1,5-Anhydroglucitol (1,5-AG), sometimes known as GlycoMark, is a monosaccharide that shows 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 endogenous synthesis. It is generally not metabolized, and in healthy subjects, it achieves a stable plasma 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
Used clinically to monitor short-term glycemic control in patients with diabetes (1-2 weeks)
Useful marker for postprandial hyperglycemia
Performs better than hemoglobin A1C for monitoring glucose profile in pregnancies complicated by type 1 diabetes
1,5-AG may be increased during IV hyperalimentation.
Individuals with renal glucose thresholds that are markedly different from 180 mg/dL (e.g., chronic renal failure, pregnancy, and dialysis) and in those undergoing steroid therapy.
α-Glucosidase inhibitors can decrease 1,5-AG by interfering with its intestinal absorption.
In patients with poorly controlled DM, 1,5-AG is less sensitive to modest changes in glycemic control because of continuous glycosuria.
Levels can be influenced by factors such as dairy product, races, uric acid, triglycerides, liver disease, gastrectomy state, and cystic fibrosis.
▼ Low values can occur in stage 4 or 5 kidney disease (eGFR below 30 mL/minute), in advanced liver disease, and during pregnancy.
▼ The diabetes drugs acarbose (Glucobay) and SGLT2 inhibitors (Invokana) cause low GlycoMark values.
▼ The Chinese medicines Polygala, Tenuifolia, and Senega syrup may cause high GlycoMark values.
11-Deoxycortisol, also known as cortodoxone, corticosterone, and compound S, is a steroid and 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) and Porter-Silber 17-OHKS measurements, which were originally used to provide some measure of cortisol production. The direct measurement of cortisol has replaced determinations of 17-KS and 17-OHKS.
Normal range: <50 ng/dL in males; <33 ng/dL in females
Diagnosis of and monitoring therapeutic response in congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency
Assessment of adrenal response in the metyrapone test; result after metyrapone stimulation is >8,000 ng/dL
Values are increased in CAH (P450cII deficiency) and following metyrapone administration in normal persons.
Values are decreased in adrenal insufficiency.
Patients with myxedema, some pregnant patients, and those on oral contraceptives respond poorly during the test.
17α-Hydroxyprogesterone, also known as hydroxyprogesterone, is a 21-carbon steroid produced in the adrenals—and also in the ovaries, testes, and placenta—that serves as a biosynthetic precursor to cortisol.
Normal range: 18-469 ng/dL (see Table 2-1)
TABLE 2-1. Range of Normal Values for 17α-Hydroxyprogesterone
Diagnosis and management of CAH, hirsutism, and infertility
The luteal phase of menstruating women and pregnancy
When defective, 21-hydroxylase and 11-β-hydroxylase are present.
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 be standardized.
Spuriously elevated levels seen in premature and sick newborns due to interference with other steroid metabolites. 17α-Hydroxypregnenolone sulfate (percent cross-reactivity: 3.8%) has been identified as the most significant interferent in direct assays.
17α-Hydroxyprogesterone values for women with late-onset CAH have been found to overlap with those encountered in hirsute, oligomenorrheic women who do not have the disorder. Accordingly, it is important to determine ACTH-stimulated 17α-hydroxyprogesterone levels in women suspected of having late-onset CAH.
17-Ketosteroids, urine (17-KS), are breakdown products of androgens and are an adrenal function test. Examples of 17-KS include androstenedione, androsterone, estrone, and dehydroepiandrosterone. An alternative and more specific test for adrenal androgen function is dehydroepiandros-terone sulfate in serum.
Normal range: depends on sex and age (Table 2-2)
TABLE 2-2. Normal Ranges for 17-Ketosteroids in the Urine
Evaluation of glucocorticoid production and neuroendocrine function
Evaluation of androgenic adrenal and testicular function in normal male individuals and primarily adrenal androgenic secretion in normal female individuals
Congenital adrenal hyperplasia (very rare)
Ovarian dysfunction (polycystic ovarian disease)
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-HIAA, also known as serotonin metabolite, is the major urinary metabolite of serotonin.
Normal range: 0.0-15.0 mg/day (24-hour urine); 0.0-14.0 mg/g creatinine
Helps diagnose and monitor treatment for serotonin-secreting carcinoid tumors
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, coumaric acid, diazepam [Valium], ephedrine, fluorouracil, glyceryl guaiacolate [guaifenesin], heparin, melphalan [Alkeran], mephenesin, methamphetamine, methocarbamol, naproxen, nicotine, Lugol solution, promethazine, phenothiazine, hydroxyl tryptophan)
Use of certain drugs (e.g., chlorpromazine, promazine, imipramine, isoniazid, monoamine oxidase inhibitors, methenamine, methyldopa, phenothiazines, promethazine)
Renal insufficiency (possible)
Foods rich in serotonin and medications, over-the-counter drugs, and herbal remedies that may affect metabolism of serotonin must be avoided at least 72 hours before and during collection of urine for 5-HIAA.
Twenty-four-hour collections are generally recommended, but random collections may be used. Refrigeration is the most important aspect of specimen preservation.
Urinary 5-HIAA is increased with malabsorption, in 75% of cases, usually when a carcinoid tumor is far advanced (with large liver metastases, often 300-1,000 mg/day), but may not be increased despite massive metastases.
Sensitivity is 73%.
The test is useful in the diagnosis of only 5-7% of patients with carcinoid tumors but in approximately 45% of those with liver metastases.
Disease extent and prognosis correlate generally with urine 5-HIAA excretion, and the level becomes normal after successful surgery. If urine HIAA is normal, the blood level of serotonin or a precursor, 5-hydroxytryptophan, should be checked.
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 to cholestasis, and its significance is similar to that of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT). However, 5′-NT is not as subject to drug induction as GGT and ALP, and it is not subject to confusion with alternate sources of the enzyme, as is seen with ALP.
