Ebook Wallach''s interpretation of diagnostic tests (10th edition): Part 2

(BQ) Part 2 book Wallach''s interpretation of diagnostic tests presents the following contents: Renal disorders, respiratory, metabolic and acid–base disorders, toxicology and therapeutic drug monitoring, transfusion medicine, laboratory tests, infectious disease assays.

SECTION 12

LAB TESTS

5,10-Methylenetetrahydrofolate Reductase (MTHFR) Molecular Assay

5-Hydroxyindoleacetic Acid (5-HIAA) Urine

5′-Nucleotidase (5′-ribonucleotidephosphohydrolase, 5′-NT)

Acetaminophen (N-Acetyl-p- Aminophenol; APAP)

Acetylsalicylic Acid

Acid Phosphatase

ACTH Stimulation (Cosyntropin) Test

Activated Clotting Time (ACT)

Activated Protein C Resistance (APCR)

Adiponectin

Adrenocorticotropic Hormone (ACTH)

Allergen Tests, Specific Immunoglobulin E (IgE)

Albumin, Serum

Alcohols (Volatiles, Solvents)

Aldosterone

Alkaline Phosphatase (ALP)

Alpha1 -Antitrypsin (AAT, Alpha-1 Trypsin Inhibitor, Alpha-1 Proteinase Inhibitor) α-Fetoprotein (AFP) Tumor Marker, Serum

Aminotransferases (AST, ALT)

Angiotensin-Converting Enzyme (ACE, Kinase II)

Anion Gap (AG)

Anti–Smooth Muscle Antibodies (ASM)

Anti-parietal Cell Antibodies (APC)

Antineutrophil Cytoplasmic Antibody (ANCA)

Antinuclear Antibody (ANA)

Blood Urea Nitrogen (BUN)

Bone Marrow Analysis

Brain Natriuretic Peptide (BNP)

Cancer Antigen 15-3 (CA 15-3)

Cancer Antigen 19-9 (CA 19-9)

Cancer Antigen 27.29 (CA 27.29)

Cancer Antigen-125 (CA-125), Serum

Cannabis Sativa

Carbon Dioxide, Total

Carboxyhemoglobin (Carbon Monoxide, COHB, HBCO) Carcinoembryonic Antigen (CEA)

Cardiovascular Drugs (See Digoxin)

Cholesterol, High-Density Lipoprotein (HDL)

Cholesterol, Low-Density Lipoprotein (LDL)

Cholesterol, Total, Serum

Cholinesterase (Pseudocholinesterase) and Dibucaine Inhibition Chorionic Villus Sampling

Cold Agglutinins

Combined First-Trimester and Second- Trimester Screening (Integrated/ Sequential Screening) Complement System Assays

Complete Blood Count (CBC)

Coombs (Antiglobulin) Test

Direct Coombs Test (DAT)

Indirect Coombs Test (IAT)

Co-oximetry

Copper

Corticotropin-Releasing Hormone (CRH)

Corticotropin-Releasing Hormone (CRH) Stimulation Test

Cortisol Free Urine, 24 Hours

Cortisol, Saliva

Cortisol, Serum

C-Peptide

C-Reactive Protein, High Sensitivity

C-Reactive Protein (Crp), Serum

Creatine

Creatine Kinase (CK), Total

Creatine Kinase Isoenzymes (CK-BB, CK-MM, CK-MB)

Crystal Identification, Synovial Fluid

Cyclic Citrullinated Peptide Antibody, IgG

Cystatin C (CysC)

Cystic Fibrosis (CF) Mutation Assay

Cystine, Urine (Cystinuria Panel)

Cytogenetics: Fluorescence In Situ Hybridization (FISH), Chromosome Analysis, and Karyotyping D-Dimers

Dehydroepiandrosterone Sulfate, Serum (DHEA-Sulfate)

Dehydroepiandrosterone, Serum (DHEA, DHEA Unconjugated)

Dexamethasone Suppression of Pituitary ACTH Secretion Test (DST)

Low-Dose Test: Overnight 1-mg Screening Test

Low-Dose Test: Standard 2-Day (2-mg) Test

High-Dose Test: Overnight (8-mg) Test

High-Dose Test: Standard 2-Day (8-mg) Test

Digoxin

Dilute Russell Viper Venom (dRVVT) Assay

Direct and Indirect Antiglobulin Tests (DAT and IAT)

Enzyme Tests That Detect Cholestasis (ALP, 5′-Nucleotidase, GGT, LAP)

Erythrocyte Sedimentation Rate (ESR)

Estradiol, Unconjugated

Estrogen/Progesterone Receptor Assay

Estrogens (Total), Serum

Estrone

Ethylene Glycol

Factor V Leiden Molecular Assay

Factor VIII (Antihemophilic Factor)

Factor XI

Factor XII (Hageman Factor)

Factor XIII

Fatty Acids, Free

Flow Cytometry Analysis in the Clinical Evaluation of Hematologic Diseases

Folate, Serum and Erythrocytes (RBCs)

Follicular-Stimulating Hormone (FSH) and Luteinizing Hormone (LH), Serum

Fructosamine, Serum

Galactose-1-Phosphate Uridyltransferase (GALT)

Gamma Glutamyl Transferase (GGT)

Gastrin

Gaucher Disease Molecular DNA Assay

Genetic Carrier Testing

Ghrelin

Gliadin (Deamidated) Antibodies, IgG and IgA

Glucagon

Glucagon Stimulation Test

Glucose Tolerance Test, Oral (OGTT)

Glucose, Cerebrospinal Fluid (CSF)

Heparin Anti-Xa (Low Molecular Weight Heparin)

Heparin-Induced Thrombocytopenia (HIT) Assays

Hereditary Hemochromatosis Mutation Assay

High Molecular Weight Kininogen and Prekallikrein (Fletcher Factor)

Homocysteine (Hcy)

Homovanillic Acid, Urine (HVA)

Human Chorionic Gonadotropin (hCG)

Human Leukocyte Antigen (HLA) Testing

HLA Testing and Disease Associations/Drug Hypersensitivity Reactions

HLA and Stem Cell Transplant

Insulin Tolerance Test

Insulin-Like Growth Factor–Binding Protein-3 (IGFBP-3)

Insulin-Like Growth Factor-I (IGF-I)

Insulin-Like Growth Factor-II

Insulin–to–C-Peptide Ratio

Intrinsic Factor Antibody

Iodine Excretion, Urine

Hours

Iron (Fe)

Iron-Binding Capacity, Total (TIBC)

Iron Saturation

Islet Autoantibodies (IAA)

Janus Kinase-2 (JAK2) DNA Mutation Assay

Mean Corpuscular Hemoglobin (MCH)

Mean Corpuscular Hemoglobin Concentration (MCHC)

Mean Corpuscular Volume (MCV)

Mean Platelet Volume (MPV)

Müllerian Inhibiting Substance

Multigene Carrier Panels

Myeloperoxidase (MPO), Plasma

Myoglobin

Neuron-Specific Enolase (NSE)

Neutrophil Tests for Dysfunction

Nicotine/Cotinine

Noninvasive Prenatal Testing (NIPT)

Occult Blood, Stool

Parathyroid Hormone–Related Peptide (PTHrP)

Partial Pressure of Carbon Dioxide (pCO2 ), Blood

Partial Pressure of Oxygen (pO2 ), Blood

Partial Thromboplastin Time (PTT, aPTT)

Peripheral Blood Smears (PBS)

Platelet Function Assay, In Vitro

Pleura, Needle Biopsy (Closed Chest)

