Page 1

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Appendix: Therapeutic Drug Monitoring, Pharmacogenetic Testing, & Laboratory Reference Intervals C. Diana Nicoll, MD, PhD, MPA Chuanyi Mark Lu, MD, PhD

Table 1.  Therapeutic drug monitoring.1 Drug

Effective Concentrations

Half-Life (hours)

Dosage Adjustments ↓ in renal dysfunction

Comments

Amikacin

Conventional 2–3; ­ ↑ in uremia dosing: Peak: 20–30 mg/L; trough: < 10 mg/L High dose once daily: Peak: 60 mg/L; trough: undetectable

Amitriptyline

95–250 ng/mL

9–25

Drug is highly protein-bound. Patient-specific decrease in protein binding may invalidate quoted therapeutic reference interval for effective concentration.

Carbamazepine

4–12 mg/L

10–15

Induces its own metabolism. Metabolite 10,11-epoxide exhibits 13% cross-reactivity by immunoassay. Adverse reactions: skin reactions, myelosuppression.

Cyclosporine

100–300 mcg/L (ng/mL) whole blood

6–12

Desipramine

100–250 ng/mL

13–23

↓ in renal dysfunction, liver disease

Concomitant kanamycin or tobramycin therapy may give falsely elevated amikacin results by immunoassay.

Cyclosporine is lipid-soluble (20% bound to leukocytes; 40% to erythrocytes; 40% in plasma, highly bound to lipoproteins); the binding is temperature-dependent in vitro and concentration-dependent in vivo. HPLC and LC-tandem mass spectrometry methods are highly specific for parent drug and considered as the gold standard assays. Monoclonal fluorescence polarization immunoassay (FPIA) and monoclonal chemiluminescence immunoassay also measure cyclosporine reliably; polyclonal immunoassays are less specific due to cross-reaction with drug metabolites. Anticonvulsants and rifampin increase metabolism. Erythromycin, ketoconazole, and calcium channel blockers decrease metabolism. The main adverse reaction is concentration-related nephrotoxicity. Drug is highly protein-bound. Patient-specific decrease in protein binding may invalidate quoted therapeutic reference interval for effective concentration. (continued )


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Table 1.  Therapeutic drug monitoring.1 (continued ) Drug

Effective Concentrations

Half-Life (hours)

Dosage Adjustments

Digoxin

CHF: 0.5–0.9 ng/mL Atrial fibrillation: 0.5–2 ng/mL

42; ↑ in uremia, CHF

Ethosuximide

40–100 mg/L

Child: 30 Adult: 50

Gentamicin

Conventional dosing: Peak: 4–8 mg/L; trough: < 2 mg/L High dose once daily: Peak: 20 mg/L; trough: undetectable

2–3; ­↑ in uremia (7.3 during dialysis)

Imipramine

180–350 ng/mL

10–16

Lidocaine

1–5 mg/L

1.8; × in uremia, CHF; ↑ ­ in cirrhosis

↓ in CHF, liver disease

Levels increased with cimetidine therapy. CNS toxicity common in the elderly.

Lithium

0.5–1.5 mmol/L

22; ↑­ in uremia

↓ in renal dysfunction

Thiazides and loop diuretics may increase serum lithium levels.

3–10 low dose; 8–15 high dose; ↑­ in uremia

↓ in renal dysfunction

Therapeutic concentrations depend on the treatment protocol (low versus high dose) and time of specimen collection. 7-Hydroxymethotrexate cross-reacts 1.5% in immunoassay. To minimize toxicity, leucovorin or glucarpidase should be continued if methotrexate level is > 0.1 mcmol/L at 48 hours after start of therapy. Methotrexate > 1 mcmol/L at > 48 hours requires an increase in rescue therapy.

Methotrexate

Nortriptyline

50–140 ng/mL

18–44

Phenobarbital

10–40 mg/L

Child: 37–73 Adult: 53–140; ↑ ­in cirrhosis

Phenytoin

10–20 mg/L; 5–10 mg/L in uremia and severe hypoalbuminemia

Dose/concentrationdependent

↓ in renal dysfunction, CHF, hypothyroidism ↑­ in hyperthyroidism

Comments Bioavailability of digoxin tablets is 50–90%. Specimen must not be drawn within 4 hours of an intravenous dose or 6 hours of an oral dose. Dialysis does not remove a significant amount. Hypokalemia potentiates toxicity. Digitalis toxicity is a clinical and not a laboratory diagnosis. Digibind (digoxin-specific antibody) therapy of digoxin overdose can interfere with measurement of digoxin levels depending on the digoxin assay. Elimination reduced by amiodarone, quinidine, and verapamil. Levels used primarily to assess clinical response and compliance. Toxicity is rare and does not correlate well with plasma concentrations.

↓ in renal dysfunction

Draw peak specimen (conventional dosing) 30 minutes after end of 30- to 60-min infusion. Draw trough just before next dose. In uremic patients, some penicillins (eg, carbenicillin, ticarcillin, piperacillin) may decrease gentamicin half-life from 46 hours to 22 hours, posing a risk of reduced antibacterial efficacy. The main adverse reactions are CNS, otic, and renal toxicities. Drug is highly protein-bound. Patient-specific decrease in protein binding may invalidate quoted therapeutic reference interval for effective concentration.