Normal range: 2.0-8.0 U/L
5′-NT is increased in the following conditions:
▼ Hepatobiliary disease with intrahepatic or extrahepatic biliary obstruction
▼ Hepatic carcinoma
▼ Early biliary cirrhosis
▼ Pregnancy (third trimester)
▼ Inflammatory arthritis
5′-NT can be elevated in hyperammonemia due to analytical interference.
Normal in pregnancy and postpartum period (in contrast to serum leucine aminopeptidase and ALP)
▼ Use of hepatotoxic medications (e.g., acetaminophen, halothane, isoniazid [INH], methyldopa, nitrofurantoin) can increase the levels.
Nonopioid analgesic, antipyretic
Relief of pain, such as headaches and toothaches
Reduction of fever
Screen of urine: indication of exposure
Screen of serum: used to assess potential toxicity
▼ Normal range: 10-25 µg/mL serum in healthy adults
▼ Potentially toxic: >150 µg/mL measured 4 hours post dose
▼ Use of Rumack-Matthew nomogram to assess probability of toxicity
▼ Serum/urine: colorimetric or immunoassay on automated chemistry analyzers.
High bilirubin concentrations (>50 µg/mL) may cause false-positive results with immunoassay-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.
▼ Serum/plasma quantitation by enzyme immunoassay on an automated chemistry analyzer or HPLC.
▼ Urine—Qualitative by HPLC or GC/MS.
▼ APAP is highly conjugated by glucuronidation and sulfation.
▼ An assay that includes a hydrolysis step provides total APAP levels, which are not useful for assessing toxicity.
Acid phosphatase is a hydrolytic enzyme secreted by various cells, and it has five isoenzymes. The greatest amount per gram of tissue is found in semen (prostate); it is also detectable in the bone, liver, spleen, kidney, RBCs, and platelets. The acid phosphatase test is also known as prostatic acid phosphatase (PAP) test, the serum acid phosphatase test, and the tartrate-resistant acid phosphatase (TRAP) test.
Normal range: 0-0.8 U/L
Predicts recurrence after radical prostatectomy for clinically localized prostate cancer and following response to androgen ablation therapy, when used in conjunction with prostate-specific antigen (PSA)
Acid phosphatase is increased in the following conditions:
▼ Prostate cancer
▼ Gaucher disease and Niemann-Pick disease
▼ 1-2 days after prostatic surgery or biopsy
▼ Prostatic manipulation or catheterization
▼ Benign prostatic hyperplasia, prostatitis, prostate infarct
▼ Vaginal swabs from rape victims
It is no longer used to screen for or to stage prostate cancer.
Levels must not be regarded as an absolute test for malignancy, since other factors including benign prostatic hyperplasia, prostatic infarction, and manipulation of the prostate gland may result in elevated serum PAP concentrations.
PAP measurements provide little additional information beyond that provided by PSA measurements.
Initial test to distinguish primary from secondary adrenal insufficiency.
Not helpful in the diagnosis of Cushing syndrome. Several protocols are used to assess the response to exogenous ACTH administration (see below).
This test involves physiologic plasma concentrations of ACTH and provides a more sensitive index of adrenocortical responsiveness.
It is performed by measuring serum cortisol immediately before and 30 minutes after IV injection 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 of cosyntropin currently available contain 250 µg and come with sterile normal saline to be used as a diluent. One prepares the lowdose solution of cosyntropin locally.
This test consists of measuring serum cortisol immediately before and 30 and 60 minutes after IV injection of 250 µg of cosyntropin. This dose of cosyntropin results in pharmacologic 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.
The 8-hour test, which is now rarely performed, consists of infusing 250 µg of cosyntropin continuously over 8 hours in 500 mL of isotonic saline. A 24-hour urine specimen is collected the day before and the day of the infusion for cortisol or 17-hydroxycorticoid and creatinine determination, and serum cortisol is determined at the end of the infusion. Plasma ACTH concentrations are supraphysiologic throughout the infusion.
The 24-hour urinary excretion of 17-hydroxycorticoid should increase three- to fivefold over baseline on the day of ACTH infusion.
The 2-day ACTH infusion test is similar to the 8-hour infusion test, except that the same dose of ACTH is infused for 8 hours on 2 consecutive days.
This test may be helpful in distinguishing secondary from tertiary adrenal insufficiency. The 1-day 8-hour test is too short for this purpose, whereas longer tests add little further useful information.
Urinary excretion of 17-hydroxycorticoid should exceed 27 mg during the first 24 hours of infusion and 47 mg during the second 48 hours.
Low-dose stimulation test: A value of 18 µg/dL or more, before or after ACTH injection, is indicative of normal adrenal function.
High-dose stimulation test: A serum cortisol value of 20 µg/dL or more at any time during the test, including before injection, is indicative of normal adrenal function.
Eight-hour stimulation test: Serum cortisol should reach 20 µg/dL in 30-60 minutes after the infusion is begun and exceed 25 µg/mL after 6-8 hours.
Two-day infusion test: Serum cortisol should reach 20 µg/mL in 30-60 minutes after the ACTH infusion is begun and exceed 25 µg/mL after 6-8 hours. Both serum and urinary steroid values increase progressively thereafter, but the ranges of normal are not well defined.
Both high- and low-dose ACTH stimulation tests had similar diagnostic accuracy. Both tests are adequate to rule in, but not rule out, secondary adrenal insufficiency.
In healthy individuals, cortisol responses are greatest in the morning, but in patients with adrenal insufficiency, the response to cosyntropin is the same in the morning and afternoon. Therefore, this testing should be done in the morning to minimize the risk of misdiagnosis in a normal individual.
The criteria for a minimal normal cortisol response of 18-20 µg/dL are derived from the responses of healthy volunteers. However, in some studies, higher cutoff points for the diagnosis 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 normal response to ACTH that apply to all centers. Studies comparing cortisol results obtained with different assays showed a positive bias of radioimmunoassays (RIAs) 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, which increase cortisol-binding globulin levels.