Prenatal Screening, First-Trimester Screening

Noninvasive Prenatal Testing (NIPT)

Prenatal Screening, Second-Trimester Screening (Maternal Serum Screening; Quad Screen) Combined First-Trimester and Second- Trimester Screening (Integrated/ Sequential Screening)

Prenatal Diagnostic Screening

Cytogenetics: Fluorescence In Situ Hybridization (FISH), and Chromosome Analysis

Genomic Microarray Analysis— Array Comparative Genomic Hybridization (aCGH)

Molecular Genetic Analysis (Prenatal DNA Analysis)

Pretransfusion Compatibility Testing

Procalcitonin (PCT)

Progesterone

Proinsulin

Prolactin

Prostate-Specific Antigen (PSA), Total and Free

Protein (Total), Serum

Protein (Total), Urine

Protein C

Protein S

Protein, Cerebrospinal Fluid

Prothrombin G20210A Molecular Mutation Assay

Prothrombin Time (PT) and the International Normalized Ratio (INR)

Pyruvate Kinase (PK), Red Blood Cell

Quantitative Pilocarpine Iontophoresis Sweat Test

Red Blood Cells (RBCs): Count and Morphology

Red Cell Distribution Width (RDW)

Second-Trimester Screening (Maternal Serum Screening; Quad Screen)

Serum Protein Electrophoresis/ Immunofixation

Sex Hormone–Binding Globulin (SHBG)

Sickle Solubility Test (SST)

Sodium (Na)

Sodium, Urine

Tay-Sachs Disease Molecular DNA Assay

Testosterone, Total, Free, Bioavailable

Theophylline (1,3-Dimethylxanthine)

Thrombin Time (TT)

Thromboelastogram (TEG)

Thyroglobulin (Tg)

Thyroid Autoantibody Tests

Thyroid Hormone–Binding Ratio (THBR)

Thyroid Radioactive Iodine Uptake (RAIU)

Thyroid-Stimulating Hormone (TSH)

Thyrotropin-Releasing Hormone (TRH) Stimulation Test

Thyroxine, Free (FT4 ) 1159 Thyroxine, Total (T4 ) 1160 Thyroxine-Binding Globulin (TBG) Tissue Transglutaminase IgA Antibody (tTG-IgA)

Transferrin (TRF)

Triglycerides

Triiodothyronine (T3 ) 1168 Triiodothyronine (T3 ) Resin Uptake (RUR)

Troponins, Cardiac-Specific Troponin I and Troponin T

Urea Nitrogen, Urine

Uric Acid (2,6,8-Trioxypurine, Urate)

Uric Acid, Urine

Urinalysis, Complete

Urine Protein Electrophoresis/ Immunofixation

Urovysion™ FISH for Bladder Cancer

Vanillylmandelic Acid (VMA), Urine

Vasoactive Intestinal Polypeptide (VIP)

Viscosity, Serum

Vitamin A (Retinol, Carotene)

Vitamin A Relative Dose–Response (RDR) Test

Water Deprivation Test

White Blood Cell: Inclusions and Morphologic Abnormalities

White Blood Cell Counts and Differentials

Xylose Absorption Test

Zinc (Zn)

This Chapter presents the most commonly ordered serum, plasma, and whole blood laboratory testsarranged in alphabetical order Each entry is titled using the most common naming convention existing

in the United States When appropriate, alternate name(s), definition, reference ranges, clinical use,interpretation, limitations, and suggested readings are given Microbiology tests such as laboratorycultures have been organized into a separate Chapter, Infectious Disease Assays (p 1203) The basis

of current molecular assays is reviewed in the Chapter on Hereditary and Genetic Diseases (p 473)

It is important to note that many of these tests are available by point-of-care testing (POCT) Themain advantage of POCT is immediate turnaround time However, it is also necessary to consider thedisadvantages of POCT, such as reliability of interpretation due to lower assay sensitivity andsusceptibility to interfering substances Other issues include ensuring personnel proficiency, qualityassurance, data management, and cost

1,5-ANHYDROGLUCITOL (1,5-AG)

Definition

1,5-Anhydroglucitol (1,5-AG), sometimes known as GlycoMark, is a monosaccharide thatshows a structural similarity to glucose Its main source in humans is dietary ingestion,particularly meats and cereals In addition, 10% of 1,5-AG is derived from endogenoussynthesis It is generally not metabolized, and in healthy subjects, it achieves a stableplasma concentration that reflects a steady balance between ingestion and urinary excretion

Normal range: 10.7–32.0 μg/mL in males; 6.8–29.3 μg/mL in females.

liver disease, gastrectomy state, and cystic fibrosis.

11-DEOXYCORTISOL

Definition

11-Deoxycortisol, also known as cortodoxone, corticosterone, and compound S, is a steroidand an immediate precursor to the production of cortisol It can be synthesized from 17-hydroxyprogesterone Excretion in urine is included in 17-ketogenic steroid (17-KGS) andPorter-Silber 17-OHKS measurements, which were originally used to provide somemeasure of cortisol production The direct measurement of cortisol has replaceddeterminations of 17-KS and 17-OHKS

Normal range: <50 ng/dL in males; <33 ng/dL in females.

Normal range: 18–469 ng/dL (see Table 16.1).

TABLE 16–1 Range of Normal Values for 17a-Hydroxyprogesterone

Diagnosis and management of congenital adrenal hyperplasia, hirsutism, and infertility

Interpretation

Increased In

The luteal phase of menstruating women and pregnancy, during which it rises

When defective 21-alpha hydroxylase and 11-beta hydroxylase are present

The most common form of CAH, where deficiency of the enzyme 21-hydroxylase blocksnormal synthesis of cortisol, leading to a compensatory increase of ACTH secretion; thisresults in increased levels

Limitations

Circulating normally exhibits a diurnal pattern similar to that of cortisol, with higher values

in the early morning than in the late afternoon Hence, the time of collection should bestandardized

Spuriously elevated levels are sometimes seen in premature and sick newborns due tointerference with other steroid metabolites 17α-Hydroxypregnenolone sulfate (percentcross-reactivity: 3.8%) has been identified as the most significant interferent in directassays

17α-Hydroxyprogesterone values for women with late-onset CAH have been found tooverlap with those encountered in hirsute, oligomenorrheic women who do not have thedisorder Accordingly, it is important to determine ACTH-stimulated 17α-hydroxyprogesterone levels in women suspected of having late-onset CAH

17-KETOSTEROIDS, URINE (17-KS)

Definition

17-Ketosteroids, urine (17-KS), are breakdown products of androgens and are an adrenalfunction test Examples of 17-KS include androstenedione, androsterone, estrone, anddehydroepiandrosterone An alternative and more specific test for adrenal androgenfunction is dehydroepiandrosterone sulfate in serum

Normal range: depends on sex and age (Table 16.2).

TABLE 16–2 Normal Ranges for 17-Ketosteroids in the Urine

Use

Evaluation of glucocorticoid production and neuroendocrine function

Evaluation of androgenic adrenal and testicular function in normal male individuals andprimarily adrenal androgenic secretion in normal female individuals

A large number of substances may interfere with this test

Decreases may be caused by carbamazepine, cephaloridine, cephalothin, chlormerodrin,digoxin, glucose, metyrapone, promazine, propoxyphene, reserpine, and others

Increases may be caused by acetone, acetophenide, ascorbic acid, chloramphenicol,chlorothiazide, chlorpromazine, cloxacillin, dexamethasone, erythromycin, ethinamate,etryptamine, methicillin, methyprylon, morphine, oleandomycin, oxacillin, penicillin,phenaglycodol, phenazopyridine, phenothiazine, piperidine, quinidine, secobarbital,spironolactone, and others.

