InternalMed_Harrison

InternalMed_Harrison. Heat cramps that are not accompanied by significant dehydration can be treated with commercially available electrolyte solutions. Although the flavored electrolyte solutions are far more palatable, two 650-mg salt tablets dissolved in 1 quart of water produces a 0.1% saline solution. Individuals should avoid the ingestion of undissolved salt tablets, which are a gastric irritant and may induce vomiting.


InternalMed_Harrison

InternalMed_Harrison. The physiologic hallmarks of heat exhaustion—in contrast to heatstroke—are the maintenance of thermoregulatory control and CNS function. The core temperature is usually elevated but is generally <40.5°C (<105°F). The two physiologic precipitants are water depletion and sodium depletion, which often occur in combination. Laborers, athletes, and elderly individuals exerting themselves in hot environments, without adequate fluid intake, tend to develop water-depletion heat exhaustion. Persons working in the heat frequently consume only two-thirds of their net water loss and are voluntarily dehydrated. In contrast, salt-depletion heat exhaustion occurs more slowly in unacclimated persons who have been consuming large quantities of hypotonic solutions.


InternalMed_Harrison

InternalMed_Harrison. Heat exhaustion is usually a diagnosis of exclusion because of the multitude of nonspecific symptoms. If any signs of heatstroke are present, rapid cooling and crystalloid resuscitation should be initiated immediately during stabilization and evaluation. Mild neurologic and gastrointestinal influenza-like symptoms are common. These symptoms may include headache, vertigo, ataxia, impaired judgment, malaise, dizziness, nausea, and muscle cramps. Orthostatic hypotension and sinus tachycardia develop frequently. More significant CNS impairment suggests heatstroke or other infectious, neurologic, or toxicologic diagnoses.


InternalMed_Harrison

InternalMed_Harrison. Hemoconcentration does not always develop, and rapid infusion of isotonic IV fluids should be guided by frequent electrolyte determinations and perfusion requirements. Most cases of heat exhaustion reflect mixed sodium and water depletion. Sodium-depletion heat exhaustion is characterized by hyponatremia and hypochloremia. Hepatic aminotransferases are mildly elevated in both types of heat exhaustion. Urinary sodium and chloride concentrations are usually low. Some patients with heat exhaustion develop heatstroke after removal from the heat-stress environment. Aggressive cooling of non-responders is indicated until their core temperature is 39°C (102.2°F). Except in mild cases, free water deficits should be replaced slowly over 24–48 h to avoid a decrease of serum osmolality by >2 mOsm/h.


InternalMed_Harrison

InternalMed_Harrison. The disposition of younger, previously healthy heat-exhaustion patients who have no major laboratory abnormalities may include hospital observation and discharge after IV rehydration. Older patients with comorbidities (including cardiovascular disease) or predisposing factors often require inpatient fluid and electrolyte replacement, monitoring, and reassessment. The clinical manifestations of heatstroke reflect a total loss of thermo-regulatory function. Typical vital-sign abnormalities include tachypnea, various tachycardias, hypotension, and a widened pulse pressure. Although there is no single specific diagnostic test, the historical and physical triad of exposure to a heat stress, CNS dysfunction, and a core temperature >40.5°C helps establish the preliminary diagnosis.


InternalMed_Harrison

InternalMed_Harrison. The definitive diagnosis should be reserved until the other potential causes of hyperthermia are excluded. Many of the usual laboratory abnormalities seen with heatstroke overlap with other conditions. If the patient's mental status does not improve with cooling, toxicologic screening may be indicated, and cranial CT and spinal fluid analysis can be considered.


InternalMed_Harrison

InternalMed_Harrison. The premonitory clinical characteristics may be nonspecific and include weakness, dizziness, disorientation, ataxia, and gastrointestinal or psychiatric symptoms. These prodromal symptoms often resemble heat exhaustion. The sudden onset of heatstroke occurs when the maintenance of adequate perfusion requires peripheral vasoconstriction to stabilize the mean arterial blood pressure. As a result, the cutaneous radiation of heat ceases. At this juncture, the core temperature rises dramatically. Since many patients with heatstroke also meet the criteria for systemic inflammatory response syndrome and have a broad differential diagnosis, rapid cooling is essential during the extensive diagnostic evaluation (Table 479e-1).


InternalMed_Harrison

InternalMed_Harrison. There are two forms of heatstroke with significantly different manifestations (Table 479e-2). Classic (epidemic) heatstroke (CHS) usually occurs during long periods of high ambient temperature and humidity, as during summer heat waves. Patients with CHS commonly have chronic diseases that predispose to heat-related illness, and they may have limited access to oral fluids. Heat dissipation mechanisms are overwhelmed by both endogenous heat production and exogenous heat stress. Patients with CHS are often compliant with prescribed medications that can impair tolerance to a heat stress. In many of these dehydrated CHS patients, sweating has ceased and the skin is hot and dry. If cooling is delayed, severe hepatic dysfunction, renal failure, disseminated intravascular coagulation, and fulminant multisystem organ failure may occur. Hepatocytes are very heat sensitive. On presentation, the serum level of aspartate aminotransferase (AST) is routinely elevated. Eventually, levels of both AST


InternalMed_Harrison

InternalMed_Harrison. multisystem organ failure may occur. Hepatocytes are very heat sensitive. On presentation, the serum level of aspartate aminotransferase (AST) is routinely elevated. Eventually, levels of both AST and alanine aminotransferase (ALT) often increase to >100 times the normal values. Coagulation studies commonly demonstrate decreased platelets, fibrinogen, and prothrombin. Most patients with CHS require cautious crystalloid resuscitation, electrolyte monitoring, and—in certain refractory cases—consideration of central venous pressure (CVP) measurements. Hypernatremia is secondary to dehydration in CHS. Many patients exhibit significant stress leukocytosis, even in the absence of infection.


InternalMed_Harrison

InternalMed_Harrison. Patients with exertional heatstroke (EHS), in contrast to those with CHS, are often young and previously healthy, and their diagnosis is usually more obvious from the history. Athletes, laborers, and military recruits are common victims. Unlike those with CHS, many EHS patients present profusely diaphoretic despite significant dehydration. As a result of muscular exertion, rhabdomyolysis and acute renal failure are more common in EHS. Studies to detect rhabdomyolysis and its complications, including hypocalcemia and hyperphosphatemia, should be considered. Hyponatremia, hypoglycemia, and coagulopathies are frequent findings. Elevated creatine kinase and lactate dehydrogenase 479e-3 levels also suggest EHS. Oliguria is a common finding. Renal failure can result from direct thermal injury, untreated rhabdomyolysis, or volume depletion. Common urinalysis findings include microscopic hematuria, myoglobinuria, and granular or red cell casts.


InternalMed_Harrison

InternalMed_Harrison. With both CHS and EHS, heat-related reversible increases in cardiac biomarker levels are often present. Heatstroke often causes thermal cardiomyopathy. As a result, the CVP may be elevated despite significant dehydration. In addition, the patient often presents with potentially deceptive noncardiogenic pulmonary edema and basilar rales despite being significantly hypovolemic. The electrocardiogram commonly displays a variety of tachyarrhythmias, nonspecific ST-T wave changes, and heat-related ischemia or infarction. Rapid cooling—not the administration of antiarrhythmic medications—is essential.


InternalMed_Harrison

InternalMed_Harrison. Above 42°C (107.6° F), heat can rapidly produce direct cellular injury. Thermosensitive enzymes become nonfunctional, and eventually there is irreversible uncoupling of oxidative phosphorylation. The production of heat-shock proteins increases, and cytokines mediate a systemic inflammatory response. The vascular endothelium is also damaged, and this injury activates the coagulation cascade. Significant shunting away from the splanchnic circulation produces gastrointestinal ischemia. Endotoxins further impair normal thermoregulation. As a result, if cooling is delayed, severe hepatic dysfunction, permanent renal failure, disseminated intravascular coagulation, and fulminant multisystem organ failure may occur.