The response to ACTH varies with the underlying disorder. If the patient has hypopituitarism with deficient ACTH secretion and secondary adrenal insufficiency, then the intrinsically normal adrenal gland should respond to maximally stimulating concentrations 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 resulting from chronically low stimulation by endogenous ACTH. If, on the other hand, the patient has primary adrenal insufficiency, endogenous ACTH secretion is already elevated, and there should be little or no adrenal response to exogenous ACTH.
Cortisol values between 18.0 and 25.4 µg/dL represent a range of uncertainty in which patients may have discordant responses to ACTH, insulin,
and/or metyrapone. Higher concentrations 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 the conclusion that a 30-minute serum cortisol concentration <18 µg/dL indicates impaired adrenocortical reserve. In addition, the lowdose test does not reliably indicate hypothalamic-pituitary-adrenal axis suppression in preterm infants whose mothers received dexamethasone for <2 weeks before delivery to hasten fetal lung development. The CRH test should be used in this situation.
Activated clotting time (ACT) is a rapid point-of-care (POC) standardized clotting time, performed by automated well-calibrated instruments, such as the Medtronic automated coagulation timer. A baseline ACT has to be established in each POC area after induction of anesthesia and opening the chest for cardiopulmonary bypass surgery, because surgery and anesthesia shorten it. The ACT may also vary slightly with the lot number of the control cartridge.
Normal range in the absence of heparin (with Medtronic coagulometer): 74-125 seconds
ACT is the most widely used measure of anticoagulation with heparin (and neutralization of heparin with protamine) during extracorporeal circulation. After the initial dose of heparin, the ACT is maintained at >275 seconds for off-pump coronary procedures and >350 seconds for on-pump procedures by periodic administration of heparin.
There is some controversy concerning whether monitoring heparinization by ACT alone ensures optimal heparin and protamine doses. A poor correlation was found between ACT and heparin measurements using anti-Xa assays. Nevertheless, experience has shown that institution of anticoagulation and monitoring under ACT guidance improves hemostasis, limits blood loss, and reduces the need for transfusions.
The response of ACT to heparin varies from individual to individual and with heparin potency.
Underlying coagulopathies such as antithrombin III deficiency, clotting factor deficiencies, and DIC 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 by heparin flushes.
APCR reflects resistance to proteolysis of activated factor V by activated protein C (APC). Ninety-five percent of APCR cases are due to factor V Leiden, a genetic mutation in factor V that predisposes to venous thromboembolism (5-10 times greater risk in heterozygotes and 50-100 times greater risk in homozygotes). The remaining 5% are found in pregnancy, malignancy, and antiphospholipid antibody syndrome. Ratios are generated either from a modified partial thromboplastin time (PTT) or, more recently, by APC with southern copperhead venom, using dilute Russell viper venom as the clotting reagent. The test is performed in the presence of added APC, where in normal individuals, there is an elongation due to delayed generation of fibrin when factor V is lysed; in the absence of APC, where factor V remains intact, there is no elongation. Patients with APCR have a lesser prolongation of clotting in the presence of APC than controls.
Normal value: >1.8
APCR is one of the assays recommended to investigate the etiology of venous thrombophilia. The congenital form, factor V Leiden, is present in 5% of individuals of European descent and in a high proportion of patients with unprovoked venous thromboembolism. It is virtually absent in patients of pure African ancestry.
Protein C levels <50% and initial anticoagulation with vitamin K antagonists may give falsely 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 icteric samples. The assay is also invalid if blood is drawn with the wrong anticoagulant or the tubes are not filled appropriately.
Adiponectin, a hormone secreted exclusively by adipose tissue, has an important role in the regulation of tissue inflammation and insulin sensitivity. Perturbations in adiponectin concentration have been associated
with obesity and the metabolic syndrome. Levels of the hormone are inversely correlated with body fat percentage in adults, whereas the association in infants and young children is more unclear.
TABLE 2-3. Normal Range of Adiponectin
Body Mass Index (kg/m2)
Normal range: see Table 2-3.
Higher adiponectin levels are associated with a lower risk of type 2 diabetes across diverse populations, consistent with a dose-response relationship.
Individuals at risk of metabolic syndrome or diabetes due to poor lifestyle choices.
Twofold before a meal and decreases to trough levels within 1 hour after eating
More than twofold in hemodialysis patients
Type 2 diabetes mellitus (9 times likely)
Obesity and metabolic syndrome (3 times greater risk)
Coronary artery disease (2 times increased risk)
Adiponectin exerts some of its weight reduction effects via the brain. This is similar to the action of leptin, but the two hormones perform complementary actions and can have additive effects.
Due to its important cardiometabolic actions, adiponectin represents a biologic molecule worth being studied as a new emerging biomarker of disease and also as a target for pharmacologic treatments.
ACTH is a polypeptide hormone produced by the anterior pituitary gland that exists principally as a chain of 39 amino acids, with a molecular mass of approximately 4,500 Da. Its biologic function is to stimulate cortisol secretion by the adrenal cortex. ACTH secretion is in turn controlled by the hypothalamic hormone CRF and by negative feedback from cortisol.
Normal range: <46 pg/mL
Pituitary-dependent Cushing disease
Ectopic ACTH-producing tumors
Pseudo-Cushing disorders (depression, alcoholism, and anorexia nervosa)
Secondary adrenocortical insufficiency
Infiltrative diseases of the hypothalamus (e.g., sarcoid, histiocytosis, tuberculosis, fungal infections)
Plasma levels of ACTH exhibit a significant diurnal variation. ACTH is normally highest in the early morning (6-8 AM) and lowest in the evening (6-11 PM). Cortisol levels are frequently measured at the same time as ACTH.
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 as precursors and fragments. Highly sensitive IRMAs measure intact ACTH only.
RIAs are recommended for investigating ectopic ACTH-producing tumors, because some of the tumors secrete ACTH precursors and fragments. IRMAs are more sensitive than RIAs and are useful for investigating disorders of the hypothalamic-pituitary-adrenal system.
Patients taking glucocorticoids may have suppressed levels of ACTH with an apparent high level of cortisol.