5,10-METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR)

MOLECULAR ASSAY *

Definition

Mutations, C677T and A1298C, in the 5,10-methylenetetrahydrofolate reductase (MTHFR)

gene increase the risk of thrombosis (OMIM# 188050) and other cardiovascular disorders

as a result of an elevated plasma homocysteine concentration (OMIM# 236250)

Normal values: negative or no mutations are found.

Small increases possible in pregnancy, ovulation, and postsurgical stress

Various food ingestions (e.g., pineapples, kiwi, bananas, eggplant, plums, tomatoes,avocados, plantains, walnuts, pecans, hickory nuts, coffee)

Use of certain drugs (e.g., acetanilid, acetaminophen, acetophenetidin, caffeine, coumaricacid, diazepam [Valium], ephedrine, fluorouracil, glyceryl guaiacolate [guaifenesin],heparin, melphalan [Alkeran], mephenesin, methamphetamine, methocarbamol, naproxen,nicotine, Lugol solution, promethazine, phenothiazine, hydroxyl tryptophan)

Twenty-four–hour collections are generally recommended, but random collections may beused Refrigeration is the most important aspect of specimen preservation

Urinary 5-HIAA is increased with malabsorption, in 75% of cases, usually when a carcinoidtumor is far advanced (with large liver metastases, often 300–1,000 mg/day), but may not beincreased despite massive metastases

NUCLEOTIDASE (5¢-RIBONUCLEOTIDEPHOSPHOHYDROLASE, NT)

5′-Definition

This membrane-bound enzyme of the liver is increased in diseases of the liver, particularly

if the hepatobiliary tract is involved The appearance of 5′-NT in serum is due tocholestasis, and its significance is similar to that of ALP and GGT However, 5′-NT is not

as subject to drug induction as GGT and ALP, and it is not subject to confusion withalternate sources of the enzyme, as is seen with ALP

Normal range: 2.0–8.0 U/L.

Increased In

5′-NT is increased in the following conditions:

Hepatobiliary disease with intrahepatic or extrahepatic biliary obstructionHepatic carcinoma

Early biliary cirrhosisPregnancy (third semester)Inflammatory arthritis

Limitations

5′-NT can be elevated in hyperammonemia due to analytical interference

Normal in pregnancy and postpartum period (in contrast to serum leucine aminopeptidaseand ALP)

ACETAMINOPHEN (N-ACETYL-p-AMINOPHENOL; APAP)

Screen of urine: indication of exposure

Screen of serum: used to assess potential toxicity

Normal range: 5–20 μg/mL serum

Potentially toxic: >150 μg/mL measured 4 hours postdose

Limitations

Screening

Serum/urine: colorimetric or immunoassay on automated chemistry analyzers

High bilirubin concentrations [>50 μg/mL] may cause false-positive results withimmunoassay-based tests

Plasma may be tested in place of serum Anticoagulants such as EDTA and heparin

do not generally interfere with the assay

Do not use whole blood

Confirmation:

Serum/urine–HPLC or GC/MC

APAP is highly conjugated by glucuronidation and sulfation.

An assay that includes a hydrolysis step provides total APAP levels, which are notuseful for assessing toxicity

Normal range: 0–0.8 U/L.

Benign prostatic hyperplasia, prostatitis, prostate infarctVaginal swabs from rape victims

PAP measurements provide little additional information beyond that provided by PSAmeasurements

Suggested Reading

Moul JW, Connelly RR, Perahia B, et al The contemporary value of pretreatment prostatic acid phosphatase to predict pathological stage

and recurrence in radical prostatectomy cases J Urol 1998;159:935–940.

ACTH STIMULATION (COSYNTROPIN) TEST

Definition

Cosyntropin is synthetic ACTH (1–24), which has the full biologic potency of native ACTH(1–39) It is a rapid stimulator of cortisol and aldosterone secretion

Use

This is the initial test used to distinguish primary from secondary adrenal insufficiency

It is not helpful in the diagnosis of Cushing syndrome Several protocols are used to assessthe response to exogenous ACTH administration (see below)

Low-Dose ACTH Stimulation Test

This test involves physiologic plasma concentrations of ACTH and provides a moresensitive index of adrenocortical responsiveness

It is performed by measuring serum cortisol immediately before and 30 minutes after IVinjection of cosyntropin in a dose of either 1 μg/1.73 m2 or 0.5 μg/1.73 m2

There is no commercially available preparation of “low-dose” cosyntropin The vials ofcosyntropin currently available contain 250 μg and come with sterile normal saline to beused as a diluent One prepares the low-dose solution of cosyntropin locally

High-Dose ACTH Stimulation Test

This test consists of measuring serum cortisol immediately before and 30 and 60 minutesafter IV injection of 250 μg of cosyntropin This dose of cosyntropin results inpharmacologic plasma ACTH concentrations for the 60-minute duration of the test

The advantage of the high-dose test is that the cosyntropin can be injected using the IM route,because pharmacologic plasma ACTH concentrations are still achieved

Salivary cortisol can also be measured during this test Salivary cortisol increases to 19 ±0.8 ng/mL (range: 8.7–36 ng/mL) 1 hour after injection

Eight-Hour ACTH Stimulation Test

The 8-hour test, which is now rarely performed, consists of infusing 250 μg of cosyntropincontinuously over 8 hours in 500 mL of isotonic saline A 24-hour urine specimen iscollected the day before and the day of the infusion for cortisol or 17-hydroxycorticoid andcreatinine determination, and serum cortisol is determined at the end of the infusion PlasmaACTH concentrations are supraphysiologic throughout the infusion

The 24-hour urinary excretion of 17-hydroxycorticoid should increase three-to fivefold overbaseline on the day of ACTH infusion

Two-Day ACTH Infusion Test

The 2-day ACTH infusion test is similar to the 8-hour infusion test, except that the samedose of ACTH is infused for 8 hours on 2 consecutive days.

This test may be helpful in distinguishing secondary from tertiary adrenal insufficiency The1-day 8-hour test is too short for this purpose, whereas longer tests add little further usefulinformation

Urinary excretion of 17-hydroxycorticoid should exceed 27 mg during the first 24 hours ofinfusion and 47 mg during the second 48 hours

Limitations

In healthy individuals, cortisol responses are greatest in the morning, but in patients withadrenal insufficiency, the response to cosyntropin is the same in the morning and afternoon.Therefore, ACTH stimulation tests should be done in the morning to minimize the risk ofmisdiagnosis in a normal individual

The criteria for a minimal normal cortisol response of 18–20 μg/dL are derived from theresponses of healthy volunteers However, in some studies, higher cutoff points for thediagnosis of adrenal insufficiency are based on the ACTH test responses of patients known

to have an abnormal response to insulin

Variability in cortisol assays creates an additional problem with setting criteria for a normalresponse to ACTH that apply to all centers Studies comparing cortisol results obtainedwith different assays showed a positive bias of Radioimmunoassays (RIA) and EIAs of 10–50% compared to a reference value obtained using isotope dilution GC/MS

In women, the response to ACTH is affected by the use of oral contraceptives, whichincrease cortisol-binding globulin levels

The response to ACTH varies with the underlying disorder If the patient hashypopituitarism with deficient ACTH secretion and secondary adrenal insufficiency, thenthe intrinsically normal adrenal gland should respond to maximally stimulatingconcentrations of exogenous ACTH if given for a sufficiently long time The response may

be less than that in normal subjects and initially sluggish due to adrenal atrophy resultingfrom chronically low stimulation by endogenous ACTH If, on the other hand, the patient hasprimary adrenal insufficiency, endogenous ACTH secretion is already elevated, and thereshould be little or no adrenal response to exogenous ACTH

A clearly subnormal response to the low-dose or high-dose ACTH stimulation test isdiagnostic of primary or secondary adrenal insufficiency, whereas a normal responseexcludes both disorders.