Drug is highly protein-bound. Patient-specific decrease in protein binding may invalidate quoted therapeutic reference interval for effective concentration. ↓ in liver disease

Metabolized primarily by the hepatic microsomal enzyme system. Many drug-drug interactions. Drug metabolite cross-reacts in immunoassays; the crossreactivity may be of significance only in the presence of advanced chronic kidney disease. Metabolism is capacity-limited. Increase dose cautiously when level approaches therapeutic reference interval, since new steady-state level may be disproportionately higher. Drug is very highly protein-bound; protein binding is decreased in uremia and hypoalbuminemia. Free drug level (pharmacologically active fraction) may be indicated in certain clinical circumstances. (continued )


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Appendix

Table 1.  Therapeutic drug monitoring.1 (continued ) Drug

1

Effective Concentrations

Half-Life (hours)

Dosage Adjustments

Comments

Sirolimus

Trough: 4–12 ng/mL when used in combination with cyclosporine A; 12–20 ng/mL if used alone

62

↓ in liver dysfunction and with drugs inhibiting CYP3A4 activity

Sirolimus is an immunosuppressant used in combination with cyclosporine and corticosteroids for prophylaxis of organ rejection after kidney transplantation. It has also been used in liver and heart transplantation. When used in combination with cyclosporine, careful monitoring of kidney function is required. Once the initial dose titration is complete, monitoring sirolimus trough concentrations weekly for the first month and every 2 weeks for the second month appears to be appropriate. The optimal time for specimen collection is 24 h after the previous dose or 0.5 to 1 h prior to the next dose (trough level).

Tacrolimus

Trough: 8–12 ng/mL

8.7–11.3

↓ in liver dysfunction and with drugs inhibiting CYP3A4 activity

Tacrolimus is used for prophylaxis of organ rejection in adult patients undergoing liver or kidney transplantation and in pediatric patients undergoing liver transplantation. It has also been used to prevent rejection in heart, small bowel, and allogeneic bone marrow transplant patients and to treat autoimmune diseases. Antacid or sucralfate administration should be separated from tacrolimus by at least 2 h. The optimal time for specimen collection is 12 h after the previous dose or 0.5 to 1 h prior to the next dose (trough level).

Theophylline

5–15 mg/L

9

↓ in CHF, cirrhosis, and with cimetidine

Caffeine cross-reacts 10%. Elimination is increased 1.5–2 times in smokers. 1,3-Dimethyl uric acid metabolite increased in uremia and, because of cross-reactivity, may cause an apparent slight increase in serum theophylline.

Tobramycin

Conventional dosing: Peak: 5–10 mg/L; trough: < 2 mg/L High dose once daily: Peak: 20 mg/L; trough: undetectable

2–3; ↑ in uremia

↓ in renal dysfunction

Tobramycin, kanamycin, and amikacin may cross-react in immunoassay. Some antibiotics may decrease tobramycin half-life in uremic patients, causing reduced antibacterial efficacy.

Valproic acid

50–100 mg/L

Child: 6–8 Adult: 10–12

Vancomycin

Trough: 10–20 mg/L

6; ↑ in uremia

Significant fraction of the drug is protein-bound in vivo (concentration-dependent). Decreased binding in uremia and cirrhosis. ↓ in renal dysfunction

Ototoxicity in uremic patients may lead to irreversible deafness. Keep peak level < 40–50 mg/L to avoid severe toxicity.

Serum from a plain red-top tube is typically used for therapeutic drug monitoring except for cyclosporine, which requires whole blood sample in a lavender (EDTA) tube. In general, the specimen should be drawn just before the next dose (trough). ↑­, increased; ↓, decreased; CYP, cytochrome P450; HPLC, high performance liquid chromatography; CHF, congestive heart failure; CNS, central nervous system. Modified, with permission, from Nicoll D et al. Pocket Guide to Diagnostic Tests, 6th ed. McGraw-Hill, 2012.


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Table 2.  Selected pharmacogenetic tests: clinical relevance.1 Pharmacogenetic Biomarker

Selected Variants (mutant allele, enzyme activity)

Allele Frequency

Drugs

Clinical Relevance

Cytochrome P450 (CYP) 2C9 variants

2C9*2 (430C > T, ↓) 2C9*3 (1075A > C, ↓↓)

2C9*2 and 2C9*3 are present in 9–20% of whites, 1–3% of blacks, and < 1% of Asians

Warfarin (Coumadin)

Hepatic CYP2C9 is responsible for the metabolic inactivation and clearance of the anticoagulant warfarin. Patients carrying 2C9*2 or 2C9*3 (or both) (heterozygote, homozygote or compound heterozygote) require reduced maintenance dose to reach a therapeutic INR. While INR remains the standard for monitoring warfarin therapy, CYP2C9 genotyping can be an important aid to dosing strategy for warfarin-naïve patients, particularly whites.

CYP 2C19 variants

2C19*2(681G > A, none) 2C19*3(636G > A, none) 2C19*4(1A > G, none) 2C19*5(1297C > T, none)

The mutant variants are present in 12–25% of Asians, and 2–7% of whites and blacks

Clopidogrel (Plavix)

Clopidogrel, an antiplatelet drug, must be metabolized in the liver by CYP isoenzymes, principally CYP 2C19, to become active. When treated with clopidogrel at recommended dosages, patients with CYP 2C19 variants have more cardiovascular events than do patients with normal CYP 2C19 function. Alternative drug or intervention strategies should be considered for patients with 2C19 variants.. CYP 2C19*17 carrier status (25% of whites) is associated with increased enzyme activity and an increased risk of bleeding.

HLA-B*1502 allele

HLA-B*1502

10–15% of Asians; 1–2% of whites

Carbamazepine (Tegretol, Epitol)

Carbamazepine is associated with serious or even fatal idiosyncratic skin reactions, eg, Stevens-Johnson syndrome and toxic epidermal necrolysis. The reactions are significantly more common in patients who carry the HLA-B*1502 allele. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. HLA-B*1502 genotyping may be useful for risk stratification in patients of Asian descent. Patients carrying the HLA-B*1502 allele should not be given carbamazepine unless the expected benefit clearly outweighs the increased risk of serious skin reactions.

