follow up colonoscopy; repeating the stool test is not acceptable.

Two connections with the musculoskeletal system deserve emphasis. First, reactive arthritis follows enteric infection with Salmonella, Shigella, Campylobacter or Yersinia (and genitourinary Chlamydia) by 1 to 4 weeks, often in HLA B27 positive people, with asymmetric lower limb arthritis, enthesitis, conjunctivitis and urethritis. Second, about 1 in 5 patients with Crohn disease or ulcerative colitis has an enteropathic arthritis: peripheral arthritis that tracks bowel activity, or sacroiliitis and spondylitis that run independently of it.

Synovial fluid analysis

Aspiration of an effusion (arthrocentesis) is the single most informative test for an acutely swollen joint, and for an acute monoarthritis it is mandatory, because septic arthritis destroys cartilage within days and has a meaningful mortality. Fluid is sent for cell count and differential, crystal examination under compensated polarized light, Gram stain and culture. Glucose, protein and LDH add little. Normal synovial fluid is clear, pale yellow, viscous (forms a long "string") and contains fewer than about 200 white cells per µL.

Crystal examination uses a red compensator. Monosodium urate crystals in gout are needle shaped and strongly negatively birefringent (yellow when aligned parallel to the slow axis of the compensator, blue when perpendicular). Calcium pyrophosphate crystals in pseudogout (CPPD disease) are rhomboid or rod shaped and weakly positively birefringent (blue when parallel). Calcium hydroxyapatite crystals are too small to see without special stains. Crystals and infection can coexist, so a fluid with crystals and a very high count is still cultured and the patient may need antibiotics until results return.

Gram stain is positive in only about half of septic joints, so a negative stain never excludes infection; culture of synovial fluid is positive in most nongonococcal cases. In gonococcal arthritis synovial cultures are often negative; the diagnosis is made by nucleic acid testing of urethral, cervical, rectal and pharyngeal specimens and blood cultures, in a young adult with migratory polyarthralgia, tenosynovitis and pustular skin lesions.

Section 4Electrophysiologic recordings

ECG basics

The electrocardiogram records the summed electrical activity of the heart from 12 viewpoints (six limb leads in the frontal plane and six precordial leads in the horizontal plane). Standard paper runs at 25 mm per second, so one small (1 mm) box is 0.04 s and one large (5 mm) box is 0.20 s; vertically, 10 mm equals 1 mV. For a regular rhythm, heart rate is 300 divided by the number of large boxes between consecutive R waves (1 box 300, 2 boxes 150, 3 boxes 100, 4 boxes 75, 5 boxes 60, 6 boxes 50). For an irregular rhythm, count the QRS complexes in a 10 second strip and multiply by 6.

The P wave is atrial depolarization; the PR interval (start of P to start of QRS, normally 0.12 to 0.20 s) is mostly delay in the AV node; the QRS complex is ventricular depolarization (normally under 0.12 s, usually under 0.10); the ST segment should be at the baseline and represents the plateau of ventricular action potentials; the T wave is ventricular repolarization; the QT interval, corrected for rate (QTc), is normally under about 0.44 s in men and 0.46 s in women. A systematic read covers rate, rhythm, axis, intervals, P wave and QRS morphology, ST segments and T waves.

Dangerous patterns

EEG

The electroencephalogram records cortical electrical activity from scalp electrodes. Its main indications are suspected seizures and epilepsy classification (interictal spikes and sharp waves; generalized 3 Hz spike and wave in childhood absence epilepsy), unexplained altered consciousness or encephalopathy (diffuse slowing, triphasic waves in hepatic encephalopathy), suspected nonconvulsive status epilepticus, sleep disorders (as part of polysomnography) and confirmation of brain death in some protocols. A normal interictal EEG does not exclude epilepsy, since a single routine study captures abnormalities in only about half of people with the disorder; sleep deprivation and repeated or prolonged recordings raise the yield. EEG has no role in the routine evaluation of headache, dizziness without loss of consciousness, or syncope that is clearly vasovagal.