Cortisol values between 18.0 and 25.4 μg/dL represent a range of uncertainty in whichpatients may have discordant responses to ACTH, insulin, and/or metyrapone Higherconcentrations represent a normal response in the non-ICU setting

The low-dose test is not valid if there has been recent pituitary injury, and it supports theconclusion that a 30-minute serum cortisol concentration <18 μg/dL indicates impairedadrenocortical reserve In addition, the low-dose test does not reliably indicatehypothalamic–pituitary–adrenal axis suppression in preterm infants whose mothers receiveddexamethasone for <2 weeks before delivery to hasten fetal lung development The CRHtest should be used in this situation

ACTIVATED CLOTTING TIME (ACT) *

Definition

Activated clotting time (ACT) is a rapid point-of-care standardized clotting time, performed

by automated well-calibrated instruments, such as the Medtronic automated coagulationtimer (ACT) A baseline ACT has to be established in each POCT area after induction ofanesthesia and opening the chest for cardiopulmonary bypass surgery, because surgery andanesthesia shorten it The ACT may also vary slightly with the lot number of the controlcartridge

Normal range in the absence of heparin (with Medtronic coagulometer): 74–125

seconds

Use

ACT is the most widely used measure of anticoagulation with heparin (and neutralization ofheparin with protamine) during extracorporeal circulation After the initial dose of heparin,the ACT is maintained at >275 seconds for off-pump coronary procedures and >350seconds for on-pump procedures by periodic administration of heparin

Interpretation

There is some controversy concerning whether monitoring heparinization by ACT aloneensures optimal heparin and protamine doses A poor correlation was found between ACTand heparin measurements using anti-Xa assays Nevertheless, experience has shown thatinstitution of anticoagulation and monitoring under ACT guidance and reversal improveshemostasis, limits blood loss, and reduces the need for transfusions

must be excluded.

Medications that inhibit platelet function (aspirin, NSAIDs) may affect ACT

Preanalytical errors (sample dilution or contamination with heparin, blood activation) must

be avoided It is particularly important to avoid the use of blood samples contaminated byheparin flushes

ACTIVATED PROTEIN C RESISTANCE (APCR) *

Normal value: >1.8.

Use

APCR is one of the assays recommended to investigate the etiology of venousthrombophilia The congenital form, factor V Leiden, is present in 5% of individuals ofEuropean descent and in a high proportion of patients with unprovoked venousthromboembolism It is virtually absent in patients of pure African ancestry

Limitations

Protein C levels <50% and initial anticoagulation with vitamin K antagonists may givefalsely low ratios In these situations, the genetic test for factor V Leiden is recommended.The APCR assay is valid in patients stabilized on vitamin K antagonists or heparin

The assay is invalid in clotted specimens, as well as in lipemic, hemolyzed, or ictericsamples The assay is also invalid if blood is drawn with the wrong anticoagulant or thetubes are not filled appropriately

ADIPONECTIN

Definition

Adiponectin, a hormone secreted exclusively by adipose tissue, has an important role in theregulation of tissue inflammation and insulin sensitivity Perturbations in adiponectinconcentration have been associated with obesity and the metabolic syndrome Levels of the

hormone are inversely correlated with body fat percentage in adults, whereas theassociation in infants and young children is more unclear.

Normal range: see Table 16.3.

TABLE 16–3 Normal Range of Adiponectin

Twofold before a meal and decreases to trough levels within 1 hour after eating

More than twofold in hemodialysis patients

Decreased In

Type 2 diabetes mellitus

Obesity and metabolic syndrome

Limitations

Adiponectin exerts some of its weight reduction effects via the brain This is similar to theaction of leptin, but the two hormones perform complementary actions and can haveadditive effects

Due to its important cardiometabolic actions, adiponectin represents a biologic moleculeworth being studied as a new emerging biomarker of disease and also as a target forpharmacologic treatments

is in turn controlled by the hypothalamic hormone CRF and by negative feedback fromcortisol.

Pituitary-dependent Cushing disease

Ectopic ACTH–producing tumors

Because ACTH is released in bursts, its levels in the blood can vary from minute to minute.ACTH is unstable in blood, and proper handling of specimen is important

Most commercial RIAs are insensitive and nonspecific, measuring intact ACTH as well asprecursors and fragments Highly sensitive IRMAs measure intact ACTH only

RIAs are recommended for investigating ectopic ACTH–producing tumors, because some ofthe tumors secrete ACTH precursors and fragments IRMAs are more sensitive than RIAsand are useful for investigating disorders of the hypothalamic–pituitary–adrenal system.Patients taking glucocorticoids may have suppressed levels of ACTH with an apparent highlevel of cortisol

Pregnancy, menstruation, and stress increase secretion

ALLERGEN TESTS, SPECIFIC IMMUNOGLOBULIN E (IgE)

Definition

Allergic diseases are manifested as hyperresponsiveness in the target organ, whether theskin, nose, lung, or GI tract Most tests for “allergy” are actually tests for allergicsensitization, or the presence of allergen-specific IgE.

Most patients who experience symptoms upon exposure to an allergen have demonstrableIgE that specifically recognizes that allergen, making these tests essential tools in thediagnosis of allergic disorders

In vitro testing for allergy has certain advantages:

It poses no risk to the patient of an allergic reaction

It is not affected by medications (antihistamines, etc.) the patient may be taking

It is not reliant upon skin integrity or affected by skin disease

It can be more convenient for the patient In vitro testing requires submitting a bloodsample and does not necessitate a separate visit for skin testing

Clinical performance of specific IgE-based serum allergen tests typically has sensitivityranging from 84% to 95% and specificity ranging from 85% to 94%

Various types of specific panels, mixes, as well as specific allergen tests currentlyperformed at various labs and contact your lab for details

To investigate the specificity of allergic reactions to insect venom allergens, drugs, orchemical allergens

Interpretation

Increased In

Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood

of allergic disease as opposed to other etiologies and defines the allergens that may beresponsible for eliciting signs and symptoms

Decreased In

Limitations

The demonstration of sensitization is not sufficient to diagnose an allergy, however, because

a sensitized individual may be entirely asymptomatic upon exposure to the allergen inquestion Thus, allergy tests must be interpreted in the context of the patient’s specificclinical history, and the diagnosis of an allergic disorder cannot be based solely on alaboratory result

If the result is markedly positive (e.g., a Class VI result), the history suggests a past reaction

to the allergen, and the allergen is well characterized, then the diagnosis of an allergy canusually be made without further evaluation If the result is weakly positive, then furtherevaluation is usually needed

A negative immunoassay result in the setting of a strongly suggestive history does notexclude allergy In this situation, a skin prick test should be considered (if notcontraindicated)

False-positive results of allergen-specific IgE can theoretically occur in patients withextremely elevated total IgE levels

Tests used largely in research settings include immunoblotting, basophil histamine orleukotriene release tests, basophil activation, and levels of eosinophil mediators, etc., arenot standardized, and are generally not superior to skin testing, and cannot be recommendedfor routine clinical use

Allergen-specific IgG and IgG4 tests, which are believed to correlate with normalimmunologic responses to foreign substances, are not useful in the diagnosis of IgE-mediated allergy, with the exception of venom allergy Unreliable testing methods includeprovocation/neutralization tests, kinesiology, cytotoxic tests, and electrodermal testing