InternalMed_Harrison

InternalMed_Harrison. Before cooling is initiated, endotracheal intubation, CVP determination, and continuous core-temperature monitoring should be considered. Hypoglycemia is a frequent finding and can be addressed by glucose infusion. Since peripheral vasoconstriction delays heat dissipation, repeated administration of discrete boluses of isotonic crystalloid for hypotension is preferable to the administration of α-adrenergic agonists.


InternalMed_Harrison

InternalMed_Harrison. Evaporative cooling is usually the most practical and effective technique. Rapid cooling is essential in both CHS and EHS, and an immediate improvement in vital signs and mental status may prove valuable for diagnostic purposes. Cool water (15°C [60° F]) is sprayed on the exposed skin while fans direct continuous airflow over the moistened skin. Cold packs applied to the axillae and groin are a useful cooling adjunct. If cardiac electrodes will not adhere, they can be applied to the patient's back. To avoid “overshoot hypothermia,” active cooling should be terminated at ~38°–39°C (100.4°–102.2°F). Immersion cooling in cold water is an alternative option in EHS but induces peripheral vasoconstriction and intense shivering. This technique presents significant monitoring and resuscitation challenges in most clinical settings. The safety of immersion cooling is best established for young, previously healthy patients with EHS (but not for those with CHS).


InternalMed_Harrison

InternalMed_Harrison. Cooling with commercially available cooling blankets should not be the sole technique used, since the rate of cooling is far too slow. Other methods are less efficacious and rarely indicated, such as IV infusion of cold fluids and cold irrigation of the bladder or gastrointestinal tract. Cold thoracic and peritoneal lavage are efficient maneuvers but are invasive and rarely necessary. Cardiopulmonary bypass provides fast and effective cooling but is labor intensive and is rarely available on a stat basis. Aspiration and seizures commonly occur in heatstroke, and endotracheal intubation is usually necessary. The metabolic demands are high, and supplemental oxygenation is essential due to hypoxemia induced by thermal stress and pulmonary dysfunction. Pneumonitis, pulmonary infarction, hemorrhage, edema, and acute respiratory distress syndrome occur frequently in heatstroke patients.


InternalMed_Harrison

InternalMed_Harrison. The circulatory fluid requirements, particularly in CHS, may be deceptively modest. Aggressive cooling and modest volume repletion usually elevate the CVP to 12–14 mmHg. The reading, however, may be deceptive. Many patients present with a thermally induced hyperdynamic circulation accompanied by a high cardiac index, low peripheral vascular resistance, and an elevated CVP caused by right-sided heart failure. Rarely, wedge pressures measured via a pulmonary artery catheter may be necessary to guide resuscitation. In contrast, most patients with EHS require far more zealous isotonic crystalloid resuscitation.


InternalMed_Harrison

InternalMed_Harrison. The hypotension that is initially common among patients with heatstroke results from both dehydration and high-output cardiac failure caused by peripheral vasodilation. Inotropes causing α-adrenergic stimulation (e.g., norepinephrine) can impede cooling by causing significant vasoconstriction. Vasoactive catecholamines such as dopamine or dobutamine may be necessary if the cardiac output remains depressed despite an elevated CVP, particularly in patients with a hyperdynamic circulation. A wide variety of tachyarrhythmias are routinely observed on presentation and usually resolve during cooling. The administration of atrial or ventricular antiarrhythmic medications is rarely indicated during cooling. Anticholinergic medications (including atropine) that inhibit sweating should not be given, and electrical cardioversion of the hyperthermic myocardium should be avoided except when there is ventricular fibrillation.


InternalMed_Harrison

InternalMed_Harrison. Significant shivering, discomfort, or extreme agitation is preferably mitigated with short-acting benzodiazepines, which are ideal due to their renal clearance. On the other hand, chlorpromazine may lower the seizure threshold, has anticholinergic properties, and can exacerbate the hypotension or cause neuroleptic malignant syndrome. Because of likely hepatic dysfunction, barbiturates should be avoided and seizures should be treated with benzodiazepines. Coagulopathies more commonly occur after the first day of illness. After cooling, the patient should be monitored for laboratory signs of disseminated intravascular coagulation, and replacement therapy with fresh-frozen plasma and platelets should be considered.


InternalMed_Harrison

InternalMed_Harrison. There is no therapeutic role for antipyretics in the control of environmentally induced hyperthermia; these drugs block the actions of pyrogens at hypothalamic receptor sites. Salicylates can further uncouple oxidative phosphorylation in heatstroke and exacerbate coagulopathies. Acetaminophen may further stress hepatic function. The safety and efficacy of other medications, including dantrolene and aminocaproic acid, are not established. Most patients with minor heat-emergency syndromes (including heat edema, heat syncope, and heat cramps) require only stabilization and treatment with outpatient follow-up. Although there are no decision rules to guide disposition choices in heat exhaustion, many of these patients have multiple predisposing factors and comorbidities that will require prolonged observation or hospital admission.


InternalMed_Harrison

InternalMed_Harrison. Essentially all patients with actual heatstroke require admission to a monitored setting, and most require intensive care. Many of these patients also require prolonged tracheal intubation, invasive hemodynamic monitoring, and support for various degrees of multiorgan dysfunction syndrome. The prognosis worsens if the initial core temperature exceeds 42°C (107.6°F) or if there was a prolonged period during which the core temperature exceeded this level. Other features of a negative prognosis include acute renal failure, massively elevated liver enzymes, and significant hyperkalemia. As expected, the number of dysfunctional organ systems also correlates directly with mortality risk.


InternalMed_Harrison

InternalMed_Harrison. 2754 appeNDIX: Laboratory Values of Clinical Importance Alexander Kratz, Michael A. Pesce, Robert C. Basner, Andrew J. Einstein This Appendix contains tables of reference values for common labo-ratory tests. A variety of factors can influence reference values. Such variables include the population studied, the duration and means of specimen transport, laboratory methods and instrumentation, and even the type of container used for the collection of the specimen. The reference or “normal” ranges given in this appendix may therefore not be appropriate for all laboratories, and these values should only be used as general guidelines. Whenever possible, reference values provided by the laboratory performing the testing should be used in the interpretation of laboratory data. Values supplied in this Appendix reflect typical reference ranges in nonpregnant adults. Pediatric reference ranges and values in pregnant patients may vary significantly from the data presented in the Appendix.


InternalMed_Harrison

InternalMed_Harrison. In preparing the Appendix, the authors have taken into account the fact that the system of international units (SI, système international d’unités) is used in most countries and in some medical journals. However, clinical laboratories may continue to report values in “traditional” or conventional units. Therefore, both systems are provided in the Appendix. The dual system is also used in the text except for those instances in which the numbers remain the same and only the terminology is changed (mmol/L for meq/L or IU/L for mIU/mL), when only the SI units are given. Laboratory Values of Clinical Importance Laboratory Values of Clinical Importance