Pregnancy, menstruation, and stress increase secretion.
Allergic diseases are manifested as hyperresponsiveness in the target organ, whether the skin, nose, lung, or GI tract. Most tests for “allergy” are actually tests for allergic sensitization, or the presence of allergen-specific IgE.
Most patients who experience symptoms upon exposure to an allergen have demonstrable IgE that specifically recognizes that allergen, making these tests essential tools in the diagnosis 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 blood sample and does not necessitate a separate visit for skin testing.
Clinical performance of specific IgE-based serum allergen tests typically has sensitivity ranging from 84% to 95% and specificity ranging from 85% to 94%.
Various types of specific panels, mixes, as well as specific allergen tests are currently performed at various labs; contact your lab for details.
To establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms
To identify allergens that may be responsible for allergic disease and/or anaphylactic episode and to confirm sensitization to particular allergens prior to beginning immunotherapy
To investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens
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 be responsible for eliciting signs and symptoms.
Specific IgE levels higher than 0.35 kU/L suggest sensitization, but that is not synonymous with clinical disease.
The demonstration of sensitization is not sufficient to diagnose an allergy. Thus, allergy tests must be interpreted in the context of the patient’s specific clinical history, and the diagnosis of an allergic disorder cannot be based solely on a laboratory 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 can usually be made without further evaluation. If the result is weakly positive, then further evaluation is usually needed.
A negative immunoassay result in the setting of a strongly suggestive history does not exclude allergy. In this situation, a skin prick test should be considered (if not contraindicated).
False-positive results of allergen-specific IgE can theoretically occur in patients with extremely elevated total IgE levels.
Allergen-specific IgG and IgG4 tests, which are believed to correlate with normal immunologic responses to foreign substances, are not useful in the diagnosis of IgE-mediated allergy, with the exception of venom allergy. Unreliable testing methods include provocation/neutralization tests, kinesiology, cytotoxic tests, and electrodermal testing.
In food allergy, circulating IgE antibodies may remain undetectable despite a convincing clinical 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 in the original food for which the patient is tested.
Identical results for different allergens may not be associated with clinically equivalent manifestations, due to differences in patient sensitivities.
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 adult liver 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 concentration reflects the rate of synthesis, the degradation, and the volume of distribution. Albumin synthesis is regulated by a variety of influences, including nutritional status, serum oncotic pressure, cytokines, and hormones.
▼ 0-4 months: 2.0-4.5 g/dL
▼ 4 months to 16 years: 3.2-5.2 g/dL
▼ >16 years: 3.5-4.8 g/dL
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 malnutrition
▼ Chronic illness
▼ Decreased growth hormone levels
▼ Genetic analbuminemia
Acute-phase reaction, inflammation, and chronic diseases:
▼ Bacterial infections
▼ Monoclonal gammopathies and other neoplasms
▼ Parasitic infestations
▼ Peptic ulcer
▼ Prolonged immobilization
▼ Rheumatic diseases
▼ Severe skin disease
Increased loss over body surface:
▼ Enteropathies related to sensitivity to ingested substances (e.g., gluten sensitivity, Crohn disease, ulcerative colitis)
▼ Fistula (gastrointestinal or lymphatic)
▼ Kidney disease
▼ Rapid hydration or overhydration
▼ Repeated thoracentesis or paracentesis
▼ Trauma and crush injuries
▼ Cushing disease
▼ Thyroid dysfunction
Plasma volume expansion:
▼ Oral contraceptives
In clinical practice, one of the two dye-binding assays—bromocresol green (BCG) and bromocresol purple (BCP)—is used for measuring albumin levels, and systematic differences 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 in pediatric patients on hemodialysis and patients in chronic renal failure. Chronic dialysis units often have little influence over the method.
Antialbumin antibodies are commonly found with hepatic dysfunction and are typically of IgA type.
Ischemia-modified albumin, in which the metal-binding capacity of albumin has decreased due to exposure to ischemic events, is a biologic marker of myocardial ischemia.
Alcohols are organic compounds that contain the −OH group, including methanol (CH3OH, methyl alcohol, wood alcohol), ethanol (ethyl alcohol; C2H5OH), and isopropanol ((CH3)2CHOH, isopropyl alcohol, rubbing alcohol). Although acetone (CH3COCH3) is a ketone, not an alcohol, it is included in this group, because it is often detected in the same testing methodology.
▼ 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 and 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 also occur at lower concentrations)
▼ Isopropanol: <10 mg/dL (normal); toxic effects are generally seen at 50-100 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.
Solvent and reagent
Vehicle in chemical and pharmaceutical industries
Testing is performed by enzyme immunoassay on automated chemistry analyzers or by headspace gas chromatography. Serum, whole blood, and urine are usually the sample matrix.
Immunoassay testing for ethanol may have cross-reactivity <1% with isopropanol alcohol, methanol, ethylene glycol, and acetaldehyde; <15% with n-propanol.
In many headspace gas chromatographic methods, acetonitrile co-elutes with acetone, leading to a false-positive result. Acetonitrile may be a component in cosmetic nail remover.
Alcohol (ethanol) metabolites, ethyl glucuronide (EtG) and ethyl sulfate, provide a longer window of detection compared with ethanol, and may be detected in urine by immunoassay (EtG), with confirmation by LC-MSMS.
Elevated concentrations of acetone are detected in specimens during diabetic ketoacidosis and fasting ketoacidosis and may range from 10 to 70 mg/dL.
A positive urine ethanol due to the presence of yeast in the patient’s urine has been described. In these cases, glucose was also present in the urine.
Primary mineralocorticoid secreted by the adrenal zona glomerulosa. The role of aldosterone in metabolism is the control of sodium and potassium. Regulating sodium ion concentration, in turn, regulates fluid volume. Aldosterone acts to decrease excretion of sodium and increase the excretion of potassium at the kidney, sweat glands, and salivary glands.