In food allergy, circulating IgE antibodies may remain undetectable despite a convincingclinical history because these antibodies may be directed toward allergens that are revealed

or altered during industrial processing, cooking, or digestion and therefore do not exist inthe original food for which the patient is tested

Identical results for different allergens may not be associated with clinically equivalentmanifestations, due to differences in patient sensitivities

ALBUMIN, SERUM

Definition

Albumin is the most important protein and constitutes 55–65% of total plasma protein.Approximately 300–500 g of albumin is distributed in the body fluids, and the average adultliver synthesizes approximately 15 g/day Albumin’s half-life is approximately 20 days,with 4% of the total albumin pool being degraded daily The serum albumin concentrationreflects the rate of synthesis, the degradation, and the volume of distribution Albuminsynthesis is regulated by a variety of influences, including nutritional status, serum oncoticpressure, cytokines, and hormones

Assess nutritional status

Evaluate chronic illness

Evaluate liver disease

Decreased synthesis by the liver:

Acute and chronic liver disease (e.g., alcoholism, cirrhosis, hepatitis)Malabsorption and malnutrition

Fasting, protein–calorie malnutritionAmyloidosis

Chronic illnessDM

Decreased growth hormone levelsHypothyroidism

HypoadrenalismGenetic analbuminemiaAcute-phase reaction, inflammation, and chronic diseases:

Bacterial infectionsMonoclonal gammopathies and other neoplasmsParasitic infestations

Peptic ulcerProlonged immobilizationRheumatic diseases

Severe skin diseaseIncreased loss over body surface:

BurnsEnteropathies related to sensitivity to ingested substances (e.g., gluten sensitivity, Crohndisease, ulcerative colitis)

Fistula (gastrointestinal or lymphatic)

HemorrhageKidney diseaseRapid hydration or overhydrationRepeated thoracentesis or paracentesisTrauma and crush injuries

Increased catabolism:

FeverCushing diseasePreeclampsiaThyroid dysfunctionPlasma volume expansion:

CHFOral contraceptivesPregnancy

Limitations

In clinical practice, one of the two dye-binding assays—bromocresol green (BCG) andbromocresol purple (BCP)—is used for measuring albumin levels, and systematicdifferences between these methods have long been recognized

BCG methods are subject to nonspecific interference from binding to nonalbumin proteins,whereas BCP is more specific BCP has been shown to underestimate serum albumin inpediatric patients on hemodialysis and patients in chronic renal failure Chronic dialysisunits often have little influence over the method

Antialbumin antibodies are commonly found with hepatic dysfunction and are typically ofIgA type

Ischemia-modified albumin, in which the metal-binding capacity of albumin has decreaseddue to exposure to ischemic events, is a biologic marker of myocardial ischemia

ALCOHOLS (VOLATILES, SOLVENTS) *

Definition

Alcohols are organic compounds that contain the −OH group, including methanol (CH3 OH),ethanol (ethyl alcohol; C2 H5 OH), isopropanol (rubbing alcohol), and methanol (woodalcohol) Although acetone (CH3 COCH3 ) is a ketone, not an alcohol, it is included in thisgroup, because it is often detected in the same testing methodology

Normal range:

Ethanol: <10 mg/dL

50 mg/dL: decreased inhibition, slight incoordination

100 mg/dL: slow reaction time; altered sensory ability

150 mg/dL: altered thought processes; personality, behavior changes

200 mg/dL: staggering gait, nausea, vomiting, mental confusion

300 mg/dL: slurred speech, sensory loss, visual disturbance

400 mg/dL: hypothermia, hypoglycemia, poor muscle control, seizures

700 mg/dL: unconsciousness, decreased reflexes, respiratory failure (may alsooccur at lower concentrations)

Isopropanol (isopropyl alcohol): <10 mg/dL (normal); toxic effects generally seen at50–100 mg/dL

Methanol: <10 mg/dL (normal); levels >25 mg/dL are generally considered toxic

Acetone: <10 mg/dL; effects are said to be similar to ethanol for similar blood levels,but the anesthetic potency is greater

Use

Beverage (ethanol)

Solvent and reagent

Vehicle in chemical and pharmaceutical industries

Antiseptic (isopropyl alcohol)

Limitations

Immunoassay testing for ethanol may have cross-reactivity <1% with isopropanol alcohol,

methanol, ethylene glycol, and acetaldehyde; <15% with n-propanol.

Elevated concentrations of acetone are detected in specimens during diabetic ketoacidosisand fasting ketoacidosis and may range from 10 to 70 mg/dL

In many headspace gas chromatographic methods, acetonitrile coelutes with acetone, leading

to a false-positive result Acetonitrile may be a component in cosmetic nail remover

A positive urine ethanol due to the presence of yeast in the patient’s urine has beendescribed In these cases, glucose was also present in the urine

ALDOSTERONE

Definition

Primary mineralocorticoid secreted by the adrenal zona glomerulosa The role ofaldosterone in metabolism is the control of sodium and potassium Regulating sodium ionconcentration, in turn, regulates fluid volume Aldosterone acts to decrease excretion ofsodium and increase the excretion of potassium at the kidney, sweat glands, and salivaryglands

Normal range:

8:00–10:00 AM (sitting): 3–34 ng/dL8:00–10:00 AM (supine): 2–19 ng/dL4:00–6:00 PM (sitting): 2–23 ng/dL

Use

Diagnosis of primary hyperaldosteronism

Differential diagnosis of fluid and electrolyte disorders

Assessment of adrenal aldosterone production

Very low–sodium diet

Urine aldosterone also increased in nephrosis

Licorice may mimic aldosterone effects and should be avoided 2 weeks before the test

ALKALINE PHOSPHATASE (ALP)

Definition

ALP refers to a family of enzymes that catalyze hydrolysis of phosphate esters at an alkaline

pH There are at least five isoenzymes derived from the liver (sinusoidal and bilecanalicular surface of hepatocytes), bone, intestine (brush border of mucosal cells),placenta, and tumor-associated tissues separated by electrophoresis Placenta and tumor-associated ALP are the most heat resistant to inactivation More than 95% of total ALPactivity comes from the bone and liver (approximately 1:1 ratio) The half-life of ALP is 7–

10 days

Normal range:

0–1 year: 150–350 IU/L1–16 years: 30–300 IU/L

>16 years: 30–115 IU/L

Diagnosis and treatment of the liver, bone, intestinal, and parathyroid diseases

Interpretation

Increased In

Increased bone formation

Bone diseases (metastatic carcinoma of the bone, myeloma, Paget disease)

Renal disease (renal rickets due to vitamin D–resistant rickets associated with secondaryhyperparathyroidism)

Liver disease (e.g., infectious mononucleosis, uncomplicated extrahepatic biliaryobstruction, liver abscess)

Miscellaneous (extrahepatic sepsis, ulcerative colitis, pancreatitis, phenytoin, and alcoholuse)

Bone origin—increased deposition of calcium

HyperparathyroidismPaget disease (osteitis deformans) (highest reported values 10–20 times normal).Marked elevation in the absence of liver disease is most suggestive of Paget disease ofbone or metastatic carcinoma from the prostate

Increase in cases of metastases to bone is marked only in prostate carcinoma

Osteoblastic bone tumors (osteogenic sarcoma, metastatic carcinoma)

Osteogenesis imperfecta (due to healing fractures)