Nerve conduction studies and needle EMG

Electrodiagnosis is an extension of the neurological examination. Nerve conduction studies stimulate a nerve and record either a sensory nerve action potential (SNAP) or a compound muscle action potential (CMAP), measuring latency, amplitude and conduction velocity. Normal velocities are roughly 50 m/s or faster in the arms and 40 m/s or faster in the legs. Demyelination slows conduction, prolongs distal latencies and F waves and can produce conduction block, while amplitudes are relatively preserved. Axonal loss reduces amplitude with near normal velocity. Needle EMG samples muscle at rest and during contraction: fibrillation potentials and positive sharp waves at rest indicate denervation (or active myopathy); large, long duration, polyphasic motor units with reduced recruitment indicate chronic denervation with reinnervation; small, short, polyphasic units with early recruitment indicate myopathy.

The location of the lesion relative to the dorsal root ganglion is the key to radiculopathy. The sensory cell body sits in the DRG within or just outside the foramen. A root lesion (disc, foraminal stenosis) is proximal to the DRG, so the sensory axon remains connected to its cell body and the SNAP is normal even when the patient has numbness. Plexus and peripheral nerve lesions are distal to the DRG and reduce the SNAP. Timing matters too: fibrillations appear in paraspinal muscles after about 1 to 2 weeks and in limb muscles after about 3 to 6 weeks, so EMG done in the first 2 to 3 weeks after onset can be falsely normal. The ideal time to study a suspected radiculopathy is about 3 weeks or later.

Section 5Ordering and interpreting tests wisely

Start with the question and the pretest probability

Every test should answer a specific question, and its result should be able to change what you do. The value of a result depends as much on the pretest probability (how likely the disease was before testing, from prevalence, history and examination) as on the test itself. A positive result for a rare disease in a low risk patient is more often a false positive than a true one; a negative result in a high risk patient may not lower the probability enough to stop.

Sensitivity, specificity and predictive values

• Sensitivity = true positives divided by all who have the disease: how often the test is positive in disease. A highly sensitive test, when negative, rules the disease out (SnNout).
• Specificity = true negatives divided by all who do not have the disease: how often the test is negative in health. A highly specific test, when positive, rules the disease in (SpPin).
• Positive predictive value = true positives divided by all positives: the chance a positive result is right. Negative predictive value = true negatives divided by all negatives. Predictive values change with prevalence: as prevalence falls, PPV falls and NPV rises, even though sensitivity and specificity stay the same.
• Likelihood ratios combine sensitivity and specificity and do not depend on prevalence. LR+ = sensitivity divided by (1 minus specificity); LR minus = (1 minus sensitivity) divided by specificity. Multiply the pretest odds by the LR to get the posttest odds.

Applied examples from earlier chapters: the straight leg raise is sensitive (about 90 percent) but not specific for lumbar disc herniation, so a negative SLR helps rule it out while a positive SLR proves little; the crossed SLR is specific (about 90 percent) but insensitive, so a positive crossed SLR strongly supports herniation. An ESR of 20 mm/h or more has moderate sensitivity for cancer as a cause of back pain, but because cancer causes well under 1 percent of back pain in primary care, a raised ESR alone produces many false positives; it is most useful combined with clinical red flags.

Serial and parallel testing

Testing in series (a sensitive screening test first, then a specific confirmatory test only in those who screen positive) maximizes specificity and limits cost: ANA then anti dsDNA; FIT then colonoscopy; ESR and radiographs then MRI. Testing in parallel (several tests at once, any positive counts) maximizes sensitivity and speed and suits urgent situations such as the hot joint (cell count, crystals, Gram stain and culture together) or suspected spinal infection (CBC, ESR, CRP and blood cultures together).

Which test answers which question

Cost and harm

Tests are not free of harm. False positives lead to further tests, procedures and anxiety (a cascade); incidental findings ("incidentalomas") lead to follow up imaging and sometimes to surgery that offers no benefit; labeling a patient with a disease marker they do not need to know about can change how they behave; radiation and contrast carry their own risks; and money spent on low value testing is unavailable for useful care. Normal ranges are set to include 95 percent of healthy people, so in a panel of 20 independent tests, a healthy person has roughly a 64 percent chance of at least one "abnormal" result. Order the test that answers the question, interpret it in light of the pretest probability, and act on the result.

Words worth knowing