HLA-B*B5701 allele

HLA-B*5701

6–8% of whites and selected Indians; 1–2% of blacks and Asians

Abacavir (Ziagen)

Abacavir is a nucleoside analog reverse transcriptase inhibitor used for HIV treatment. The major treatment-limiting toxicity for abacavir use is drug hypersensitivity, occurring in 5–8% of recipients within 6 weeks of commencing therapy. There is an established association between carriage of the HLAB*5701 allele and abacavir hypersensitivity reactions. HLA-B*5701positive patients should not be prescribed abacavir or an abacavir-containing regimen. (continued )


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Appendix

Table 2.  Selected pharmacogenetic tests: clinical relevance.1 (continued ) Pharmacogenetic Biomarker

Selected Variants (mutant allele, enzyme activity)

Allele Frequency

Drugs

Clinical Relevance

Thiopurine methyltransferase (TPMT) variants

TPMT 2 (238G > C, ↓) TPMT*3A (460G > A and 719A>G, ↓↓) TPMT*3B (460G > A, ↓) TPMT*3C (719A > G, ↓)

About 10–12% of whites and blacks have reduced enzyme activity because they are heterozygous for one of the mutant alleles. About 1 in 300 whites is homozygous for a mutant allele.

Azathioprine (AZA), 6-mercaptopurine (6-MP)

AZA is a prodrug that is metabolized to 6-MP, which is then further metabolized to active 6-thioguanine (6-TG) and inactive 6-methylmercaptopurine (6-MMP) through hypoxanthine phosphoribosyltransferase and TPMT, respectively. Variation in the TPMT gene can result in functional inactivation of the enzyme and an increased risk of lifethreatening, 6-TG associated myelosuppression. TPMT genotyping before instituting AZA or 6-MP can help prevent toxicity by identifying individuals with low or absent TPMT enzyme activity. Patients with homozygous or compound heterozygous mutant alleles (“poor metabolizers”) should not be given AZA or 6-MP, while heterozygotes with a single mutant allele should be treated with lower doses.

Uridine diphosphoglucuronosyltransferase 1A1 (UGT 1A1) variants

UGT1A1*28 (7 TA repeats in promoter, ↓)

Homozygosity in 9-23% of whites, blacks and Indians, and in 1–2% of eastern Asians.

Irinotecan (Camptosar)

Irinotecan is used in the treatment of metastatic colorectal cancer. It is metabolized to active SN-38, a topoisomerase I inhibitor. SN-38 is further glucuronidated to inactive SN-38G by UGT1A1 and excreted. Heterozygous and homozygous UGT1A1*28 genotypes show a 25% and 70% decrease in enzyme activity, respectively. The presence of the UGT1A1*28 allele is a risk factor for the development of adverse drug reactions (eg, neutropenia, severe diarrhea). Testing for the allele can prevent drug toxicity at high doses of irinotecan.

Vitamin K epoxide reductase complex (VKORC1) variants

VKORC1 (-1639G > A)

The homozygous (-1639G > A) allele (-1639AA genotype) is present in approximately 15% of whites and 80% of Chinese.

Warfarin (Coumadin)

The primary therapeutic target of the anticoagulant warfarin is VKOR. Polymorphisms in the VKOR encoding gene (VKORC1) explain about 30% of the phenotypic variability in drug effect. Patients carrying the VKORC1 (-1639G>A) allele require a lower warfarin maintenance dose to reach a therapeutic INR.

BRAF gene

BRAF V600E mutation

40-60% of advanced melanomas

Vemurafenib (Zelboraf)

Activating mutations in BRAF (a serine– threonine protein kinase) are present in 40-60% of advanced melanomas. Most, with (80-90%) of the mutations are the substitution of glutamic acid for valine at amino acid 600 (V600E mutation), and this is associated with a more aggressive clinical course. Vemurafenib, a potent inhibitor of the mutant BRAF, has a high level of therapeutic activity against advanced melanomas containing the V600E mutation.

*

1 Testing of these genetic biomarkers prior to instituting drug therapy is now recommended per US Food and Drug Administrationapproved drug labels. Note, however, that these tests are not yet mandated as standard practice. ↓, decreased; ↓↓, markedly decreased; >, single wild-type to variant nucleotide switch at the specific gene location; CYP, cytochrome P450 oxidase.


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Table 3.  Reference intervals for commonly used tests.1,2 Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Conventional Units

Conversion Factor

SI Units2

Collection3

Acetaminophen

Serum

10–20 mcg/mL Panic: > 50 mcg/mL

6.616

66–132 mcmol/L

Serum separator tube (SST)

Acetoacetate

Serum or urine

Negative (0 mg/dL)

0.098

Negative (0 mmol/L)

SST or urine container

Activated clotting time (ACT)

Whole blood

70–180 seconds (methodspecific)

Adrenocorticotropic hormone (ACTH)

Plasma

9–52 pg/mL (laboratoryspecific)

0.22

2–11 pmol/L

Siliconized glass or plastic lavender

Alanine aminotransferase (ALT, SGPT, GPT)

Serum or plasma

0-35 units/L(laboratoryspecific)

0.02

0-0.7 mckat/L (laboratory-specific)

SST, plasma preparation tube (PPT) (green)

Albumin

Serum or plasma

3.4–4.7 g/dL

10.00

34–47 g/L

SST, PPT (green)

27.74

83–277 pmol/L 139–831 pmol/L

SST

Aldosterone

Serum

+

Salt-loaded (120 mEq Na /d for 3–4 days):   Supine: 3–10 ng/dL   Upright: 5–30 ng/dL

Collect in a plastic syringe without anticoagulant

Salt-depleted (20 mEq Na+/d for 3–4 days):   Supine: 12–36 ng/dL   Upright: 17–137 ng/dL Urine

Salt-loaded (120 mEq Na+/d for 3–4 days): 1.5–12.5 mcg/24 h

332–997 pmol/L 471–3795 pmol/L

2.77

Salt-depleted (20 mEq Na+/d for 3–4 days): 18–85 mcg/24 h

4.2–34.6 nmol/d

Urine bottle containing boric acid

49.9–235.5 nmol/d

Alkaline phosphatase

Serum or plasma

41–133 units/L (method- and age-dependent)

0.02

0.7–2.2 mckat/L (method- and age-dependent)

SST, PPT (green)

Ammonia (NH3)

Plasma

18–60 mcg/dL

0.587

11–35 mcmol/L

Green (iced)