Familial osteoectasia

Osteomalacia, rickets

Polyostotic fibrous dysplasia

Osteomyelitis

Late pregnancy; reverts to normal level by 20th day postpartum

Children <10 years of age and again during prepubertal growth spurt may have three tofour times adult values; adult values are attained by age 20

Any obstruction of the biliary system (e.g., stone, carcinoma, primary biliary cirrhosis)

is a sensitive indicator of intrahepatic or extrahepatic cholestasis Whenever the ALP iselevated, a simultaneous elevation of 5′-nucleotidase (5′-N) establishes biliary disease

as the cause of the elevated ALP If the 5′-N is not increased, the cause of the elevatedALP must be found elsewhere (e.g., bone disease)

Liver infiltrates (e.g., amyloid or leukemia)

Cholangiolar obstruction in hepatitis (e.g., infectious, toxic)

Hepatic congestion due to heart disease

Adverse reaction to therapeutic drug (e.g., chlorpropamide) (progressiveelevation of serum ALP may be first indication that drug therapy should behalted); may be 2–20 times normal

Increased synthesis of ALP in the liver

Diabetes mellitus—44% of diabetic patients have 40% increase of ALP

Parenteral hyperalimentation of glucose

Liver diseases with increased ALP

Less than three to four times increase lacks specificity and may be present in all forms

of liver disease

Two times increase: acute hepatitis (viral, toxic, alcoholic), acute fatty liver, cirrhosis.Two to ten times increase: nodules in the liver (metastatic or primary tumor, abscess,cyst, parasite, TB, sarcoid); is a sensitive indicator of a hepatic infiltrate

Increase more than two times the upper limit of normal in patients with primary breast

or lung tumor with osteolytic metastases is more likely caused by liver than by bonemetastases

Five times increase: infectious mononucleosis, postnecrotic cirrhosis

Ten times increase: carcinoma of the head of the pancreas, choledocholithiasis, anddrug cholestatic hepatitis

Fifteen to twenty times increase: primary biliary cirrhosis, primary or metastaticcarcinoma The GGT-to-ALP ratio >2.5 is highly suggestive of alcohol abuse

Chronic therapeutic use of anticonvulsant drugs (e.g., phenobarbital, phenytoin)

Placental origin: appears at 16th–20th week of normal pregnancy, increases progressively totwo times normal up to onset of labor, and disappears 3–6 days after delivery of placenta.ALP may be increased during complications of pregnancy (e.g., hypertension, preeclampsia,eclampsia, threatened abortion) but is difficult to interpret without serial determinations It

is lower in diabetic than in nondiabetic pregnancy

Intestinal origin: is a component in approximately 25% of normal sera; increases 2 hoursafter eating in persons with blood type B or O who are secretors of the H blood group ALPhas been reported to be increased in cirrhosis, various ulcerative diseases of the GI tract,severe malabsorption, chronic hemodialysis, and acute infarction of the intestine

Benign familial hyperphosphatasemia

Ectopic production by neoplasm (Regan isoenzyme) without involvement of the liver orbone (e.g., Hodgkin disease; cancer of the lung, breast, colon, or pancreas; highestincidence in ovary and cervical cancers)

Vascular endothelium origin—some patients with myocardial, pulmonary, renal (onethird of cases), or splenic infarction, usually after 7 days during the phase oforganization

Hyperphosphatasia (liver and bone isoenzymes)

Hyperthyroidism (liver and bone isoenzymes) Increased ALP alone in a chemicalprofile, especially with a decreased serum cholesterol and lymphocytosis, should

suggest excess thyroid medication or hyperthyroidism.

Primary hypophosphatemia (often increased)

ALP isoenzyme determinations are not widely used clinically; heat inactivation may bemore useful to distinguish bone from liver source of increased ALP (extremely Ninetypercent heat-labile: bone, vascular endothelium, reticuloendothelial system; extremely90% heat-stable: placenta, neoplasms; intermediate 60–80% heat stable: liver,intestine) Also differentiate by chemical inhibition (e.g., L-phenylalanine) or use serumGGT, leucine aminopeptidase

Children—mostly bone; little or no liver or intestine

Adults—liver with little or no bone or intestine; after age 50, increasing amounts ofbone

Nutritional deficiency of zinc or magnesium

Excess vitamin D ingestion

Milk-alkali (Burnett) syndrome

Congenital hypophosphatasia (enzymopathy of liver, bone, kidney isoenzymes)

Postmenopausal women with osteoporosis taking estrogen replacement therapy

Therapeutic agents (e.g., corticosteroids, trifluoperazine, antilipemic agents, somehyperalimentation)

Cardiac surgery with cardiopulmonary bypass pump

Normal In

Inherited metabolic diseases (Dubin-Johnson, Rotor, Gilbert, and Crigler-Najjar syndromes;type I–V glycogenoses, mucopolysaccharidoses; increased in Wilson disease andhemochromatosis related to hepatic fibrosis)

Consumption of alcohol by healthy persons (in contrast to GGT); may be normal even inalcoholic hepatitis

In acute icteric viral hepatitis, the increase is less than two times normal in 90% of cases,but when ALP is high and serum bilirubin is normal, infectious mononucleosis should beruled out as a cause of hepatitis

The elevation in ALP tends to be more marked (more than threefold) in extrahepatic biliaryobstruction (e.g., by stone or by cancer of the head of the pancreas) than in intrahepaticobstruction, and it is greater the more complete the obstruction Serum enzyme activitiesmay reach 10–12 times the upper limit of normal, returning to normal on surgical removal ofthe obstruction

Day-to-day variation is 5–10%

Recent food ingestion can increase as much as 30 U/L

ALP is 15% and 10% higher in African American men and women, respectively, compared

to other racial/ethnic groups

Twenty-five percent higher with increased body mass index, 10% higher with smoking, 20%lower with the use of oral contraceptives

Common drugs, including penicillin derivatives, antiepileptic drugs, antihistamines,cardiovascular drugs, etc., can increase blood levels

ALPHA1 -ANTITRYPSIN (AAT, ALPHA-1 TRYPSIN INHIBITOR, ALPHA-1 PROTEINASE INHIBITOR)

Definition

AAT is a member of the serpin family of protease inhibitors, produced mostly in the liver Itprotects the lungs from damage caused by the proteolytic enzyme, neutrophil elastase Thenormal AAT allele is the M allele Over 100 allelic variants have been described, of whichthe most common severely deficient variants are the S and Z alleles It is normally the majorconstituent of the alpha-1 band on routine serum electrophoresis AAT deficiency isseverely underrecognized, with long intervals between the first symptom and diagnosis.Clinical manifestations of severe deficiency of AAT typically involve the lung (e.g., early-onset emphysema with a basilar predominant pattern on imaging), the liver (e.g., cirrhosis),and, rarely, the skin (e.g., panniculitis)

Normal range: 88–174 mg/dL.

Use

Workup of individuals with suspected disorders such as familial chronic obstructive lungdisease, emphysema, asthma, bronchiectasis

Diagnosis of AAT deficiency

Diagnosis of juvenile and adult cirrhosis of the liver

Interpretation

Increased In

Inflammation (acute-phase reacting protein)

Infection, tissue injury or necrosis, rheumatic disease, and some malignancies

Estrogen administration (oral contraceptives, pregnancy, especially third semester)

Decreased In

Deficiency states (hereditary)

Hepatic disease (hepatitis, cholestasis, cirrhosis, or hepatic cancer)

Pulmonary emphysema, COPD

Limitations

Phenotypic studies are recommended to confirm a suspected hereditary deficiency

False-positive results can occur if rheumatoid factor present

α-FETOPROTEIN (AFP) TUMOR MARKER, SERUM

Definition

AFP is a glycoprotein that is normally produced during gestation by the fetal liver and yolksac, the serum concentration of which is often elevated in patients with hepatocellularcarcinoma (HCC) It is also found in some patients with cancer of the testes and ovaries

Normal range: 0.6–6.60 ng/mL.