▼ 8:00-10:00 AM (sitting): 3-34 ng/dL
▼ 8:00-10:00 AM (supine): 2-19 ng/dL
▼ 4:00-6:00 PM (sitting): 2-23 ng/dL
Diagnosis of primary hyperaldosteronism
Differential diagnosis of fluid and electrolyte disorders
Assessment of adrenal aldosterone production
Hyporeninemic hypoaldosteronism (Cushing syndrome)
Congenital deficiency of aldosterone synthetase
Very high-sodium diet
Many physiologic factors affect plasma aldosterone. Posture; salt intake; use of antihypertensive drugs, steroids, and oral contraceptives; age; stress; exercise; menstrual cycle; and pregnancy can all have a strong influence on aldosterone results.
Licorice may mimic aldosterone effects and should be avoided 2 weeks before the test.
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 bile canalicular 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 ALP activity comes from the bone and liver (approximately 1:1 ratio). The half-life of ALP is 7-10 days.
▼ 0-1 year: 150-350 IU/L
▼ 1-16 years: 30-300 IU/L
▼ >16 years: 30-115 IU/L
Diagnosis and treatment of the liver, bone, intestinal, and parathyroid diseases
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 secondary hyperparathyroidism)
Liver disease (e.g., infectious mononucleosis, uncomplicated extrahepatic biliary obstruction, liver abscess)
Miscellaneous (extrahepatic sepsis, ulcerative colitis, pancreatitis, phenytoin, and alcohol use)
Bone origin—increased deposition of calcium
▼ Paget disease (osteitis deformans) (highest reported values 10-20 times normal). Marked elevation in the absence of liver disease is most suggestive of Paget disease of the bone 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 and rickets.
▼ Polyostotic fibrous dysplasia.
▼ Late pregnancy; reverts to normal level by 20th day postpartum.
▼ Children <10 years of age and again during prepubertal growth spurt may have three to four times adult values; adult values are attained by age 20.
▼ Administration of ergosterol.
▼ Transient hyperphosphatasemia of infancy.
▼ Hodgkin disease.
▼ Healing of extensive fractures (slightly).
▼ 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 is elevated, 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 elevated ALP 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) (progressive elevation of serum ALP may be first indication that drug therapy should be halted); 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, and 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 bone metastases.
▼ Five times increase: infectious mononucleosis and postnecrotic cirrhosis.
▼ Ten times increase: carcinoma of the head of the pancreas, choledocholithiasis, and drug cholestatic hepatitis.
▼ Fifteen to twenty times increase: primary biliary cirrhosis and primary or metastatic carcinoma. 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 to two times normal up to onset of labor, and disappears 3-6 days after delivery of the 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 hours after eating in persons with blood type B or O who are secretors of the H blood group. ALP has 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 or bone (e.g., Hodgkin disease; cancer of the lung, breast, colon, or pancreas; highest incidence in ovary and cervical cancers).
▼ Vascular endothelium origin—some patients with myocardial, pulmonary, renal (one third of cases), or splenic infarction, usually after 7 days during the phase of organization.
▼ Hyperphosphatasia (liver and bone isoenzymes).
▼ Hyperthyroidism (liver and bone isoenzymes). Increased ALP alone in a chemical profile, 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 be more useful to distinguish bone from liver source of increased ALP
Extremely heat-labile (90%): bone, vascular endothelium, reticuloendothelial system.
Extremely heat-stable (90%): placenta, neoplasms.
Intermediate heat-stable (60-80%): liver, intestine.
▼ Also, differentiate by chemical inhibition (e.g., l-phenylalanine) or use serum GGT and 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 of bone.
Vitamin B12 deficiency
Nutritional deficiency of zinc or magnesium
Excess vitamin D ingestion
Milk-alkali (Burnett) syndrome
Congenital hypophosphatasia (enzymopathy of liver, bone, kidney isoenzymes)
Hypothyroidism and cretinism
Pernicious anemia (one third of patients)
Postmenopausal women with osteoporosis taking estrogen replacement therapy
Therapeutic agents (e.g., corticosteroids, trifluoperazine, antilipemic agents, some hyperalimentation)
Cardiac surgery with cardiopulmonary bypass pump
Inherited metabolic diseases (Dubin-Johnson, Rotor, Gilbert, and Crigler-Najjar syndromes; type I-V glycogenoses, mucopolysaccharidoses; increased in Wilson disease and hemochromatosis related to hepatic fibrosis).
Consumption of alcohol by healthy persons (in contrast to GGT); may be normal even in alcoholic 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 be ruled out as a cause of hepatitis.
The elevation in ALP tends to be more marked (more than threefold) in extrahepatic biliary obstruction (e.g., by stone or by cancer of the head of the pancreas) than in intrahepatic obstruction, and it is greater the more complete the obstruction. Serum enzyme activities may reach 10-12 times the upper limit of normal, returning to normal on surgical removal of the 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, and 20% lower with the use of oral contraceptives.
Common drugs, including penicillin derivatives, antiepileptic drugs, antihistamines, cardiovascular drugs, etc., can increase blood levels.
AAT is a member of the serpin family of protease inhibitors, produced mostly in the liver. It protects the lungs from damage caused by the proteolytic enzyme, neutrophil elastase. The normal AAT allele is the M allele. Over 100 allelic variants have been described, of which the most common severely deficient variants are the S and Z alleles. It is normally the major constituent of the alpha-1 band on routine serum electrophoresis. AAT deficiency is severely 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: 80-220 mg/dL (nephelometry) or 150-350 mg/dL (radial immunodiffusion)
Workup of individuals with suspected disorders such as familial chronic obstructive lung disease, emphysema, asthma, and bronchiectasis
Diagnosis of AAT deficiency
Diagnosis of juvenile and adult cirrhosis of the liver
Inflammation (acute-phase reacting protein)
Infection, tissue injury or necrosis, rheumatic disease, and some malignancies
Estrogen administration (oral contraceptives, pregnancy, especially third trimester)
Deficiency states (hereditary)
Hepatic disease (hepatitis, cholestasis, cirrhosis, or hepatic cancer)
Pulmonary emphysema and chronic obstructive pulmonary disease (COPD)
Phenotypic studies are recommended to confirm a suspected hereditary deficiency.