InternalMed_Harrison

InternalMed_Harrison. B-type natriuretic peptide (BNP) P Age and gender specific: <100 ng/L Age and gender specific: <100 pg/mL Bence Jones protein, serum qualitative S Not applicable None detected Bence Jones protein, serum quantitative S 3.3–19.4 mg/L 0.33–1.94 mg/dL Free lambda 5.7–26.3 mg/L 0.57–2.63 mg/dL K/L ratio 0.26–1.65 0.26–1.65 Beta-2-microglobulin S 1.1–2.4 mg/L 1.1–2.4 mg/L Bile acids S 0–1.9 μmol/L 0–1.9 μmol/L Chenodeoxycholic acid 0–3.4 μmol/L 0–3.4 μmol/L Deoxycholic acid 0–2.5 μmol/L 0–2.5 μmol/L Ursodeoxycholic acid 0–1.0 μmol/L 0–1.0 μmol/L Total 0–7.0 μmol/L 0–7.0 μmol/L Bilirubin S Total 5.1–22 μmol/L 0.3–1.3 mg/dL Direct 1.7–6.8 μmol/L 0.1–0.4 mg/dL Indirect 3.4–15.2 μmol/L 0.2–0.9 mg/dL C peptide S 0.27–1.19 nmol/L 0.8–3.5 ng/mL C1-esterase-inhibitor protein S 210–390 mg/L 21–39 mg/dL CA 125 S <35 kU/L <35 U/mL CA 19-9 S <37 kU/L <37 U/mL CA 15-3 S <33 kU/L <33 U/mL CA 27-29 S 0–40 kU/L 0–40 U/mL Calcitonin S 0–7.5 ng/L 0–7.5 pg/mL Female 0–5.1 ng/L 0–5.1 pg/mL Calcium S 2.2–2.6


InternalMed_Harrison

InternalMed_Harrison. CA 125 S <35 kU/L <35 U/mL CA 19-9 S <37 kU/L <37 U/mL CA 15-3 S <33 kU/L <33 U/mL CA 27-29 S 0–40 kU/L 0–40 U/mL Calcitonin S 0–7.5 ng/L 0–7.5 pg/mL Female 0–5.1 ng/L 0–5.1 pg/mL Calcium S 2.2–2.6 mmol/L 8.7–10.2 mg/dL Calcium, ionized WB 1.12–1.32 mmol/L 4.5–5.3 mg/dL Carbon dioxide content (TCO2) P (sea level) 22–30 mmol/L 22–30 meq/L Carboxyhemoglobin (carbon monoxide content) WB 0.0–0.025 0–2.5% of total hemoglobin (Hgb) value Smokers 0.04–0.09 4–9% of total Hgb value Loss of consciousness and death >0.50 >50% of total Hgb value Carcinoembryonic antigen (CEA) S Nonsmokers 0.0–3.0 μg/L 0.0–3.0 ng/mL Smokers 0.0–5.0 μg/L 0.0–5.0 ng/mL Ceruloplasmin S 250–630 mg/L 25–63 mg/dL Chloride S 102–109 mmol/L 102–109 meq/L


InternalMed_Harrison

InternalMed_Harrison. Cholesterol (LCL, Total, HDL): Ranges depend on individual patient factors; see 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol Cholinesterase S 5–12 kU/L 5–12 U/mL Chromogranin A S 0–95 μg/L 0–95 ng/mL Complement S 0.83–1.77 g/L 83–177 mg/dL C4 0.16–0.47 g/L 16–47 mg/dL Complement total Cortisol Fasting, 8 A.M.–12 noon S 138–690 nmol/L 5–25 μg/dL 12 noon–8 P.M. 138–414 nmol/L 5–15 μg/dL 8 P.M.–8 A.M. 0–276 nmol/L 0–10 μg/dL C-reactive protein S <10 mg/L <10 mg/L C-reactive protein, high sensitivity S Cardiac risk Cardiac risk Low: <1.0 mg/L Low: <1.0 mg/L Average: 1.0–3.0 mg/L Average: 1.0–3.0 mg/L High: >3.0 mg/L High: >3.0 mg/L Laboratory Values of Clinical Importance Laboratory Values of Clinical Importance Laboratory Values of Clinical Importance Laboratory Values of Clinical Importance


InternalMed_Harrison

InternalMed_Harrison. Aluminum S <0.2 μmol/L <5.41 μg/L Arsenic WB 0.0–0.17 μmol/L 0–13 μg/L Cadmium WB <44.5 nmol/L <5.0 μg/L Coenzyme Q10 (ubiquinone) P 433–1532 μg/L 433–1532 μg/L β-Carotene S 0.07–1.43 μmol/L 4–77 μg/dL Copper S 11–22 μmol/L 70–140 μg/dL Folic acid RC 340–1020 nmol/L cells 150–450 ng/mL cells Folic acid S 12.2–40.8 nmol/L 5.4–18.0 ng/mL Lead S <0.5 μmol/L <10 μg/dL Children <0.25 μmol/L <5 μg/dL Mercury WB 0–50 μmol/L 0–10 μg/L Selenium S 0.8–2.0 μmol/L 63–160 μg/L Vitamin A S 0.7–3.5 μmol/L 20–100 μg/dL Vitamin B1 (thiamine) S 0–75 nmol/L 0–2 μg/dL Vitamin B2 (riboflavin) S 106–638 nmol/L 4–24 μg/dL Vitamin B6 P 20–121 nmol/L 5–30 ng/mL Vitamin B12 S 206–735 pmol/L 279–996 pg/mL Vitamin C (ascorbic acid) S 23–57 μmol/L 0.4–1.0 mg/dL Vitamin D 1,25-dihydroxy, total S, P 36–180 pmol/L 15–75 pg/mL Vitamin D 25-hydroxy, total P 75–250 nmol/L 30–100 ng/mL Vitamin E S 12–42 μmol/L 5–18 μg/mL Vitamin K S 0.29–2.64 nmol/L 0.13–1.19 ng/mL Zinc S 11.5–18.4 μmol/L 75–120 μg/dL


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: P, plasma; RC, red cells; S, serum; WB, whole blood. Electrolytes Sodium 137–145 mmol/L 137–145 meq/L Potassium 2.7–3.9 mmol/L 2.7–3.9 meq/L Calcium 1.0–1.5 mmol/L 2.1–3.0 meq/L Magnesium 1.0–1.2 mmol/L 2.0–2.5 meq/L Chloride 116–122 mmol/L 116–122 meq/L CO2 content 20–24 mmol/L 20–24 meq/L PCO2 6–7 kPa 45–49 mmHg pH 7.31–7.34 Glucose 2.22–3.89 mmol/L 40–70 mg/dL Lactate 1–2 mmol/L 10–20 mg/dL Total protein: Lumbar 0.15–0.5 g/L 15–50 mg/dL Cisternal 0.15–0.25 g/L 15–25 mg/dL Ventricular 0.06–0.15 g/L 6–15 mg/dL Albumin 0.066–0.442 g/L 6.6–44.2 mg/dL IgG 0.009–0.057 g/L 0.9–5.7 mg/dL IgG indexb 0.29–0.59 Oligoclonal bands (OGB) <2 bands not present in matched serum sample


InternalMed_Harrison

InternalMed_Harrison. Ammonia 15–47 μmol/L 25–80 μg/dL Creatinine 44–168 μmol/L 0.5–1.9 mg/dL Myelin basic protein <4 μg/L Cerebrospinal fluid aSince cerebrospinal fluid (CSF) concentrations are equilibrium values, measurements of the same parameters in blood plasma obtained at the same time are recommended. However, there is a time lag in attainment of equilibrium, and cerebrospinal levels of plasma constituents that can fluctuate rapidly (such as plasma glucose) may not achieve stable values until after a significant lag phase. bIgG index = CSF IgG (mg/dL) × serum albumin (g/dL)/serum IgG (g/dL) × CSF albumin (mg/dL). Laboratory Values of Clinical Importance The contributions of Drs. Daniel J. Fink, Patrick M. Sluss, James L. Januzzi, Kent B. Lewandrowski, Amudha Palanisamy, and Scott Fink to this chapter in previous editions are gratefully acknowledged. We also express our gratitude to Drs. Alex Rai and Jeffrey Jhang for helpful suggestions.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Values of Clinical Importance the Clinical Laboratory in Modern health Care Anthony A. Killeen Modern medicine relies extensively on the clinical laboratory as a 480e key component of health care. It is estimated that, in current practice, at least 60–70% of all clinical decisions rely to some extent on a laboratory result. For many diseases, the clinical laboratory provides essential diagnostic information. As an example, histopathologic analysis provides basic information about histologic type and classification of tumors and their degree of invasion into adjacent tissues. Microbiologic testing is required to identify infectious organisms and determine antibiotic susceptibility. For many common diseases, expert groups have produced standard guidelines for diagnosis that rely on defined clinical laboratory values, e.g., blood glucose or hemoglobin A1C levels form the basis for diagnosis of diabetes mellitus; the presence of specific serum antibodies is required for


InternalMed_Harrison

InternalMed_Harrison. rely on defined clinical laboratory values, e.g., blood glucose or hemoglobin A1C levels form the basis for diagnosis of diabetes mellitus; the presence of specific serum antibodies is required for diagnosis of many rheumatologic diseases; and serum levels of cardiac markers are a mainstay in diagnosis of acute coronary syndromes.