Amylase

Serum or plasma

20–110 units/L (laboratoryspecific)

0.02

0.33–1.83 mckat/L (laboratory-specific)

SST, PPT (green)

Angiotensin-converting enzyme (ACE)

Serum

12–35 units/L (methoddependent)

16.67

200–583 nkat/L (method-dependent)

SST

Antithrombin (AT)

Plasma

84–123% (qualitative/activity) 80–130% (quantitative/antigen)

α1-Antitrypsin, α1-Antiprotease

Serum or plasma

110–270 mg/dL

0.01

1.1–2.7 g/L

SST, PPT (green)

Aspartate aminotransferase (AST, SGOT, GOT)

Serum or plasma

0–35 units/L (laboratoryspecific)

0.02

0–0.58 mckat/L (laboratory-specific)

SST, PPT (green)

Basophil count

Whole blood

0.01–0.12 × 103/mcL

1.00

0.01–0.12 × 109/L

Lavender

bcr/abl, t (9;22) translocation by reversetranscriptase polymerase chain reaction (RT-PCR), qualitative

Whole blood

Negative (Positive: chronic myeloid leukemia, some acute B-lymphoblastic leukemia)

b2 microglobulin

Serum or plasma

< 0.2 mg/dL

Blue

Lavender

10

< 2 mg/L

SST, PPT (green) (continued )


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Appendix

Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test Bilirubin

Specimen Serum or plasma

Conventional Units Total: 0.1–1.2 mg/dL

Conversion Factor 17.10

SI Units2 2–21 mcmol/L

Direct (conjugated to glucuronide): 0.1–0.5 mg/dL

< 8 mcmol/L

Indirect (unconjugated): 0.1–0.7 mg/dL

< 12 mcmol/L

Collection3 SST, PPT (green)

Blood urea nitrogen (BUN)

Serum or plasma

8–20 mg/dL

0.357

2.9–7.1 mmol/L

SST, PPT (green)

B-type natriuretic peptide (BNP)

Plasma

< 100 pg/mL

1.0

< 100 ng/L

Lavender

C-peptide

Serum or plasma

0.8–4.0 ng/mL

0.333

0.27–1.33 nmol/L

SST or green/iced (fasting)

C-reactive protein, high sensitivity (hs-CRP)

Serum or plasma

< 1.0 mg/dL

10.00

< 10 mg/L

SST, PPT (green)

C-telopeptide, betacross-linked (CTx)

Serum

Male: 60-850 pg/mL Female: premenopausal 60-650 pg/mL, postmenopausal 100-1000 pg/mL (age- and laboratory-specific)

1.00

Male: 60-850 ng/L Female: premenopausal 60-650 ng/L, postmenopausal 1001000 ng/L (age- and laboratoryspecific)

Red, SST

Calcitonin

Plasma or serum

Male: 0–11.5 pg/mL Female: 0–4.6 pg/mL

1.00

Male: 0–11.5 ng/L Female: 0–4.6 ng/L

Green, SST

Calcium (Ca2+)

Serum or plasma

8.5–10.5 mg/dL Panic: < 6.5 or > 13.5 mg/dL

0.25

2.1–2.6 mmol/L

SST, PPT (green)

Calcium (ionized)

Serum or whole blood

4.6–5.3 mg/dL

0.25

1.15–1.32 mmol/L

SST, PPT (green) (anaerobic)

Calcium (UCa)

Urine

100–300 mg/24 h

0.025

2.5–7.5 mmol/24 h

Urine bottle containing hydrochloric acid

Carbon dioxide, partial pressure (Pco2)

Whole blood

32–48 mm Hg

0.13

4.26–6.38 kPa

Heparinized syringe (iced)

Carbon dioxide (CO2), total (bicarbonate)

Serum or plasma

22–32 mEq/L Panic: < 15 or > 40 mEq/L

1.00

22–32 mmol/L Panic: < 15 or > 40 mmol/L

SST, PPT (green)

Carboxyhemoglobin (HbCO)

Whole blood

< 9% of total hemoglobin (Hb)

0.01

< 0.09 fraction of total hemoglobin

Heparinized syringe or Green

Carcinoembryonic antigen (CEA)

Serum

0–5 ng/mL

1.00

0–5 mcg/L

SST

Catecholamines

Urine

Norepinephrine: 15–80 mcg/24 h Epinephrine: 0–20 mcg/24 h Dopamine: 65–400 mcg/24 h

5.91

89–473 nmol/24 h

Urine container with hydrochloride acid

5.46 6.53

0–109 nmol/24 h 425–2610 nmol/24 h

0.36–1.73 × 103/mcL

1.00

0.36–1.73 × 106/L

CD4 T cell count

Whole blood

Lavender (order T-cell subsets and a CBC with differential) (continued )


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Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Conventional Units

Conversion Factor

SI Units2

Collection3

Ceruloplasmin

Serum or plasma

20–60 mg/dL (laboratoryspecific)

10.00

200–600 mg/L

SST, PPT (green)

Chloride (Cl–)

Serum or plasma

101–112 mEq/L

1.00

101–112 mmol/L

SST, PPT (green)

Cholesterol

Serum or plasma

Desirable: < 200 mg/dL

0.0259

Desirable: < 6.0 mmol/L Borderline: 6.0–7.2 mmol/L High risk: > 7.2 mmol/L

SST, PPT (green)

Borderline: 200–240 mg/dL High risk: > 240 mg/dL Chorionic gonadotropin, β-subunit (β-hCG), quantitative

Serum

Males and nonpregnant females: undetectable or < 5 mU/mL

1.00

Males and nonpregnant females: undetectable or < 5 units/L

SST

Complement C3

Serum

64–166 mg/dL

10.00

640–1660 mg/L

SST

Complement C4

Serum

15–45 mg/dL

10.00

150–450 mg/L

Complement CH50

Serum

(Laboratory-specific)

Cortisol

Serum or plasma

8:00 am: 5–20 mcg/dL

27.59

140–550 nmol/L

SST, PPT (green)

