15 Nov 1998
The various multiparameter blood chemistry and hematology profiles offered by most labs represent an economical way by which a large amount of information concerning a patient's physiologic status can be made available to the physician. The purpose of this monograph is to serve as a reference for the interpretation of abnormalities of each of the parameters.
Because reference ranges (except for some lipid studies) are typically defined as the range of values of the median 95% of the healthy population, it is unlikely that a given specimen, even from a healthy patient, will show "normal" values for all the tests in a lengthy profile. Therefore, caution should be exercised to prevent overreaction to miscellaneous, mild abnormalities without clinical correlate.
American labs use a different version of the metric system than does most of the rest of the world, which uses the Système Internationale (SI). In some cases translation between the two systems is easy, but the difference between the two is most pronounced in measurement of chemical concentration. The American system generally uses mass per unit volume, while SI uses moles per unit volume. Since mass per mole varies with the molecular weight of the analyte, conversion between American and SI units requires many different conversion factors. Where appropriate, in this paper SI units are given after American units.
Decrease in sodium is seen in states characterized by intake of free water or hypotonic solutions, as may occur in fluid replacement following sweating, diarrhea, vomiting, and diuretic abuse. Dilutional hyponatremia may occur in cardiac failure, liver failure, nephrotic syndrome, malnutrition, and SIADH. There are many other causes of hyponatremia, mostly related to corticosteroid metabolic defects or renal tubular abnormalities. Drugs other than diuretics may cause hyponatremia, including ammonium chloride, chlorpropamide, heparin, aminoglutethimide, vasopressin, cyclophosphamide, and vincristine.
Drugs causing hyperkalemia include amiloride, aminocaproic acid, antineoplastic agents, epinephrine, heparin, histamine, indomethacin, isoniazid, lithium, mannitol, methicillin, potassium salts of penicillin, phenformin, propranolol, salt substitutes, spironolactone, succinylcholine, tetracycline, triamterene, and tromethamine. Spurious hyperkalemia can be seen when a patient exercises his/her arm with the tourniquet in place prior to venipuncture. Hemolysis and marked thrombocytosis may cause false elevations of serum K+ as well. Failure to promptly separate serum from cells in a clot tube is a notorious source of falsely elevated potassium.
Decrease in serum potassium is seen usually in states characterized by excess K+ loss, such as in vomiting, diarrhea, villous adenoma of the colorectum, certain renal tubular defects, hypercorticoidism, etc. Redistribution hypokalemia is seen in glucose/insulin therapy, alkalosis (where serum K+ is lost into cells and into urine), and familial periodic paralysis. Drugs causing hypokalemia include amphotericin, carbenicillin, carbenoxolone, corticosteroids, diuretics, licorice, salicylates, and ticarcillin.
Decrease in serum chloride is seen in excessive sweating, prolonged vomiting, salt-losing nephropathy, adrenocortical defficiency, various acid base disturbances, conditions characterized by expansion of extracellular fluid volume, acute intermittent porphyria, SIADH, etc. Drugs causing decreased chloride include bicarbonate, carbenoxolone, corticosteroids, diuretics, laxatives, and theophylline.
Decrease in blood CO2 is seen in metabolic acidosis and compensated respiratory alkalosis. Substances causing metabolic acidosis include ammonium chloride, acetazolamide, ethylene glycol, methanol, paraldehyde, and phenformin. Salicylate poisoning is characterized by early respiratory alkalosis followed by metabolic acidosis with attendant decreased bicarbonate.
Critical studies on bicarbonate are best done on anaerobically collected heparinized whole blood (as for blood gas determination) because of interaction of blood and atmosphere in routinely collected serum specimens. Routine electrolyte panels are usually not collected in this manner.
The tests "total CO2" and "CO2 content" measure essentially the same thing. The "PCO 2" component of blood gas analysis is a test of the ventilatory component of pulmonary function only.
Decreased serum anion gap is seen in dilutional states and hyperviscosity syndromes associated with paraproteinemias. Because bromide is not distinguished from chloride in some methodologies, bromide intoxication may appear to produce a decreased anion gap.
At least one of the above criteria must be met on more than one occasion, and the third method (2-hour plasma glucose after oral glucose challenge) is not recommended for routine clinical use. The criteria apply to any age group. This means that the classic oral glucose tolerance test is now obsolete, since it is not necessary for the diagnosis of either diabetes mellitus or reactive hypoglycemia.