InternalMed_Harrison

InternalMed_Harrison. With their ever-increasing number and scope, clinical laboratory tests provide the clinician with a powerful set of tools but pose challenges in terms of appropriate selection and judicious, cost-effective use to deliver effective patient care.


InternalMed_Harrison

InternalMed_Harrison. One of the most frequent reasons for performing clinical laboratory tests is to support, confirm, or refute a diagnosis of disease that is suspected on the basis of other information sources, such as history, physical examination findings, and imaging studies. The following questions need to be considered: Which clinical laboratory tests may be of value in supporting, confirming, or excluding the clinical impression? What is the most efficient test-ordering strategy? Will a positive test result confirm the clinical impression or even definitively establish the diagnosis? Will a negative result disprove the clinical suspicion, and, if so, what further testing or alternative approach will be needed? What are the known sources of false-positive and false-negative results, and how are these misleading results recognized?


InternalMed_Harrison

InternalMed_Harrison. Another reason for ordering clinical laboratory tests is to screen for disease in asymptomatic individuals (Chap. 4). Perhaps the most common examples of this application are the newborn screening programs now routinely used in most developed countries. Their purpose is to identify newborns with treatable conditions for which early intervention—even before clinical symptoms develop—is known to be beneficial. In adults, screening tests for diabetes mellitus, renal disease, prostate cancer (measurement of serum prostate-specific antigen [PSA] levels), and colorectal cancer (testing for occult blood in stool), for example, are widely applied to apparently healthy individuals on the grounds that early diagnosis and intervention lead to improved long-term outcomes.


InternalMed_Harrison

InternalMed_Harrison. Differences between Screening Tests and Confirmatory Tests It is important to distinguish between clinical laboratory tests that can be used to screen for disease and those that offer a confirmatory result. Screening tests are generally less expensive and more widely available than are confirmatory tests, which often require more specialized equipment or personnel. As a general principle, screening tests are designed to identify all individuals who have the disease of interest, even if, in the process, some healthy individuals are misidentified as possibly having the disease. In other words, maximization of the diagnostic sensitivity of screening tests inevitably comes at the expense of reduced diagnostic specificity. Confirmatory testing is intended to correctly separate those individuals who have a disease from those who do not.


InternalMed_Harrison

InternalMed_Harrison. These principles are exemplified by screening for hepatitis C virus 480e-1 (HCV) infection. A common approach is to test first for the presence of antibodies to HCV in serum. A positive result generally indicates either a current infection or a previous infection that the patient’s immune system has successfully cleared. In the latter situation, antibodies may persist at detectable levels for life. However, a small proportion of patients have false-positive results in the serologic screening test for HCV. To resolve uncertainty in these instances, a positive serologic screening test should be followed by confirmatory identification of HCV RNA with molecular techniques. This confirmatory testing can provide evidence of current viral infection and can identify patients who are not infected.


InternalMed_Harrison

InternalMed_Harrison. Another reason for clinical laboratory testing is to assess a patient’s risk of developing disease in the future. A number of diseases are associated with well-established clinical laboratory–defined risk factors that, if present, indicate the need for more frequent monitoring for the disease in question. The need for risk assessment is even clearer if there are useful interventions that decrease the risk of developing disease. For example, hypercholesterolemia is a well-established risk factor for coronary artery disease that may be modified by pharmacologic intervention (Chap. 291e). Many genetic mutations are known to be associated with increased risk of cancer. For example, hereditary mutations in the BRCA1 and BRCA2 genes predispose to breast and/ or ovarian cancer. Individuals who are known to carry these mutations require more vigilant monitoring for early signs of cancer and may even opt for prophylactic surgery in an attempt to prevent cancer (Chap. 84). Individuals with


InternalMed_Harrison

InternalMed_Harrison. are known to carry these mutations require more vigilant monitoring for early signs of cancer and may even opt for prophylactic surgery in an attempt to prevent cancer (Chap. 84). Individuals with factor V Leiden are at increased risk of developing deep venous thrombosis and may benefit from prophylactic anticoagulation in the perioperative period.


InternalMed_Harrison

InternalMed_Harrison. Many clinical laboratory tests offer useful information on the progress of disease and the response to therapy. One example is the measurement of viral load in HIV-1-infected patients who are taking antiretroviral agents. According to current guidelines from the Centers for Disease Control and Prevention, a successful antiretroviral response is defined by a fall in plasma HIV-1 levels of 0.5 log10 copies/mL, and a key goal of treatment is a reduction in the viral load to below the level of detection, which is typically in the range of 40–75 copies/mL. Other examples of the use of clinical laboratory testing for monitoring disease include measurement of tumor markers such as PSA, especially following surgical removal of tumors. In this situation, the expectation is that successful treatment of a tumor will cause a decrease in the level of the tumor marker. A later increase in the level of the tumor marker suggests a recurrence of the disease. Finally, the clinical laboratory offers


InternalMed_Harrison

InternalMed_Harrison. of a tumor will cause a decrease in the level of the tumor marker. A later increase in the level of the tumor marker suggests a recurrence of the disease. Finally, the clinical laboratory offers direct monitoring of levels of some therapeutic agents, such as drugs. This monitoring is important if a drug has a defined therapeutic concentration range above which it is toxic and below which it is ineffective. Monitoring of drug levels in this situation facilitates optimal dosing and avoidance of toxicity.


InternalMed_Harrison

InternalMed_Harrison. It is common practice for clinical laboratories to establish a list of “critical values.” These are values of test results that indicate immediate risk to the health or life of the patient and therefore require urgent communication with the patient’s physician so that appropriate medical intervention may be initiated. Critical values are reported regardless of whether the test was ordered as a “stat” or a routine test. The critical values themselves are generally created by the clinical laboratory medical director in conjunction with the medical staff. A representative list of critical values is shown in Table 480e-1. Tests that are ordered on a “stat” basis receive priority in the clinical laboratory’s testing queue; testing of specimens from other patients may be delayed while a stat specimen is analyzed. Ordering a test stat Chapter 480e The Clinical Laboratory in Modern Health Care


InternalMed_Harrison

InternalMed_Harrison. Chapter 480e The Clinical Laboratory in Modern Health Care Malarial smear aAny positive result is critical. Abbreviations: CO2, carbon dioxide; CSF, cerebrospinal fluid; INR, international normalized ratio; PCO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen; PTT, partial thromboplastin time; WBCs, white blood cells. should be reserved for situations in which a result is needed for urgent medical care—a judgment that must be made by the ordering physician. Stat testing should not be used merely for the convenience of either the patient or the health care provider.