False-positive results can occur if rheumatoid factor is present.
Given the variability in reference ranges, patients with a serum AAT level below 100 mg/dL should be evaluated further with isoelectric focusing or genotyping.
AFP is a glycoprotein that is normally produced during gestation by the fetal liver and yolk sac, the serum concentration of which is often elevated in patients with hepatocellular carcinoma (HCC). It is also found in some patients with cancer of the testes and ovaries.
Normal range: 0.6-6.60 ng/mL
Marker for hepatocellular and germ cell (nonseminoma) carcinoma.
Follow-up management of patients undergoing cancer therapy, especially for testicular and ovarian tumors and for HCC. The measurement of AFP in serum, in conjunction with serum human chorionic gonadotropin, is an established regimen for monitoring 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 measuring serum AFP concentration over time.
Serial serum AFP testing is a useful adjunctive test for managing nonseminomatous testicular cancer.
AFP is increased in the following disorders:
▼ Hereditary tyrosinemia
▼ Primary HCC
▼ Gastrointestinal tract cancers with and without liver metastases
▼ Benign hepatic conditions such as acute viral hepatitis, chronic active hepatitis, and cirrhosis
AFP is not recommended as a screening procedure to detect cancer in the general population. This assay is intended only as an adjunct in the diagnosis and monitoring of AFP-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 screening for HCC in patients with different types of chronic liver disease. The following sensitivities and 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. Lysis of tumor cells during the initiation of chemotherapy may result in a transient increase in serum AFP.
Failure of the AFP value to return to normal by approximately 1 month after surgery suggests the presence of residual tumor.
Elevation of AFP after remission suggests tumor recurrence; however, tumors originally producing AFP may recur without an increase in AFP.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are members of the transaminase family of enzymes, widely distributed in cells throughout the body. AST is primarily found in the heart, liver, skeletal muscle, and kidney, whereas ALT is found primarily in the liver and kidney, with lesser amounts in the heart and skeletal muscle. AST and ALT activities in the liver are about 7,000 and 3,000 times serum activities, respectively.
Most sensitive tests for acute hepatocellular injury (e.g., viral, drug); precedes increase in serum bilirubin by approximately 1 week
Hepatocellular damage, liver cell necrosis, or injury of any cause.
AST levels of 500 U/L suggest acute hepatocellular injury; seldom >500 U/L in obstructive jaundice, cirrhosis, viral hepatitis, AIDS, and alcoholic liver disease.
Acute fulminant viral hepatitis: Abrupt AST rise may be seen (rarely >4,000 IU/L) and declines 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 reflect underlying disease.
Trauma to skeletal or heart muscle.
Severe exercise, burns, and heat stroke.
Drug-induced injury to the liver.
Chronic renal dialysis
Pyridoxal phosphate deficiency states (e.g., malnutrition, pregnancy, alcoholic liver disease)
AST >10 times normal indicates acute hepatocellular injury, but lesser increases are nonspecific 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 disorder.
Rarely increased >500 U/L (usually <200 U/L) in posthepatic jaundice, AIDS, cirrhosis, and viral 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 in 25% of cases of alcoholic cirrhosis.
Degree of increase has a poor prognostic value.
Serial determinations reflect clinical activity of liver disease. Persistent increase may indicate chronic hepatitis.
Mild increase of AST and ALT (usually <500 U/L) with ALP increased greater than three times 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 indicates hepatocellular jaundice.
Rapid decline in AST and ALT is a sign of recovery from disease but in acute fulminant hepatitis may represent loss of hepatocytes and poor prognosis.
Poor correlation of increased concentration with extent of liver cell necrosis and has a little prognostic value.
Although AST, ALT, and bilirubin are most characteristic of acute hepatitis, they are unreliable markers of severity of injury.
Ammonia is derived mostly from protein degradation. Most of the ammonia in the blood comes from the intestine, where colonic bacteria use ureases to break down urea to ammonia and CO2. Eighty-five percent of blood from the intestine is carried directly to the liver via the portal vein, and 85% of ammonia is converted back to urea and excreted by the kidneys and colon. Helicobacter pylori in the stomach appear to be an important source of ammonia in patients with cirrhosis.
Normal range: <50 µmol/L
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 cycle metabolic pathway.
Should be measured in cases of unexplained lethargy and vomiting, encephalopathy, or any neonate with unexplained neurologic deterioration.
Not useful to assess the degree of dysfunction (e.g., in Reye syndrome, hepatic function improves and the ammonia level falls, even in patients who finally die of these disorders).
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 the first 48 hours.
May occur in any patient with severe liver disease (e.g., acute hepatic necrosis, terminal cirrhosis, and after portacaval anastomosis). Increased in most cases of hepatic coma but correlates 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 a specific disease.
GU tract infection with distention and stasis.
Some hematologic disorders, including acute leukemia and after bone marrow transplantation.
Total parenteral nutrition.
Smoking, exercise, and valproic acid therapy.
An elevated plasma ammonia concentration combined with normal blood glucose and anion gap strongly suggests a urea cycle disorder.
Hyperornithinemia (deficiency of ornithine aminotransaminase activity) with gyrate atrophy of the choroid and retina
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.
Plasma ammonia is >100-150 µmol/L; further testing is performed to establish a diagnosis. Mild elevations below this threshold should be interpreted in the context of the clinical course and followed to ensure resolution.
Sympathomimetic amines with central nervous system stimulant activity.
Other names include 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, p-methoxyamphetamine (PMA), and p-methoxymethamphetamine (PMMA). These are not generally detected in screening tests and may not be reported in confirmation tests unless specifically requested.
Drugs that are metabolized to methamphetamine and subsequently amphetamine include benzphetamine, famprofazone, fencamine, and selegiline.
Drugs that are metabolized to amphetamine include clobenzorex, fenethylline, fenproporex, mefenorex, mesocarb, prenylamine, amphetaminil, and lisdexamfetamine.