Use

Marker for hepatocellular and germ cell (nonseminoma) carcinoma

Follow-up management of patients undergoing cancer therapy, especially for testicular andovarian tumors and for hepatocellular carcinoma The measurement of AFP in serum, inconjunction with serum human chorionic gonadotropin, is an established regimen formonitoring patients with nonseminomatous testicular cancer In addition, monitoring the rate

of AFP clearance from serum after treatment is an indicator of the effectiveness of therapy.Conversely, the growth rate of progressive cancer can be monitored by serially measuringserum AFP concentration over time

Serial serum AFP testing is a useful adjunctive test for managing nonseminomatous testicularcancer

Interpretation

AFP is increased in the following disorders:

Ataxia telangiectasiaHereditary tyrosinemiaPrimary hepatocellular carcinomaTeratocarcinoma

Gastrointestinal tract cancers with and without liver metastasesBenign hepatic conditions such as acute viral hepatitis, chronic active hepatitis, andcirrhosis

AFP is not recommended as a screening procedure to detect cancer in the generalpopulation This assay is intended only as an adjunct in the diagnosis and monitoring ofAFP-producing tumors The diagnosis should be confirmed by other tests or procedures.Serum levels of AFP do not correlate well with other clinical features of HCC, such as size,stage, or prognosis

A case–control study evaluated the diagnostic characteristics of the serum AFP in screeningfor HCC in patients with different types of chronic liver disease The following sensitivitiesand specificities were observed:

AFP cutoff 16 μg/L (sensitivity 62%, specificity 89%)AFP cutoff 20 μg/L (sensitivity 60%, specificity 91%)AFP cutoff 100 μg/L (sensitivity 31%, specificity 99%)AFP cutoff 200 μg/L (sensitivity 22%, specificity 99%)False-positive elevations can occur with tumors of the GI tract or with liver damage (e.g.,cirrhosis, hepatitis, or drug or alcohol abuse) and pregnancy

Failure of the AFP value to return to normal by approximately 1 month after surgery suggeststhe presence of residual tumor

Elevation of AFP after remission suggests tumor recurrence; however, tumors originallyproducing AFP may recur without an increase in AFP

Fucosylated form of serum AFP that is most closely associated with HCC is recognized by alectin from the common lentil (AFP-L3) AFP-L3 is most useful in the differential diagnosis

of individuals with total serum AFP ≤200 ng/mL

Suggested Reading

Trevisani F, D’Intino PE, Morselli-Labate AM, et al Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with

chronic liver disease: influence of HBsAg and anti-HCV status J Hepatol 2001;34(4):570–575.

AMINOTRANSFERASES (AST, ALT)

Definition

Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) are members of thetransaminase family of enzymes, widely distributed in cells throughout the body AST isprimarily found in the heart, liver, skeletal muscle, and kidney, whereas ALT is foundprimarily in the liver and kidney, with lesser amounts in the heart and skeletal muscle ASTand ALT activities in the liver are about 7,000 and 3,000 times serum activities,respectively

Less than or equal to 1 year: 5–50 U/LGreater than 1 year: 10–40 U/L

Hepatocellular damage, liver cell necrosis, or injury of any cause

Alcoholic hepatitis (AST > ALT)

Viral and chronic hepatitis (ALT > AST)

Early acute hepatitis: AST is usually higher initially, but by 48 hours, ALT is usually higher.AST levels of 500 U/L suggest acute hepatocellular injury; seldom >500 U/L in obstructivejaundice, cirrhosis, viral hepatitis, AIDS, alcoholic liver disease

Acute fulminant viral hepatitis: Abrupt AST rise may be seen (rarely >4,000 IU/L) anddeclines more slowly; positive serologic tests and acute chemical injury

Congestive heart failure, arrhythmia, sepsis, and GI hemorrhage AST levels reach to a peak

of 1,000–9,000 U/L, declining by 50% within 3 days and to <100 U/L within a week,suggesting shock liver with centrolobular necrosis Serum bilirubin and ALP reflectunderlying disease

Trauma to skeletal or heart muscle

Acute heart failure (AST > ALT)

Severe exercise, burns, heat stroke

Hypothyroidism

Drug-induced injury to the liver

Acute bile duct obstruction due to a stone: Rapid rise of AST and ALT to very high levels(e.g., >600 U/L and often >2,000 U/L) followed by a sharp fall in 12–72 hours is said to betypical

Decreased In

Azotemia

Chronic renal dialysis

Pyridoxal phosphate deficiency states (e.g., malnutrition, pregnancy, alcoholic liver disease)

Limitations

Half-life of AST is 18 hours and that of ALT is 48 hours

The patient is rarely asymptomatic with ALT and AST levels >1,000 U/L

AST >10 times normal indicates acute hepatocellular injury, but lesser increases arenonspecific and may occur with virtually any form of liver injury

Increases ≤8 times upper limit of normal are nonspecific; may be found in any liver

Rarely increased >500 U/L (usually <200 U/L) in posthepatic jaundice, AIDS, cirrhosis, andviral hepatitis

Usually <50 U/L in fatty liver

Less than 100 U/L in alcoholic cirrhosis; ALT is normal in 50%, and AST is normal in 25%

of these cases

Less than 150 U/L in alcoholic hepatitis (may be higher if the patient has delirium tremens).Less than 200 U/L in approximately 50% of patients with cirrhosis, metastatic liver disease,lymphoma, and leukemia

Normal values may not rule out liver disease: ALT is normal in 50%, and AST is normal in25% of cases of alcoholic cirrhosis

Degree of increase has a poor prognostic value

Serial determinations reflect clinical activity of liver disease Persistent increase mayindicate chronic hepatitis

Mild increase of AST and ALT (usually <500 U/L) with ALP increased greater than threetimes normal indicates cholestatic jaundice, but more marked increase of AST and ALT(especially >1,000 U/L) with ALP increased less than three times normal indicateshepatocellular jaundice

Rapid decline in AST and ALT is a sign of recovery from disease but in acute fulminanthepatitis may represent loss of hepatocytes and poor prognosis

Poor correlation of increased concentration with extent of liver cell necrosis and has a littleprognostic value

Although AST, ALT, and bilirubin are most characteristic of acute hepatitis, they areunreliable markers of severity of injury

ALT has 45% variation during the day; highest in afternoon and lowest at night Both ASTand ALT exhibit 10–30% variation from 1 day to next AST levels are 15% higher inAfrican American men

AMMONIA (BLOOD NH3 , NH3 , NH4 )

Definition

Ammonia is derived mostly from protein degradation Most of the ammonia in the bloodcomes from the intestine, where colonic bacteria use ureases to breakdown urea to ammoniaand CO2 Eight-five percent of blood from the intestine is carried directly to the liver viathe portal vein and 85% of ammonia is converted back to urea and excreted by the kidneys

and colon Helicobacter pylori in the stomach appears to be an important source of

ammonia in patients with cirrhosis

Normal range: <50 μmol/L.

Use

In the diagnosis of hepatic encephalopathy and hepatic coma in the terminal stages of liver

cirrhosis, hepatic failure, acute and subacute necrosis, and Reye syndrome.Hyperammonemia in infants may be an indicator of inherited deficiencies of the urea cyclemetabolic pathway.