InternalMed_Harrison

InternalMed_Harrison. The commonly used metrics of a clinical laboratory test are the diagnostic sensitivity, specificity, and positive and negative predictive values. These concepts are discussed in Chap. 3. In the clinical laboratory, the terms sensitivity and specificity have alternative meanings that are applied to tests, and the different uses of these terms may cause confusion. Analytic sensitivity can refer to the lowest detectable concentration of analyte that can be measured with some defined certainty or to the rate of change of signal intensity as analyte concentration changes. For example, newer generations of laboratory assays frequently exhibit improved sensitivity over that of earlier generations, i.e., they can detect lower concentrations of the analyte—a feature that is often of value in disease diagnosis. Analytic specificity refers to the extent to which other substances in the test system interfere with measurement of the analyte of interest. This concept is frequently applied to


InternalMed_Harrison

InternalMed_Harrison. disease diagnosis. Analytic specificity refers to the extent to which other substances in the test system interfere with measurement of the analyte of interest. This concept is frequently applied to immunoassays, in which a detection antibody may also bind with compounds that have a structure similar to the substance sought. For instance, immunoassays for drugs may show cross-reactivity with drug metabolites, and immunoassays for glucocorticoids may show cross-reactivity with other glucocorticoids of similar structure. Certain chemical assays are also subject to nonspecificity. For example, the Jaffe reaction, a chemical method commonly used to measure creatinine, is subject to positive interference from a number of other compounds, including glucose, certain ketones, and cephalosporin antibiotics. Elevated concentrations of bilirubin, free hemoglobin, or turbidity in plasma or serum specimens may also interfere with some assays. The clinical laboratory should be able to provide


InternalMed_Harrison

InternalMed_Harrison. antibiotics. Elevated concentrations of bilirubin, free hemoglobin, or turbidity in plasma or serum specimens may also interfere with some assays. The clinical laboratory should be able to provide advice about the presence or magnitude of these effects in the assays it performs.


InternalMed_Harrison

InternalMed_Harrison. Clinical laboratory diagnosis, like all diagnosis, is based on observation of disease-related changes from normality. 1.


InternalMed_Harrison

InternalMed_Harrison. 1. Tissue injury or necrosis allows leakage of intracellular components into the circulation, with consequent detectable rises in blood levels of these components. Many intracellular molecules are common across tissue types and are therefore not indicative of injury to a specific tissue. Other constituents are selectively expressed in relatively high concentrations—or are even uniquely present—in certain tissues. Therefore, their presence in the blood is evidence of injury to that tissue. This principle forms the rationale for measurement of blood levels of, for example, liver enzymes in evaluating liver disease (Chap. 358), cardiac troponins in acute coronary syndromes (Chap. 295), and myoglobulin in muscle injury. The extent of the rise in blood levels of these markers generally correlates with the extent of tissue damage, although there are exceptions; for example, liver enzyme levels may fall in end-stage liver disease. 2.


InternalMed_Harrison

InternalMed_Harrison. 2. An increase in blood levels of some analytes indicates failure of normal excretory processes. This principle is illustrated by elevations in conjugated bilirubin that accompany obstruction of the biliary system, by elevations in ammonia in advanced or metabolic liver disease, by rises in creatinine and potassium levels in renal failure, and by increases in Pco2 in some pulmonary diseases. 3.


InternalMed_Harrison

InternalMed_Harrison. 3. Increases in the blood concentration of tissue-specific markers may result from expansion of the total volume of that tissue. This principle forms the basis for the measurement of levels of many tumor markers such as PSA (prostate cancer), CA-125 (ovarian cancer), CEA (colon cancer), and CA-19–9 (pancreatic cancer). In practice, the usefulness of these markers varies with the degree to which they are produced by a tumor and by the tumor’s size. Small colon cancers, for example, may not produce a significant rise in CEA levels, whereas small prostate cancers often produce detectable rises in PSA concentrations. 4.


InternalMed_Harrison

InternalMed_Harrison. 4. Disease processes often manifest characteristic patterns of coincident changes in levels of several analytes. These patterns of change can be understood by consideration of the underlying pathophysiology. For example, acute intravascular hemolysis is characterized by a fall in levels of hemoglobin and haptoglobin and by a rise in unconjugated bilirubin. In endocrine diseases, there are often changes in concentrations of several hormones because of disturbance of feedback loops. Primary hyperthyroidism, as an example, is characterized by increases in thyroxine and by suppression of thyroid-stimulating hormone. In diabetic ketoacidosis caused by insulin deficiency, there are concomitant elevations of plasma glucose, ketones, and (frequently) potassium. In response to metabolic acidosis, levels of bicarbonate are typically reduced. 5.


InternalMed_Harrison

InternalMed_Harrison. Genetic changes underlie many diseases, both inherited and acquired. In the era of molecular medicine, there is increasing recognition of the contribution of hereditary factors to many common diseases. Often, the epidemiology of common diseases such as hypertension is characterized by a minority of families that have mutations in recognized genes, whereas the genetic basis of the same disease phenotype in the larger population is unclear. The search for the genetic factors that contribute to many common diseases remains a topic of intense research interest. It is now clear that essentially all tumors have genetic abnormalities. Although there is an inherited predisposition in some families, most of these genetic changes are acquired. Identification of the genetic abnormalities in cancer offers new tools for clinical laboratory diagnosis and classification of tumors in ways that surpass traditional histopathology and also provides insights into cellular processes that may be targets


InternalMed_Harrison

InternalMed_Harrison. offers new tools for clinical laboratory diagnosis and classification of tumors in ways that surpass traditional histopathology and also provides insights into cellular processes that may be targets for treatment.


InternalMed_Harrison

InternalMed_Harrison. 6. Clinical laboratory results should always be interpreted in the context of the patient’s history and physical examination as well as any other relevant information (e.g., imaging studies). The clinician should avoid treating laboratory results rather than the patient. 7.


InternalMed_Harrison

InternalMed_Harrison. Recommended clinical laboratory tests change with time. As new markers of disease emerge, they may replace older markers. For example, measurement of serum creatine kinase (CK) levels was introduced for diagnosis of acute myocardial infarction in the 1980s. Use of the cardiac-specific isoenzyme CK-MB later became widespread in clinical practice. Today, cardiac troponins are replacing CK (or CK-MB) measurements in recommended guidelines. Many other assays have fallen out of use as better assays have become available. Measurement of urine 17-ketosteroids (arising from androgens) and of urine 17-hydroxycorticosteroids (arising from glucocorticoids) has been supplanted by immunoassays or mass spectroscopy determinations of specific steroid hormones. Today, many steroid hormones are measured by mass spectrometry, often with better analytic specificity than is provided by immunoassays. As new tests are introduced, it is essential that they be evaluated critically before adoption for


InternalMed_Harrison

InternalMed_Harrison. by mass spectrometry, often with better analytic specificity than is provided by immunoassays. As new tests are introduced, it is essential that they be evaluated critically before adoption for clinical use. At a minimum, consideration needs to be given to questions of clinical validation, specimen stability, diagnostic sensitivity and specificity, positive and negative predictive values, analytic accuracy and precision, and relative costs.


InternalMed_Harrison

InternalMed_Harrison. In the interpretation of clinical laboratory results, comparison is usually made to a reference range (sometimes called a normal range) that defines the values seen in health or considered to be desirable for health. Several common methods are used to describe reference ranges in the clinical laboratory.


InternalMed_Harrison

InternalMed_Harrison. 1. For many quantitative clinical laboratory tests, the range of observed values in a healthy population shows an approximately Gaussian distribution. The factors that contribute to this range include the interand intraindividual variation in the concentration of the analyte and the analytic imprecision. When there is an approximately Gaussian distribution of values in the population, the reference range is commonly defined as being the central 95% of the range of distribution of those values. According to this method, 2.5% of the population will have a measured value that is below the reference range for the analyte, and 2.5% will have a value that is above the reference range. The fact that 5% of healthy individuals will have a test value that is outside the reference range has important implications when multiple tests are ordered. If N independent tests are performed on a specimen, then the probability that at least one result will be outside the reference range is (1–0.95N). The


InternalMed_Harrison

InternalMed_Harrison. implications when multiple tests are ordered. If N independent tests are performed on a specimen, then the probability that at least one result will be outside the reference range is (1–0.95N). The greater the number of tests ordered (even for a healthy individual), the greater is the likelihood of an abnormal result (Fig. 480e-1). If 20 independent tests are performed on a healthy subject, the probability of at least one abnormal result is almost two-thirds.