Stimulant compounds, which are chemically similar to amphetamine and methamphetamine, are known as substituted cathinones (SC). These are synthetic analogs of cathinone, a substance found in the plant, khat (Catha edulis). SC are β-keto phenethylamines, also known colloquially as “bath salts,” and include mephedrone, methylone, and 3,4-methylenedioxypyrovalerone (MDPV). These substances do not generally produce presumptive positive results with standard amphetamine/methamphetamine immunoassays. Definitive testing in urine by targeted LC-MSMS or equivalent assays may be required.
Mood enhancers (psychotropics).
Treatment of attention deficit hyperactivity disorder.
Nasal decongestants, bronchodilators.
Screen [urine]: Immunoassay on automated chemistry analyzers.
▼ Amphetamine: Generally do not give positive results for L-amphetamine, MDA, MDMA, ephedrine, and phentermine.
Screen [serum]: ELISA.
▼ Target analyte: D-amphetamine. Will not give positive results with L-amphetamine, L-methamphetamine, phenylpropanolamine, MDMA, and MDE.
▼ May produce positive results with MDA.
▼ Confirmation techniques do not typically differentiate between D and L forms of amphetamine and methamphetamine. Specific chromatographic characteristics are required.
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 the digestion of starch. It is also produced by the small intestine mucosa, ovaries, placenta, liver, and fallopian tubes.
Normal range: 5-125 U/L
To diagnose and monitor pancreatitis or other pancreatic diseases
In the workup of any intra-abdominal inflammatory event
Acute pancreatitis (e.g., alcoholic, autoimmune). Urine levels reflect serum changes by a time 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], chloride and fluoride salts [enhance amylase activity], lipemic serum [turbidimetric methods]).
Obstruction of pancreatic duct by:
▼ Stone or carcinoma
Drug-induced spasm of the sphincter of Oddi (e.g., opiates, codeine, methyl choline, cholinergics, chlorothiazide) to levels 2-15 times normal
Partial obstruction + drug stimulation
▼ Biliary tract disease
▼ Common bile duct obstruction
▼ Acute cholecystitis
Complications of pancreatitis (pseudocyst, ascites, abscess).
Pancreatic trauma (abdominal injury; following endoscopic retrograde cholangiopancreatography [ERCP]).
Altered GI tract permeability:
▼ Ischemic bowel disease or frank perforation
▼ Esophageal rupture
▼ Perforated or penetrating peptic ulcer
▼ Postoperative upper abdominal surgery, especially partial gastrectomy (≤2 times normal 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.
Others, such as chronic liver disease (e.g., cirrhosis; ≤2 times normal), burns, pregnancy (including ruptured tubal pregnancy), ovarian cyst, diabetic ketoacidosis, recent thoracic surgery, myoglobinuria, presence of myeloma proteins, some cases of intracranial bleeding (unknown mechanism), splenic rupture, and dissecting aneurysm.
Increased serum amylase with low urine amylase may be seen in renal insufficiency and macroamylasemia. Serum amylase ≤4 times normal in renal disease only when creatinine clearance (CrCl) is <50 mL/minute due to pancreatic or salivary isoamylase; but rarely more than four times normal in the absence of acute pancreatitis.
Extensive marked destruction of the pancreas (e.g., acute fulminant pancreatitis, advanced chronic pancreatitis, advanced cystic fibrosis). Decreased levels are clinically significant only 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 binding calcium ions):
▼ Normal: 1-5%
▼ Macroamylasemia: <1%; very useful for this diagnosis
▼ Acute pancreatitis: >5%; use is presently discouraged for this diagnosis
Amylase-to-creatinine clearance ratio = (urine amylase/serum amylase) (serum creatinine/urine creatinine) × 100
Relapsing chronic pancreatitis
Patients with hypertriglyceridemia (technical interference with test)
Frequently normal in acute alcoholic pancreatitis
Composed of pancreatic and salivary types of isoamylases distinguished by various methodologies; nonpancreatic etiologies are almost always salivary; both types may be increased 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.
Pancreatic amylase results may be elevated in patients with macroamylase. This elevated pancreatic amylase is not diagnostic for pancreatitis. By utilizing serum lipase and urinary amylase values, the presence or absence of macroamylase may be determined.
Current guidelines and recommendations indicate that lipase should be preferred over total and pancreatic amylase for the initial diagnosis of acute pancreatitis and that the assessment should not be repeated over time to monitor disease prognosis.
Differential diagnosis of pancreatitis
Diagnosis of pseudocyst of the pancreas, where the urine amylase may remain elevated for weeks after the serum amylase has returned to normal, after a bout of acute pancreatitis.
Large doses of corticosteroids
Myeloma and light chain disease
Macroamylasemia is characterized by high serum amylase but normal urine amylase. The ALCR remains useful for the diagnosis of macroamylasemia. In macroamylasemia, the clearance is very low.
Androstenedione, also known as 4-androstenedione, is a 19-carbon steroid hormone produced in the adrenal glands and the gonads (testes as well as ovaries) as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol. It is a major adrenal androgen in serum.
Normal range: 0.0-4.4 ng/mL (see Table 2-4)
Diagnosis of virilism and hirsutism
Suspicion of anabolic steroid abuse
Diagnosis of CAH, in conjunction with measurement of other androgenic precursors
TABLE 2-4. Normal Ranges for Serum Androstenedione
CAH caused by 21-hydroxylase deficiency; marked increase is suppressed to normal levels by adequate glucocorticoid therapy:
▼ Suppressed level reflects adequacy of therapeutic control.
▼ Androstenedione may be better than 17-hydroxyprogesterone for monitoring therapy because it shows minimal diurnal variation, better correlation with urinary 17-KS excretion, and plasma levels that are not immediately affected by a dose of glucocorticoid.