Cortisol (urinary free)

Urine

10–110 mcg/24 h

2.76

27.6–303.6 nmol/24 h

Urine bottle containing boric acid

Creatine kinase (CK)

Serum or plasma

32–267 units/L (methoddependent)

0.02

0.53–4.45 mckat/L (method-dependent)

SST, PPT (green)

Creatine kinase MB (CKMB)

Serum or plasma

< 16 units/L or < 4% of total CK (laboratory-specific) Mass units: 0–7 mcg/L

0.04

< 0.27 mckat/L

SST, PPT (green)

Creatinine (Cr)

Serum or plasma

0.6–1.2 mg/dL

88.4

50–100 mcmol/L

SST, PPT (green)

Creatinine clearance (ClCr)

See Collection column

Adults: 90–140 mL/min/ 1.73 m2 body surface area (BSA)

0.0167

1.5–2.3 mL/s/1.73 m2 BSA

Carefully timed 24-hour urine and simultaneous serum or plasma creatinine sample

Cryoglobulins

Serum

Negative

D-dimer, quantitative

Plasma

< 500 ng/mL

1.00

< 500 mcg/L

Blue

Dehydroepiandrosterone sulfate (DHEA-S)

Serum or plasma

Male: 40-500 mcg/dL Female: 20-320 mcg/dL

10.00

Male: 400-5000 mcg/L Female: 200-3200 mcg/L

SST, PPT (green)

Eosinophil count

Whole blood

0.04–0.5 × 103/mcL

1.00

0.04–0.5 × 109/L

Lavender

Erythrocyte count (RBC count)

Whole blood

4.7–6.1 × 10 /mcL

1.00

4.7–6.1 × 10 /L

Lavender

Erythrocyte sedimentation rate

Whole blood

Male: < 10 mm/h Female: < 15 mm/h (laboratory-specific)

Same

Lavender (test must be run within 2 h)

Erythropoietin (EPO)

Serum

5–30 mU/mL

1.00

5–30 units/L

SST

Estradiol

Serum

Early follicular: 30–100 pg/mL Late follicular: 100–400 pg/mL Luteal: 50–150 pg/mL Postmenopausal: 2–21 pg/mL

3.671

110–367 pmol/L 367–1468 pmol/L 183–550 pmol/L 7–77 pmol/L

SST

SST Red

Red (transported at 37 °C)

6

12

(continued )


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Appendix

Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Conventional Units

Conversion Factor

SI Units2

Collection3

Estrogens, total

Serum

Follicular: 60–200 pg/mL Luteal: 160–400 pg/mL Postmenopausal: < 130 pg/mL

1.00

60–200 ng/L 160–400 ng/L < 130 ng/L

SST

Ethanol

Serum or plasma

0 mg/dL Legal “driving under the influence” in many states is defined as > 80 mg/dL (> 17 mmol/L) blood alcohol level; serum alcohol levels are 10–35% higher than whole blood alcohol levels

0.217

0 mmol/L

SST, PPT

Factor VIII assay

Plasma

50–150% of normal (varies with age)

Blue (iced)

Fecal fat

Stool

Random: < 60 droplets of fat per high-power field 72-hour: < 7 g/24 h

Qualitative: Random stool sample Quantitative: 72-hour collection following 2-day dietary fat regimen

Ferritin

Serum or plasma

Male: 16–300 ng/mL Female: 4–161 ng/mL

2.247

Male: 36-674 pmol/L Female: 9-362 pmol/L

SST, PPT (green)

α-Fetoprotein (AFP)

Serum

0–15 ng/mL

1.00

0–15 mcg/L

SST

Fibrinogen (functional)

Plasma

175–433 mg/dL Panic: < 75 mg/dL

0.0294

5.15–12.73 mcmol/L Panic: < 2.2 mcmol/L

Blue

Follicle-stimulating hormone (FSH)

Serum or plasma

Female:   Follicular phase 4–13 mU/mL   Luteal phase 2–13 mU/mL   Midcycle 5–22 mU/mL   Postmenopausal 30–138 mU/mL Male: 1–10 mU/mL (laboratory-specific)

1.00

Female:   4–13 units/L   2–13 units/L   5–22 units/L   30–138 units/L

SST, PPT (green)

Male: 1–10 units/L (laboratory-specific)

Free erythrocyte protoporphyrin (FEP)

Whole blood

< 35 mcg/dL (methoddependent)

Fructosamine

Serum or plasma

190–270 mcmol/L

1.0

190–270 mcmol/L

SST, PPT (green)

γ-Glutamyl transpeptidase (GGT)

Serum or plasma

9–85 units/L (laboratoryspecific)

0.02

0.15–1.42 mckat/L (laboratory-specific)

SST, PPT (green)

Gastrin

Serum

< 100 pg/mL (laboratoryspecific)

1.00

< 100 ng/L

SST

Glomerular filtration rate, estimated (eGFR)

Serum or plasma

> 60 mL/min/1.73 m2 (calculated based on creatinine level)

Glucagon

Plasma

20−100 pg/mL

1.00

20–100 ng/L

Lavender

Glucose

Serum or plasma

60–110 mg/dL Panic: < 40 or > 500 mg/dL

0.0555

3.33–6.11 mmol/L Panic: < 2.22 or > 27.75 mmol/L

(Fasting) SST, PPT, gray

Glucose-6-phosphate dehydrogenase (G6PD) screen

Whole blood

5–14 units/g Hb

0.02

0.1–0.28 mckat/L

Lavender

Glutamine

Cerebrospinal fluid (CSF)

6–15 mg/dL Panic: > 40 mg/dL

68.42

411–1028 mcmol/L

Collect CSF in a plastic tube

Lavender

SST, PPT (green)

(continued )


Appendix

1731

CMDT 2013

Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Conventional Units

Conversion Factor

SI Units2

Collection3

Glycated (glycosylated) hemoglobin (HbA1c)

Whole blood

3.9–5.6% (methoddependent)