InternalMed_Harrison

InternalMed_Harrison. In some settings, a narrower range of values is considered to be abnormal. For example, current American Heart Association guidelines recommend the use of a serum level of cardiac troponins that is greater than the 99th percentile of values found in a healthy population as evidence of acute myocardial infarction. Number of tests performed FIGURE 480e-1 Probability that at least one laboratory result will be abnormal in a healthy individual as an increasing number of independent tests are performed. The reference range is the central 95% of values measured in a healthy population.


InternalMed_Harrison

InternalMed_Harrison. 2. An alternative approach to using population means and standard deviations is to define a range of analyte values that is judged to be consistent with health on the basis of expert consensus opinion. These ranges are often referred to as decision limits. Examples of reference ranges established in this way include those for total, high-density, and low-density cholesterol (Table 480e-2). Such ranges may deviate considerably from those that would be established if the analyte concentrations of the population (mean ± 2 standard deviations) were used as a basis for establishing the reference range. For example, the “desirable” total cholesterol value according to the National Cholesterol Education Program is <200 mg/dL. This value is actually very close to the mean concentration among U.S. adults; in fact, almost one-half of


InternalMed_Harrison

InternalMed_Harrison. U.S. adults have a total cholesterol concentration that is above the “desirable” range. If the central 95% of cholesterol concentrations in the population were taken as the reference range, the upper end of that range would be ~240 mg/dL, well beyond what is considered desirable. Reference ranges may vary with age, gender, ethnic background, and physiologic state (e.g., pregnancy, high-altitude adaptation). Some examples of these variations are shown in the Appendix. The existence of different reference ranges poses challenges for interpretation of results. In particular, creatinine stands out as an analyte for which conventional reference ranges are not always easy to apply in clinical practice. Plasma levels of creatinine vary with age, gender, and ethnic group. This fact makes it difficult in practice to use a simple reference Probability of ˜1 result outside the reference range (%) Chapter 480e The Clinical Laboratory in Modern Health Care


InternalMed_Harrison

InternalMed_Harrison. Probability of ˜1 result outside the reference range (%) Chapter 480e The Clinical Laboratory in Modern Health Care High ≥60 Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein. GFR (mL/min/1.73 m2) 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 Plasma creatinine (mg/dL) FIGURE 480e-2 Relationship between plasma creatinine and estimated glomerular filtration rate (eGFR) using the 4-parameter Modification of Diet in Renal Disease (MDRD) equation. IDMS, isotope dilution mass spectrometry.


InternalMed_Harrison

InternalMed_Harrison. range for this analyte when attempting to gauge a patient’s renal function. A large decrease in glomerular filtration rate (GFR) is associated with slight increases in the plasma creatinine concentration within the typical reference range provided by many laboratories (Fig. 480e-2). A 60-year-old white woman with a serum creatinine level of 1.00 mg/dL, which is well within the typical reference range, has an estimated GFR of only 57 mL/min per 1.73 m2, whereas the same creatinine concentration in a 20-year-old African-American male is consistent with normal renal function. To better estimate the GFR, which is widely considered to be the most useful index of overall renal function, it has become customary to use equations that incorporate plasma creatinine with other parameters. The most widely used of these equations in current practice is the 4-parameter Modification of Diet in Renal Disease (MDRD) equation that incorporates plasma creatinine, age, gender, and ethnic group (African


InternalMed_Harrison

InternalMed_Harrison. widely used of these equations in current practice is the 4-parameter Modification of Diet in Renal Disease (MDRD) equation that incorporates plasma creatinine, age, gender, and ethnic group (African American or not African American). The more recent CKD-EPI equation, which uses the same 4 parameters, is beginning to replace the MDRD equation. Recommended clinical laboratory practice is to report the estimated GFR with all creatinine measurements in adults. This addition provides more useful information than would a creatinine reference range alone.


InternalMed_Harrison

InternalMed_Harrison. Errors can arise at all stages of the testing process, from specimen collection to result interpretation. An error arising at any stage may adversely affect patient care. In clinical laboratory practice, it is customary to divide the testing process into three phases: preanalytic, analytic, and postanalytic. Examples of each type of error are shown in Table 480e-3. The most common error in the testing process is specimen mislabeling, in which a specimen from one patient is placed in a container labeled with another patient’s name or identifiers. Specimen mislabeling errors may have very serious consequences for a patient. For example, if erroneous typing of a patient’s blood group results from specimen mislabeling and is followed by transfusion of a mismatched unit of blood, the outcome may be fatal. A mislabeled biopsy specimen can lead either to an erroneous diagnosis and inappropriate therapy or to a failure to make a diagnosis and institute appropriate therapy.


InternalMed_Harrison

InternalMed_Harrison. In addition to errors, many preanalytic factors can influence clinical laboratory results. Posture (i.e., recumbent versus upright), exercise, diet, recently ingested food, and use of prescribed or recreational drugs (including tobacco, alcohol, caffeine, and herbal supplements) can influence a variety of analyte concentrations. After blood has been collected, certain analytes undergo changes in their concentration during storage or transportation. Glucose levels fall as a result of red cell metabolism. Ammonia levels rise as a result of protein breakdown. Increasing permeability and breakdown of red cell membranes leads to increases in plasma potassium and free hemoglobin levels. Bacterial contamination can lead to overgrowth of specimens. To minimize tabLe 480e-3 exaMpLeS of preaNaLytiC, aNaLytiC, aNd poStaNaLytiC errorS duriNg the Laboratory teStiNg proCeSS Preanalytic Sources of Error


InternalMed_Harrison

InternalMed_Harrison. Preanalytic Sources of Error Test selection Inappropriate test for the clinical need Lack of clinical usefulness, regardless of possible results Test order misunderstood or not communicated Specimen collection Incorrect time of collection Patient not prepared for collection (e.g., not fasting) Incorrect specimen type (e.g., wrong anticoagulant, wrong tissue fixative) Use of incorrect specimen container Insufficient specimen collected Contamination of specimen by IV fluids, drugs, or bacteria Specimen mislabeled or unlabeled Important clinical information not provided Delays in transportation to the lab, leading to alterations in specimen constituents Analytic Sources of Error Incorrect storage conditions prior to analysis Specimen misidentification in the laboratory Wrong test performed Assay interferences Assay failure (e.g., assay out of control) Postanalytic Sources of Error


InternalMed_Harrison

InternalMed_Harrison. Postanalytic Sources of Error Delay in communication of assay results Results not communicated to correct person Incorrect result communicated Misinterpretation of result these precollection alterations, specimens should be processed or transported to the clinical laboratory as soon as possible after collection. The list of known preanalytic variables and their effects is extensive, and the reader is referred to the compendium on this subject (see Young DS: Effects of Preanalytical Variables on Clinical Laboratory Tests, 3rd ed. Washington, DC, AACC Press, 2007).