Polycystic ovarian disease
Any condition that causes partial or complete adrenal or gonadal failure
Angiotensin II is the biologically active product of renin-angiotensin system. It is an oligopeptide of eight amino acids and very strong physiologic vasoconstrictor. ACE concentration is highest in the lung, and it had been thought that most angiotensin II formation occurred in the pulmonary circulation. However, ACE can be produced in the vascular endothelium of many tissues; therefore, angiotensin II can be synthesized at a variety of sites, including the kidney, vascular endothelium, adrenal gland, and brain.
Alternative enzymatic pathways not involving ACE may contribute to angiotensin II production. Angiotensin II binds to its specific receptors and exerts its effects in the brain, kidney, adrenal, vascular wall, and the heart. The actions of circulating angiotensin II contribute to hypertension. This may indirectly influence cardiac function, irrespective of any direct effect on the heart and myocardium.
Circulating angiotensin II promotes sodium and water reabsorption, increasing intravascular fluid volume, which in turn increases cardiac preload and, therefore, stroke volume. Circulating angiotensin II causes systemic arteriolar vasoconstriction, thereby increasing vascular resistance and cardiac afterload. Angiotensin II also affects the autonomic nervous system, stimulating the sympathetic nervous system and reducing vagal activity. These actions are oriented toward maintaining the blood pressure when the renin-angiotensin system is activated by effective volume depletion.
Normal range: 10-60 pg/mL.
Renin-secreting juxtaglomerular renal tumor
Patient should be on normal-sodium diet and be recumbent for 30 minutes before specimen collection.
Short-lived in plasma (half-life is 5 minutes) and degraded into inactive peptides, plasma should be separated and frozen immediately.
ACE production occurs mainly in the epithelial cells of the pulmonary bed. Smaller amounts are found in blood vessels and renal tissue, where ACE converts angiotensin I to angiotensin II; this conversion helps regulate arterial blood pressure. Angiotensin II stimulates the adrenal cortex to produce aldosterone. Aldosterone helps the kidneys maintain water balance by retaining sodium and promoting the excretion of potassium.
Normal range: 8-53 U/L.
Evaluation of patients with suspected sarcoidosis
Evaluation of the severity and activity of sarcoidosis
Evaluation of hypertension
Evaluation of Gaucher disease
Active pulmonary sarcoidosis (50-75% of patients but only 11% with inactive disease)
Gaucher disease (100%)
Chronic renal disease
Connective tissue diseases
Fungal disease and histoplasmosis
Far-advanced lung neoplasms
Anorexia nervosa associated with hypothyroidism
COPD, emphysema, lung cancer, cystic fibrosis
False-positive rate equals 2-4%.
Levels may be normal in lymphoma and lung cancer.
The reference interval for children and adolescents may be as much as 50% higher than specimens from adults.
Serum ACE abnormality has been reported in 20-30% of α1-antitrypsin variants (MZ, ZZ, and MS Pi types) but in only about 1% of individuals with normal MM Pi type. There is evidence that paraquat poisoning (because of its effect on pulmonary capillary endothelium) is associated with elevated serum ACE.
The AG is an arithmetic approximation of difference between routinely measured serum anions (23) and cations (11) = 12 mmol/L.
Unmeasured ions include proteins (mostly albumin) = 15 mmol/L, organic acids = 5 mmol/L, phosphates = 2 mmol/L, and sulfates = 1 mmol/L; total = 23 mmol/L.
Unmeasured cations include calcium = 5 mmol/L, potassium = 4.5 mmol/L, and magnesium = 1.5 mmol/L; total = 11 mmol/L.
Calculated as Na+ − (Cl− + HCO3−); typical normal values = 8-16 mmol/L; if K+ is included, normal = 10-20 mmol/L; reference interval varies considerably depending on instrumentation and between individuals. Increased AG reflects amount of organic (e.g., lactic acid, ketoacids) and fixed acids present.
AG initially began as a measure of quality assurance.
Identify cause of a metabolic acidosis
Supplement to laboratory quality control, along with its components
Organic (e.g., lactic acidosis, ketoacidosis)
Inorganic (e.g., administration of phosphate, sulfate)
Protein (e.g., hyperalbuminemia, transient)
Exogenous (e.g., salicylate, formate, paraldehyde, nitrate, penicillin, carbenicillin)
Not completely identified (e.g., hyperosmolar hyperglycemic nonketotic coma, uremia, poisoning by ethylene glycol, methanol)
▼ Falsely increased serum sodium
▼ Falsely decreased serum chloride or bicarbonate
When AG >12-14 mmol/L, diabetic ketoacidosis is the most common cause, uremic acidosis is the second most common cause, and drug ingestion (e.g., salicylates, methyl alcohol, ethylene glycol, ethyl alcohol) is the third most common cause; lactic acidosis should always be considered when these three causes are ruled out. In small children, rule out inborn errors of metabolism.
Hypoalbuminemia (most common cause), hypocalcemia, and hypomagnesemia.
Artifactual (laboratory error, most frequent cause).
“Hyperchloremia” in bromide intoxication (if chloride determination by colorimetric method).
False increase in serum chloride or HCO3−.
False decrease in serum sodium (e.g., hyperlipidemia, hyperviscosity):
▼ Increased unmeasured cations
▼ Hyperkalemia, hypercalcemia, and hypermagnesemia
Increased proteins in multiple myeloma, paraproteinemias, and polyclonal gammopathies (these abnormal proteins are positively charged and lower the AG).
Lithium and bromide overdose.
Simultaneous changes in ions may cancel each other out, leaving AG unchanged (e.g., increased Cl− and decreased HCO3−). The change in AG should equal change in HCO3−; otherwise, a mixed, rather than simple, acid-base disturbance is present.
Antibiotics are substances that destroy or inhibit the growth of microorganisms. Antibiotics consist of chemical groups such as β-lactams, polyenes, macrolides, tetracyclines, aminoglycosides, and sulfonamides. Names include amikacin, chloramphenicol, gentamicin, kanamycin, streptomycin, tobramycin, and vancomycin.
Normal therapeutic (and toxic) levels: see Table 2-5.
TABLE 2-5. Therapeutic and Toxic Serum Concentrations for Antibiotics