Growth hormone (GH)

Serum or plasma

0–5 ng/mL

1.00

0–5 mcg/L

SST, PPT (green)

Haptoglobin

Serum or plasma

46–316 mg/dL

0.01

0.5–3.2 g/L

SST, PPT (green)

HDL cholesterol

Serum or plasma

Male: 27–67 mg/dL Female: 34–88 mg/dL (HDL cholesterol > 60 mg/dL is thought to lower risk of coronary heart disease)

0.0259

0.7–1.73 mmol/L 0.88–2.28 mmol/L

SST, PPT (green)

Hematocrit (Hct)

Whole blood

Male: 39–49% Female: 35–45% (age-dependent)

0.01

Male: 0.39–0.49 Female: 0.35–0.45

Lavender, Pink

Hemoglobin A1c (See Glycated Hemoglobin)

Whole blood

3.9–5.6% (method-dependent)

Hemoglobin A2 (HbA2)

Whole blood

1.5–3.5% of total hemoglobin

0.01

0.015–0.035

Lavender

Hemoglobin electrophoresis

Whole blood

HbA: > 95% HbA2: 1.5–3.5% HbF: < 2% (age-dependent)

Hemoglobin, total (Hb)

Whole blood

Male: 13.6–17.5 g/dL Female: 12.0–15.5 g/dL (age dependent) Panic: ≤ 7 g/dL

Heparin-associated antibody (heparin-induced thrombocytopenia)

Serum

Negative

SST

HIV antibody

Serum or plasma

EIA: Negative Western blot: Nonreactive

SST, PPT

HIV RNA, quantitative (viral load)

Plasma

Negative (or < 75 copies/mL, assay-specific)

Lavender, PPT (white)

Homocysteine

Serum or plasma

4.5–12 mg/dL (method- and age-dependent)

7.397

33.29–88.76 mcmol/L

SST, PPT

5-Hydroxyindoleacetic acid (5-HIAA)

Urine

2–8 mg/24 h

5.23

10–40 mcmol/d

Urine bottle containing hydrochloric acid

IgG index

Serum and CSF

0.29–0.59 ratio (CSF: serum ratio)

Immunoglobulins (Ig)

Serum

IgA: 78–367 mg/dL IgG: 583–1761 mg/dL IgM: 52–335 mg/dL

0.01

IgA: 0.78–3.67 g/L IgG: 5.83–17.6 g/L IgM: 0.52–3.35 g/L

SST

Insulin, immunoreactive

Serum or plasma

6–35 mcU/mL

6.945

42–243 pmol/L

SST, PPT

Insulin-like growth factor-1

Plasma

123–463 ng/mL (age- and sex-dependent)

1.0

123–463 mcg/L

Lavender

Iron (Fe)

Serum or plasma

50–175 mcg/dL

0.179

9–31 mcmol/L

SST, PPT (green)

Iron-binding capacity, total (TIBC)

Serum or plasma

250–460 mcg/dL

0.179

45–82 mcmol/L

SST, PPT (green)

Lavender, pink

Lavender

10.00

Male: 136–175 g/L Female: 120–155 g/L

Lavender

SST (for serum) and plastic tube (for CSF)

(continued )


1732

CMDT 2013

Appendix

Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Whole blood JAK2 mutations (V617F or exon 12/13 mutation), qualitative

Conventional Units

Conversion Factor

SI Units2

Collection3 Lavender

Negative (Positive: myeloproliferative neoplasms, ie, polycythemia vera, essential thrombocythemia, and primary myelofibrosis)

Kappa and lambda free light chains, quantitative

Serum

Free kappa: 0.57–2.63 mg/dL Free lambda: 0.33–1.94 mg/dL Free kappa/lambda ratio: 0.26–1.65

0.01

5.7–26.3 × 10-3 g/L 3.3–19.4 × 10-3 g/L

SST, red

Ketone bodies

Serum or plasma

Qualitative: Negative Quantitative: <10 mg/dL

10.0

< 100 mg/L

SST, PPT (green)

Lactate dehydrogenase (LDH)

Serum or plasma

88–230 units/L (laboratoryspecific)

0.02

1.46–3.82 mckat/L (laboratory-specific)

SST, PPT (green)

Lactic acid (lactate)

Venous blood

0.5–2.0 mEq/L

1.00

0.5–2.0 mmol/L

Gray (iced)

LDL cholesterol (calculated or direct)

Serum or plasma

Desirable: < 130 mg/dL (< 99 mg/dL for patients with CHD); Borderline: 130–159 mg/dL; High risk: ≥ 160 mg/dL

0.0259

< 3.37 mmol/L (< 2.57 mmol/L);

SST, PPT (green)

3.38–4.13 mmol/L; > 4.16 mmol/L

Lead (Pb)

Whole blood

Child: < 25 mcg/dL Adult: < 40 mcg/dL

0.0483

Child: < 1.21 mcmol/L Adult: < 1.93 mcmol/L

Dark blue (trace metal free)

Leukocyte (white blood cell) count, total (WBC count)

Whole blood

4.8–10.8 × 103/mcL Panic: < 1.5 × 103/mcL

1.00

4.8–10.8 × 109/L

Lavender

Lipase

Serum

0–160 units/L (laboratoryspecific)

0.02

0–2.66 mckat/L (laboratory-specific)

SST

Luteinizing hormone (LH)

Serum or plasma

Female:   Follicular phase 1–18 mU/mL   Luteal phase 0.4–20 mU/mL   Midcycle 24–105 mU/mL   Postmenopausal 15–62 mU/mL Male: 1–10 mU/mL (laboratory-specific)

1.00

Female:   1–18 units/L   0.4–20 units/L   24–105 units/L   15–62 units/L Male: 1–10 units/L (laboratory-specific)

SST, PPT

Lymphocyte count

Whole blood

0.8–3.5 × 103/mcL

1.00

0.8–3.5 × 109/L

Lavender

Magnesium (Mg )