InternalMed_Harrison

InternalMed_Harrison. The great majority of tests continue to be performed in dedicated clinical laboratory facilities, but for several decades there has been a trend toward point-of-care testing. This change has been made possible by the development of portable analytic devices, including single-purpose instruments such as glucometers and oxygen saturation monitors, and multifunction instruments that can perform a wider variety of analyses, particularly in chemistry and hematology but also in some areas of microbiology. The use of these devices is driven largely by the convenience of faster result availability. In some settings (e.g., in rural areas and developing countries), there may be no easily accessible clinical laboratory and a point-of-care device may be the best or only option for testing. However, the per-specimen cost of point-of-care testing, in terms both of reagents and supplies and of personnel, is often greater than that of centralized testing. Other concerns relate to the adequacy of


InternalMed_Harrison

InternalMed_Harrison. the per-specimen cost of point-of-care testing, in terms both of reagents and supplies and of personnel, is often greater than that of centralized testing. Other concerns relate to the adequacy of personnel training for point-of-care testing, the quality of the results, and the incorporation of results into the medical record.


InternalMed_Harrison

InternalMed_Harrison. One of the largest markets for point-of-care testing is home testing by patients, which has long been an important element in the management of persons with diabetes who monitor their own blood glucose levels. Over-the-counter kits for home pregnancy testing have been available for decades. More recently, kits have become available for home testing of the international normalized ratio or prothrombin time by patients taking oral anticoagulants. Kits are also available for cholesterol monitoring, fecal occult-blood detection, and hemoglobin measurement. In these areas, there is often little information on the quality of test performance, the accuracy of the results, or the correctness of result interpretation. The principles of genetic medicine in clinical practice are dis cussed in Chaps. 82–84. Here we will concentrate on issues related to clinical laboratory testing for genetic disease.


InternalMed_Harrison

InternalMed_Harrison. The principles of genetic medicine in clinical practice are dis cussed in Chaps. 82–84. Here we will concentrate on issues related to clinical laboratory testing for genetic disease. The distinction between genetic testing for inherited disorders and that for acquired disorders affects the type of tissue that should be obtained for analysis. In inherited disorders, all nucleated cells are expected to carry the inherited mutation; thus white blood cells or buccal cells (obtained by scraping the inside of the cheek) are convenient sources of DNA for clinical laboratory testing. For prenatal testing of the fetus, chorionic villi or amniocytes are commonly used. In tests for acquired genetic disorders (e.g., in tumors), the tissue of interest that contains a suspected mutation must be sampled. It is often useful to compare tumor DNA with the patient’s normal DNA in order to identify acquired mutations (e.g., testing for microsatellite instability in colorectal cancer; Chap. 101e).


InternalMed_Harrison

InternalMed_Harrison. Although it is assumed that all clinical laboratory testing is performed with the consent of the patient (or, in the case of minors, the parents), regulations may require formal written consent for genetic testing. Such regulations vary among jurisdictions, and the practicing clinician should be aware of local regulations. In some jurisdictions, there are regulations on the storage and use of genetic information and on the maximal period for which genetic specimens may be stored.


InternalMed_Harrison

InternalMed_Harrison. For some late-onset genetic diseases, such as Huntington’s disease (Chap. 449), genetic testing allows a prediction about the future development of the disease. The degree of certainty that is possible on the basis of this testing surpasses that associated with identifica-480e-5 tion of more traditional disease risk factors (e.g., hyperlipidemia as a risk factor for future myocardial infarction). When deciding to undertake predictive genetic testing, it is important for the patient to consider the broad implications of a positive or negative test result, to be made aware of any support and counseling that is available, and to understand the implications of a result for other family members. In dealing with these issues, genetic counselors play an important role (Chap. 84). Their expertise includes the ability to explain genetic disorders at an understandable level to patients and their families, to arrange for support services, and to provide genetic risk assessments to members of


InternalMed_Harrison

InternalMed_Harrison. includes the ability to explain genetic disorders at an understandable level to patients and their families, to arrange for support services, and to provide genetic risk assessments to members of families with genetic disorders.


InternalMed_Harrison

InternalMed_Harrison. When testing for genetic disorders, the clinical laboratory will use different analytic approaches according to the disease of interest. Some disorders, such as sickle cell anemia, are caused by single-point mutations. Testing for these disorders involves mere assessment for one or a few mutations in a single gene. Other disorders (e.g., hyperphenylalaninemias) may be caused by numerous mutations in a single gene. Still others (e.g., hereditary breast cancer) may be caused by mutations in many genes. The number of possible mutations and genes that underlie a clinical phenotype affects the cost of and time required for clinical laboratory testing as well as the likelihood of finding a disease-causing mutation.


InternalMed_Harrison

InternalMed_Harrison. If a disease phenotype can be caused by many mutations, a clinical laboratory result that is negative should be interpreted with care. For example, it is common to screen healthy pregnant women (and their partners) for mutations in the CFTR gene, which is mutated in patients with cystic fibrosis (CF). The goal of this screening is to identify women who are carriers of a CFTR mutation and therefore are at increased risk of having a baby with CF. Because CF is an autosomal recessive disorder, a fetus has a 1:4 chance of being affected if both parents are carriers of disease-causing CFTR mutations. The screening test approach that is commonly used to identify mutations in carriers detects 80–85% of all known disease-causing CFTR mutations in Caucasians and up to 97% of mutations among Ashkenazi Jews. A negative screening result therefore does not completely eliminate the possibility that a woman (or her partner) actually has a mutation. What can be inferred from a negative test result is


InternalMed_Harrison

InternalMed_Harrison. Jews. A negative screening result therefore does not completely eliminate the possibility that a woman (or her partner) actually has a mutation. What can be inferred from a negative test result is that the risk of having a CF-affected baby has decreased significantly to an extent that depends on the woman’s ethnic group and the mutations that were examined. The clinical laboratory should calculate and report the woman’s new risk of being a carrier if the screening result is negative.


InternalMed_Harrison

InternalMed_Harrison. The increasing availability of large-scale (next-generation) sequencing of a patient’s whole genome or exome will greatly affect genetic testing over the next decade, with implications for the number of mutations that can be detected and the increased complexity of result interpretation.


InternalMed_Harrison

InternalMed_Harrison. Genetic testing has limitations that are often unique to this field. Results may be inconclusive. For example, a search for mutations in a gene that is suspected of causing a disease may fail to reveal any known disease-causing mutations. A mutation may be discovered that is of unknown clinical significance. In this situation, consideration of the predicted change in the amino acid sequence of the encoded protein may suggest a biologic effect—e.g., replacement of a charged amino acid by one of the opposite charge or by a neutral amino acid; replacement of an amino acid by one of a different size; or replacement of an amino acid that is conserved across multiple species. Further information may be obtained by determining whether the mutation is found in healthy individuals. Even with all of these considerations, it is not uncommon that the biologic significance of an identified mutation remains uncertain, and further research may be needed to assess its significance.


InternalMed_Harrison

InternalMed_Harrison. It is also important to understand the limitations of the clinical laboratory approach used to detect mutations. At this time, next-generation sequencing remains an impractical undertaking for financial reasons, although extensive sequence analysis has become the Chapter 480e The Clinical Laboratory in Modern Health Care standard of care for a few genes (e.g., analysis of BRCA1 and BRCA2 in assessing the risk of breast and ovarian cancer in individuals with a strong family history of these disorders). As sequencing technologies become less expensive, they can be expected to be more commonly used for both identifying mutations in patients with genetic disorders and screening asymptomatic individuals at risk of genetic disease.


InternalMed_Harrison

InternalMed_Harrison. Another unique aspect of genetic testing is the concern that genetic information about individuals may be used to discriminate against them by employers or by insurance companies. In the United States, the Genetic Information Nondiscrimination Act of 2008 (GINA) prohibits the use of genetic information by employers in making decisions related to employment and by health insurance companies in issuing insurance policies or setting premium rates based on knowledge of the applicant’s genetic status. GINA does not cover disability insurance, long-term care insurance, or life insurance policies.