Should be measured in cases of unexplained lethargy and vomiting, encephalopathy, or anyneonate with unexplained neurologic deterioration

Not useful to assess the degree of dysfunction (e.g., in Reye syndrome, hepatic functionimproves and the ammonia level falls, even in patients who finally die of these disorders)

Interpretation

Increased In

Certain inborn errors of metabolism (e.g., defects in urea cycle, organic acid defects)

Transient hyperammonemia in newborn; unknown etiology; may be life threatening in thefirst 48 hours

May occur in any patient with severe liver disease (e.g., acute hepatic necrosis, terminalcirrhosis, and after portacaval anastomosis) Increased in most cases of hepatic coma butcorrelates poorly with degree of encephalopathy Not useful in known liver disease but may

be useful in encephalopathy of unknown cause

Moribund children: Moderate increases (≤300 μmol/L) without being diagnostic of aspecific disease

GU tract infection with distention and stasis

Ureterosigmoidostomy

Some hematologic disorders, including acute leukemia and after bone marrowtransplantation

Total parenteral nutrition

Smoking, exercise, valproic acid therapy

Decreased In

Hyperornithinemia (deficiency of ornithine aminotransaminase activity) with gyrate atrophy

of the choroid and retina

Limitations

Atmospheric ammonia may cause falsely elevated results

The presence of ammonium ions in anticoagulants may produce falsely elevated results.Ammonia levels are not always high in all patients with urea cycle disorders

High-protein diet may cause increased levels

Ammonia levels may also be elevated with GI hemorrhage

Ammonia increases due to cellular metabolism: 20% in 1 hour and 100% by 2 hours

Prolonged tourniquet application can falsely raise blood ammonia levels

AMNIOCENTESIS

See Prenatal Screening.

AMPHETAMINES *

Definition

Sympathomimetic amines with central nervous system stimulant activity

Other names: amphetamine (Adderall, Dexedrine, Benzedrine, “bennies”),methamphetamine (Desoxyn, “ice,” “speed,” “meth”), ecstasy (3,4-methylenedioxymethamphetamine; MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA, MDE, “Eve”), pseudoephedrine (Sudafed),ephedrine, phentermine (Adipex), and methylphenidate (Ritalin)

Other psychotropic amines include 4-bromo-2,5-dimethoxyamphetamine, methoxyamphetamine (PMA), and p-methoxymethamphetamine (PMMA) These are not

p-generally detected in screening tests and may not be reported in confirmation tests unlessspecifically requested

Other drugs that are metabolized to methamphetamine/amphetamine: benzphetamine,clobenzorex, famprofazone, fenethylline, and fenproporex

Use

Appetite suppressants

Mood enhancers (psychotropics)

Treatment of attention deficit hyperactivity disorder

Nasal decongestants, bronchodilators

Limitations

Screen [urine]: immunoassay on automated chemistry analyzers

Amphetamine: Generally do not give positive results for L-amphetamine, MDA,MDMA, ephedrine, phentermine

Ecstasy: The target analyte of most immunoassays is MDMA Screen will not givepositive results with D/L-amphetamine, D/L-methamphetamine, phentermine, ephedrine,pseudoephedrine, PMA, PMMA

Screen [serum]: ELISA

Target analyte: D-amphetamine Will not give positive results with L-amphetamine, Lmethamphetamine, phenylpropanolamine, MDMA, MDE

-May produce positive results with MDA

Confirmation [serum/urine]:

Confirmation techniques do not typically differentiate between D and L forms ofamphetamine and methamphetamine

AMYLASE

Amylases are a group of hydrolases that degrade complex carbohydrates into fragments.Amylase is produced by the exocrine pancreas and the salivary glands to aid in thedigestion of starch It is also produced by the small intestine mucosa, ovaries, placenta,liver, and fallopian tubes

Normal range: 5–125 U/L.

Use

To diagnose and monitor pancreatitis or other pancreatic diseases

In the workup of any intra-abdominal inflammatory event

Interpretation

Increased In

Acute pancreatitis (e.g., alcoholic, autoimmune) Urine levels reflect serum changes by atime lag of 6–10 hours

Acute exacerbation of chronic pancreatitis

Drug-induced acute pancreatitis (e.g., aminosalicylic acid, azathioprine, corticosteroids,dexamethasone, ethacrynic acid, ethanol, furosemide, thiazides, mercaptopurine,phenformin, triamcinolone)

Drug-induced methodologic interference (e.g., pancreozymin [contains amylase], chlorideand fluoride salts [enhance amylase activity], lipemic serum [turbidimetric methods])

Obstruction of pancreatic duct by

Complications of pancreatitis (pseudocyst, ascites, abscess)

Pancreatic trauma (abdominal injury; following ERCP)

Altered GI tract permeability:

Ischemic bowel disease or frank perforationEsophageal rupture

Perforated or penetrating peptic ulcerPostoperative upper abdominal surgery, especially partial gastrectomy (≤2 timesnormal in one third of patients)

Acute alcohol ingestion or poisoning

Salivary gland disease (mumps, suppurative inflammation, duct obstruction due to calculus,radiation)

Malignant tumors (especially pancreas, lung, ovary, esophagus; also breast, colon); usually

>25 times upper reference limit, which is rarely seen in pancreatitis

Advanced renal insufficiency; often increased even without pancreatitis

Macroamylasemia

Others, such as chronic liver disease (e.g., cirrhosis; ≤2 times normal), burns, pregnancy(including ruptured tubal pregnancy), ovarian cyst, diabetic ketoacidosis, recent thoracicsurgery, myoglobinuria, presence of myeloma proteins, some cases of intracranial bleeding(unknown mechanism), splenic rupture, and dissecting aneurysm

It has been suggested that a level >1,000 Somogyi units is usually due to surgicallycorrectable lesions (most frequently stones in biliary tree), the pancreas being negative orshowing only edema; but 200–500 U is usually associated with pancreatic lesions that arenot surgically correctable (e.g., hemorrhagic pancreatitis, necrosis of pancreas)

Increased serum amylase with low urine amylase may be seen in renal insufficiency andmacroamylasemia Serum amylase ≤4 times normal in renal disease only when creatinineclearance is <50 mL/minute due to pancreatic or salivary isoamylase; but rarely more thanfour times normal in the absence of acute pancreatitis

Decreased In

Extensive marked destruction of the pancreas (e.g., acute fulminant pancreatitis, advancedchronic pancreatitis, advanced cystic fibrosis) Decreased levels are clinically significantonly in occasional cases of fulminant pancreatitis

Severe liver damage (e.g., hepatitis, poisoning, toxemia of pregnancy, severe thyrotoxicosis,severe burns)

Methodologic interference by drugs (e.g., citrate and oxalate decrease activity by bindingcalcium ions)

Normal: 1–5%

Macroamylasemia: <1%; very useful for this diagnosisAcute pancreatitis: >5%; use is presently discouraged for this diagnosisAmylase-to-creatinine clearance ratio = (urine amylase/serum amylase) (serumcreatinine/urine creatinine) × 100

Normal In

Relapsing chronic pancreatitis

Patients with hypertriglyceridemia (technical interference with test)

Frequently normal in acute alcoholic pancreatitis

Limitations

Composed of pancreatic and salivary types of isoamylases distinguished by variousmethodologies; nonpancreatic etiologies are almost always salivary; both types may beincreased in renal insufficiency

An elevation of total serum α-amylase does not specifically indicate a pancreatic disorder,since the enzyme is produced by the salivary glands, mucosa of the small intestine, ovaries,placenta, liver, and the lining of the fallopian tubes