Serum or plasma

1.8–3.0 mg/dL Panic: < 0.5 or > 4.5 mg/dL

0.411

0.75–1.25 mmol/L

SST, PPT (green)

Mean corpuscular hemoglobin (MCH)

Whole blood

27–34 pg

Mean corpuscular hemoglobin concentration (MCHC)

Whole blood

31–36 g/dL

Mean corpuscular volume (MCV)

Whole blood

80–100 fL

Lavender

Metanephrines, free

Plasma

Normetanephrine: < 0.9 nmol/L Metanephrine: < 0.5 nmol/L

Lavender

2+

Lavender 10.00

310–360 g/L

Lavender

(continued )


Appendix

1733

CMDT 2013

Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Conventional Units

Conversion Factor

SI Units2

Collection3

Metanephrines

Urine

0.3–0.9 mg/24 h

5.46

1.6–4.9 mcmol/24 h

Urine bottle containing hydrochloric acid

Methemoglobin (MetHb)

Whole blood

< 1% of total hemoglobin

0.01

< 0.01 fraction of total hemoglobin

Blood gas syringe, lavender, or green

Methylmalonic acid

Serum or plasma

0–0.05 mg/L

8.475

0–0.4 mcmol/L

SST, PPT (green)

Monocyte count

Whole blood

0.2–0.8 × 103/mcL

1.00

0.2–0.8 × 109/L

Lavender

Neutrophil count

Whole blood

2.2–8.6 × 103/mcL

1.00

2.2–8.6 × 109/L

Lavender

Osmolality

Serum or plasma

275–293 mosm/kg H2O Panic: < 240 or > 320 mosm/ kg H2O

1.00

275–293 mmol/kg H2O

SST, PPT

Urine

Random: 100–900 mosm/kg H2O

1.00

Random: 100–900 mmol/kg H2O

Urine container

Serum or plasma

Child or adolescent (age 7-17 years): 25-300 ng/mL

1.00

Child or adolescent (age 7-17 years): 25-300 mcg/L Adult: 10-15 mcg/L

SST, PPT (green)

0.13

11.04–14.36 kPa

Heparinized syringe (iced)

Osteocalcin

Adult: 10-15 ng/mL Oxygen, partial pressure (Po2)

Whole blood

83–108 mm Hg

Pancreatic elastase, fecal

Formed stool

> 200 mcg/g

Parathyroid hormone (PTH), intact

Serum or plasma

Intact PTH: 11–54 pg/mL (laboratory-specific)

Partial thromboplastin time, activated (PTT)

Plasma

25–35 seconds (reference interval varies) Panic: ≥ 60 seconds

Blue

pH

Whole blood

Arterial: 7.35–7.45 Venous: 7.31–7.41

Heparinized syringe (iced)

Phosphorus

Serum or plasma

2.5–4.5 mg/dL Panic: < 1.0 mg/dL

0.323

0.8–1.45 mmol/L

SST, PPT (green)

Plasminogen

Plasma

70–113% (activity)

1.00

70–113%

Blue

Platelet count (Plt)

Whole blood

150–450 × 10 /mcL Panic: < 25 × 103/mcL

1.0

150–450 × 10 /L Panic: < 25 × 109/L

Platelet-associated IgG

Plasma or serum

Negative

Platelet function test (PFA-100 closure time) (CEPI: collagen/ epinephrine cartridge; CADP: collagen/ADP cartridge)

Whole blood

CEPI: 70–170 seconds (laboratory-specific) CADP: 50–110 seconds (laboratory-specific)

Porphobilinogen (PBG)

Urine

Leak-proof container (freeze immediately)

3

Negative

0.11

Intact PTH: 1.2–5.7 pmol/L (laboratoryspecific)

9

Red, SST, PPT

Lavender Lavender, PPT, SST

1.0

CEPI: 70–170 seconds

Blue

CADP: 50–110 seconds

Protect from light (continued )


1734

CMDT 2013

Appendix

Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Conventional Units

Conversion Factor

SI Units2

Collection3

Potassium (K+)

Serum or plasma

3.5–5.0 mEq/L Panic: < 3.0 or > 6.0 mEq/L

1.00

3.5–5.0 mmol/L

SST, PPT (green)

Procalcitonin

Serum or plasma

< 0.10 ng/mL

1.00

< 0.10 mcg/L

SST, PPT (green)

Prolactin (PRL)

Serum or plasma

< 20 ng/mL

1.00

< 20 mcg/L

SST, PPT (green)

Prostate-specific antigen (PSA)

Serum or plasma

0–4 ng/mL

1.00

0–4 mcg/L

SST, PPT

Protein C

Plasma

71–176% (functional) 60–150% (antigenic)

Protein electrophoresis

Serum

Adult: Albumin: 3.3–4.7 g/dL α1: 0.1–0.4 g/dL α2: 0.3–0.9 g/dL b2: 0.7–1.5 g/dL g: 0.5–1.4 g/dL (polyclonal)

Blue SST, red

10.00 33–47 g/L 1–4 g/L 3–9 g/L 7–15 g/L 5–14 g/L (polyclonal)

Protein S (antigen)

Plasma

76–178%

Protein, total

Serum or plasma

6.0–8.0 g/dL

Blue

Prothrombin time (PT)

Plasma

11–15 seconds Panic: ≥ 30 seconds (laboratory-specific)

Red blood cell count

Whole blood

4.7–6.1 × 106/mcL (male) 3.5–5.5 × 106/mcL (female)

Renin activity

Plasma

High-sodium diet (75–150 mEq Na+/d): Supine: 0.2–2.3 ng/mL/h Standing: 1.3–4.0 ng/mL/h Low-sodium diet (30–75 mEq Na+/d): Standing: 4.0–7.7 ng/mL/h

Reticulocyte count

Whole blood

33–137 × 103/mcL

Russell viper venom clotting time (dilute) (RVVT)

Plasma

24–37 seconds

Salicylate (aspirin)