InternalMed_Harrison

InternalMed_Harrison. Although public attention has been most closely focused on DNA testing, other clinical laboratory investigations that are not usually thought of as genetic may provide important genetic information about the person being tested. For example, serum protein electrophoresis may reveal α-1 antitrypsin deficiency. Depending on the clinical laboratory technology used, measurement of hemoglobin A1C, commonly used for monitoring diabetes control, may reveal a hemoglobin variant such as HbS (sickle cell). Measurement of cholesterol and triglyceride levels may reveal any of a number of hereditary disorders. All of these results are types of genetic information.


InternalMed_Harrison

InternalMed_Harrison. In the United States, all clinical laboratory testing performed for clinical purposes (but not for research purposes) is regulated by the federal Clinical Laboratory Improvement Amendments Act of 1988 (CLIA). Home monitoring by patients who are testing their own specimens is not covered by CLIA. The statute and the regulations, which are administered by the Centers for Medicare and Medicaid Services, apply to all laboratories, whether located in a physician’s office, a large hospital, or a reference laboratory; and all laboratories are required to hold a valid CLIA certificate that is appropriate for the highest complexity level of the tests they perform. The U.S. Food and Drug Administration is responsible for assigning the complexity level of commercial tests. The lowest category of complexity is the “waived” category, which is followed (in order of increasing complexity) by the categories of “provider-performed microscopy,” “moderatecomplexity testing,” and “high-complexity


InternalMed_Harrison

InternalMed_Harrison. of complexity is the “waived” category, which is followed (in order of increasing complexity) by the categories of “provider-performed microscopy,” “moderatecomplexity testing,” and “high-complexity testing.” The category of provider-performed microscopy is used to cover tests such as the use of potassium hydroxide preparations on skin scrapings to examine for fungi, fern tests, and sperm motility tests; it does not encompass histopathology that falls into the high-complexity category. Even if a clinical laboratory is performing only testing in the “waived” category, it must still hold a valid CLIA certificate. Laboratories that hold certificates for nonwaived tests are required to participate in proficiency testing and are regularly inspected to monitor their performance.


InternalMed_Harrison

InternalMed_Harrison. Placement Gyorgy Frendl, Kurt Fink 481e Clinical Procedure Tutorial: Central Venous Catheter Maria A. Yialamas, William E. Corcoran,


InternalMed_Harrison

InternalMed_Harrison. Maria A. Yialamas, William E. Corcoran, Clinical procedures are an important component of medical student and resident training, and some are required for board and hospital certification. In these Harrison’s Chaps. 481e–486e, video tutorials are presented for performing abdominal paracentesis, thoracentesis, endotracheal intubation, central venous catheter placement, percutaneous arterial blood gas sampling, and lumbar puncture. These videos have been created specifically for Harrison’s. Each includes the indications, contraindications, equipment, potential complications, and related patient safety considerations. Additional video tutorials covering clinical procedures such as breast biopsy, IV line insertion, phlebotomy, arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s Online and AccessMedicine (available at www.accessmedicine.com).


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 481e Clinical Procedure Tutorial: Central Venous Catheter Placement


InternalMed_Harrison

InternalMed_Harrison. Clinical Procedure Tutorial: Thoracentesis Charles A. Morris, Andrea Wolf Clinical procedures are an important component of medical student and resident training, and some are required for board and hospital 482e certification. In these new Harrison’s Chaps. 481e–486e, video tutorials are presented for performing abdominal paracentesis, thoracentesis, endotracheal intubation, central venous catheter placement, percutaneous arterial blood gas sampling, and lumbar puncture. These videos have been created specifically for Harrison’s. Each includes the indications, contraindications, equipment, potential complications, and related patient safety considerations. Additional video tutorials covering clinical procedures such as breast biopsy, IV line insertion, phlebotomy, arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s Online and AccessMedicine


InternalMed_Harrison

InternalMed_Harrison. arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s Online and AccessMedicine (available at www.accessmedicine.com).


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 482e Clinical Procedure Tutorial: Thoracentesis


InternalMed_Harrison

InternalMed_Harrison. Clinical Procedure Tutorial: Abdominal Paracentesis Maria A. Yialamas, Anna E. Rutherford, Lindsay King Clinical procedures are an important component of medical student and resident training, and some are required for board and hospital cer-483e tification. In these new Harrison’s Chaps. 481e–486e video tutorials are presented for performing abdominal paracentesis, thoracentesis, endotracheal intubation, central venous catheter placement, percutaneous arterial blood gas sampling, and lumbar puncture. These videos have been created specifically for Harrison’s. Each includes the indications, contraindications, equipment, potential complications, and related patient safety considerations. Additional video tutorials covering clinical procedures such as breast biopsy, IV line insertion, phlebotomy, arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s


InternalMed_Harrison

InternalMed_Harrison. arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s Online and AccessMedicine (available at www.accessmedicine.com).


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 483e Clinical Procedure Tutorial: Abdominal Paracentesis


InternalMed_Harrison

InternalMed_Harrison. Clinical Procedure Tutorial: Endotracheal Intubation Charles A. Morris, Emily Page Nelson Clinical procedures are an important component of medical student and resident training, and some are required for board and hospital 484e certification. In these new Harrison’s Chaps. 481e–486e, video tutorials are presented for performing abdominal paracentesis, thoracentesis, endotracheal intubation, central venous catheter placement, percutaneous arterial blood gas sampling, and lumbar puncture. These videos have been created specifically for Harrison’s. Each includes the indications, contraindications, equipment, potential complications, and related patient safety considerations. Additional video tutorials covering clinical procedures such as breast biopsy, IV line insertion, phlebotomy, arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s Online and


InternalMed_Harrison


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 484e Clinical Procedure Tutorial: Endotracheal Intubation Gas Sampling Christian D. Becker 485e Clinical Procedures Tutorial: Percutaneous Arterial Blood Medical Editors: Sean Sadikot, Jeremy Matloff


InternalMed_Harrison

InternalMed_Harrison. Medical Editors: Sean Sadikot, Jeremy Matloff Clinical procedures are an important component of medical student and resident training, and some are required for board and hospital certification. In these Harrison’s Chaps. 481e–486e, video tutorials are presented for performing abdominal paracentesis, thoracentesis, endotracheal intubation, central venous catheter placement, percutaneous arterial blood gas sampling, and lumbar puncture. These videos have been created specifically for Harrison’s. Each includes the indications, contraindications, equipment, potential complications, and related patient safety considerations. Additional video tutorials covering clinical procedures such as breast biopsy, IV line insertion, phlebotomy, arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s Online and AccessMedicine (available at www.accessmedicine.com).


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 485e Clinical Procedures Tutorial: Percutaneous Arterial Blood Gas Sampling


InternalMed_Harrison

InternalMed_Harrison. Clinical Procedures Tutorial: Lumbar Puncture Beth Rapaport, Stephen Krieger, Corey McGraw Medical Editors: Sean Sadikot, Jeremy Matloff Clinical procedures are an important component of medical student 486e and resident training, and some are required for board and hospital certification. In these Harrison’s Chaps. 481e–486e, video tutorials are presented for performing abdominal paracentesis, thoracentesis, endotracheal intubation, central venous catheter placement, percutaneous arterial blood gas sampling, and lumbar puncture. These videos have been created specifically for Harrison’s. Each includes the indications, contraindications, equipment, potential complications, and related patient safety considerations. Additional video tutorials covering clinical procedures such as breast biopsy, IV line insertion, phlebotomy, arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to


InternalMed_Harrison

InternalMed_Harrison. IV line insertion, phlebotomy, arterial line insertion, arthrocentesis, bone marrow biopsy, pelvic examination, thyroid aspiration, basic suturing, and urethral catheterization are available to subscribers of Harrison’s Online and AccessMedicine (available at www.accessmedicine.com).


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 486e Clinical Procedures Tutorial: Lumbar Puncture