Serum

200–300 mg/L Panic: > 350 mg/L

0.00724

1.45–2.17 mmol/L Panic: > 2.53 mmol/L

Red

Sodium (Na+)

Serum or plasma

135–145 mEq/L Panic: < 125 or > 155 mEq/L

1.00

135–145 mmol/L Panic: < 125 or > 155 mmol/L

SST, PPT (green)

Somatostatin

Plasma

< 25 pg/mL (laboratoryspecific)

0.611

< 15.28 pmol/L (laboratory-specific)

Lavender, PPT (white)

Testosterone

Serum or plasma

Male: 175–781 ng/dL Female: 10–75 ng/dL

0.0347

Male: 6–27 nmol/L Female: 0.3–2.6 nmol/L

SST, PPT (green)

Thyroglobulin

Serum or plasma

3–42 ng/mL

1.00

3–42 mcg/L

SST, PPT (green)

Thyroid-stimulating hormone (TSH)

Serum or plasma

0.4–4 mcU/mL

1.00

0.4–4 mU/L

SST, PPT (green)

10.00

60–80 g/L

SST, PPT (green) Blue

1.00

4.7–6.1 × 1012/L 3.5–5.5 × 1012/L

Lavender Lavender

1.00

33–137 × 109/L

Lavender Blue

(continued )


Appendix

1735

CMDT 2013

Table 3.  Reference intervals for commonly used tests.1,2 (continued ) Current metric units ë Conversion factor = SI units SI units ï Conversion factor = Current metric units Test

Specimen

Conventional Units

Conversion Factor

Collection3

Thyroid-stimulating antibody, Thyroid stimulating hormone receptor antibody (TSH-R Ab [stim])

Serum

< 130% of basal activity; based on cAMP generation in thyroid cell tissue culture

Thyroxine, free (FT4)

Serum or plasma

0.7-1.86 ng/dL

12.87

9–24 pmol/L (varies with method)

SST, PPT (green)

Thyroxine (T4), total

Serum or plasma

5–11 mcg/dL

12.87

64–142 nmol/L

SST, PPT (green)

Transferrin

Serum or plasma

190–375 mg/dL

0.01

1.9–3.75 g/L

SST, PPT (green)

Transferrin receptor, soluble (sTfR)

Serum or plasma

2.2–5 mg/L (male) 1.9–4.4 mg/L (female) (laboratory-specific)

Triglycerides

Serum or plasma

< 165 mg/dL

0.0113

< 1.8 mmol/L

SST, PPT (green) (fasting)

Triiodothyronine (T3), total

Serum

95–190 ng/dL

0.0154

1.5–2.9 nmol/L

Red

Troponin-I (cTnI)

Plasma

< 0.1 ng/mL (method-dependent)

1.0

< 0.1 mcg/L (method-dependent)

Lavender

Uric acid

Serum or plasma

Male: 2.4–7.4 mg/dL

59.48

Male: 140–440 mcmol/L Female: 80–350 mcmol/L

SST, PPT (green)

SST, PPT (green)

Female: 1.4–5.8 mg/dL

1

SI Units2

Vanillylmandelic acid (VMA)

Urine

2–7 mg/24 h

5.05

10–35 mcmol/d

Urine bottle containing hydrochloric acid

Vitamin B12

Serum or plasma

170–820 pg/mL

0.738

125–600 pmol/L

SST, PPT (green)

Vitamin D, 25-hydroxy (25[OH]D)

Serum or plasma

20–50 ng/mL

2.496

50–125 nmol/L

SST, PPT (green)

Vitamin D, 1,25dihydroxy (1,25[OH]2D)

Serum or plasma

20–76 pg/mL

2.6

48–182 pmol/L

SST, PPT (green)

von Willebrand factor (vWF)

Plasma

50–180% (activity and antigen)

White blood cell count

Whole blood

4.8–10.8 × 103/mcL

Blue 1.00

4.8–10.8 × 109/L

Lavender

The reference intervals given here in conventional units and in SI units are from several large medical centers. Always use the reference intervals provided by your clinical laboratory, since intervals may be method-dependent. 2 References: Young DS. Implementation of SI units for clinical laboratory data. Ann Intern Med. 1987 Jan;106(1):114–29. [PMID: 3789557]; Systeme Internationale (SI) conversion factors for selected laboratory components. JAMA Author Instructions. 2001 Sep 28. http://jama.ama-assn.org/site/misc/auinst_si.xhtml; and Stein K. Journal adopts use of conventional and SI units. J Am Diet Assoc. 2005 Aug;105(8):1186–7. [PMID: 16182628] 3 See Table 4 for commonly used blood specimen collection tubes.


1736

CMDT 2013

Appendix

Table 4.â&#x20AC;&#x201A; Commonly used blood specimen collection tubes. Tube

Tube Contents

Typical Use

Lavender or Pink

K2EDTA

Complete blood count; blood banking (plasma); molecular testing

Gold SST

Clot activator and gel for serum separation

Serum chemistry tests

White PPT

K2EDTA and gel for plasma separation

Molecular testing (plasma-based)

Red

None

Blood banking (serum); therapeutic drug monitoring

Blue

Na citrate

Coagulation studies

Gray

Inhibitor of glycolysis (sodium fluoride)

Lactic acid; glucose

Green PPT, light green PPT

Sodium heparin or lithium heparin (green PPT, without gel; light green PPT, with gel for plasma separation)

Plasma chemistry tests (light green PPT); chromosome analysis (sodium heparin) (green PPT)

Yellow

Acid citrate dextrose (ACD) Sodium polyanethol sulfonate (SPS)

ACD: HLA typing; blood banking (plasma); flow cytometry immunophenotyping SPS: blood culture (microbiology)

Dark Blue

Clot activator (trace metal free)

Trace metals (eg, lead, mercury, arsenic)

Orange RST

Thrombin and gel for serum separation

Serum chemistry tests

EDTA, ethylenediamine tetraacetic acid; PPT, plasma preparation tube; RST, rapid serum tube; SST, serum separator tube.

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