Diagnosis of gestational diabetes mellitus (GDM) is slightly different. The screening test, performed between 24 and 28 weeks of gestation, is done by measuring plasma glucose 1 hour after a 50-gram oral glucose challenge. If the plasma glucose is 140 mg/dL or greater, then the diagnostic test is performed. This consists of measuring plasma glucose after a 100-gram oral challenge. The diagnostic criteria are given in the table below.
|Time||Glucose (mg/dL)||Glucose (mmol/L)|
In adults, hypoglycemia can be observed in certain neoplasms (islet cell tumor, adrenal and gastric carcinoma, fibrosarcoma, hepatoma), severe liver disease, poisonings (arsenic, CCl4, chloroform, cinchophen, phosphorous, alcohol, salicylates, phenformin, and antihistamines), adrenocortical insufficiency, hypothroidism, and functional disorders (postgastrectomy, gastroenterostomy, autonomic nervous system disorders). Failure to promptly separate serum from cells in a blood collection tube causes falsely depressed glucose levels. If delay in transporting a blood glucose to the lab is anticipated, the specimen should be collected in a fluoride-containing tube (gray-top in the US, yellow in the UK).
In the past, the 5-hour oral glucose tolerance test was used to diagnose reactive (postprandial) hypoglycemia, but this has fallen out of favor. Currently, the diagnosis is made by demonstrating a low plasma glucose (<50 mg/dL[2.8 mmol/L]) during a symptomatic episode.
Decreased serum urea nitrogen (BUN) is seen in high carbohydrate/low protein diets, states characterized by increased anabolic demand (late pregnancy, infancy, acromegaly), malabsorption states, and severe liver damage.
In Europe, the test is called simply "urea."
Nephrotoxic drugs and other chemicals include:
|acetazolamide||aminocaproic acid||aminosalicylate||boric acid|
Deranged metabolic processes may cause increases in serum creatinine, as in acromegaly and hyperthyroidism, but dietary protein intake does not influence the serum level (as opposed to the situation with BUN). Some substances interfere with the colorimetric system used to measure creatinine, including acetoacetate, ascorbic acid, levodopa, methyldopa, glucose and fructose. Decrease in serum creatinine is seen in pregnancy and in conditions characterized by muscle wasting.
The BUN:creatinine ratio is not widely reported in the UK.
Decreased serum uric acid level may not be of clinical significance. It has been reported in Wilson's disease, Fanconi's syndrome, xanthinuria, and (paradoxically) in some neoplasms, including Hodgkin's disease, myeloma, and bronchogenic carcinoma.
Hypophosphatemia can be seen in a variety of biochemical derangements, incl. acute alcohol intoxication, sepsis, hypokalemia, malabsorption syndromes, hyperinsulinism, hyperparathyroidism, and as result of drugs, e.g., acetazolamide, aluminum-containing antacids, anesthetic agents, anticonvulsants, and estrogens (incl. oral contraceptives). Citrates, mannitol, oxalate, tartrate, and phenothiazines may produce spuriously low phosphorus by interference with the assay.
Hypocalcemia must be interpreted in relation to serum albumin concentration (Some laboratories report a "corrected calcium" or "adjusted calcium" which relate the calcium assay to a normal albumin. The normal albumin, and hence the calculation, varies from laboratory to laboratory). True decrease in the physiologically active ionized form of Ca++ occurs in many situations, including hypoparathyroidism, vitamin D deficiency, chronic renal failure, magnesium deficiency, prolonged anticonvulsant therapy, acute pancreatitis, massive transfusion, alcoholism, etc. Drugs producing hypocalcemia include most diuretics, estrogens, fluorides, glucose, insulin, excessive laxatives, magnesium salts, methicillin, and phosphates.
Iron can be decreased in iron-deficiency anemia, acute and chronic infections, carcinoma, nephrotic syndrome, hypothyroidism, in protein- calorie malnutrition, and after surgery.
Decreased serum alkaline phosphatase may not be clinically significant. However, decreased serum levels have been observed in hypothyroidism, scurvy, kwashiokor, achrondroplastic dwarfism, deposition of radioactive materials in bone, and in the rare genetic condition hypophosphatasia.
There are probably more variations in the way in which alkaline phosphatase is assayed than any other enzyme. Therefore, the reporting units vary from place to place. The reference range for the assaying laboratory must be carefully studied when interpreting any individual result.
Decrease of serum LD is probably not clinically significant.
There are two main analytical methods for measuring LD: pyruvate->lactate and lactate->pyruvate. Assay conditions (particularly temperature) vary among labs. The reference range for the assaying laboratory must be carefully studied when interpreting any individual result.
Many European labs assay alpha-hydroxybutyrate dehydrogenase (HBD or HBDH), which roughly equates to LD isoenzymes 1 and 2 (the fractions found in heart, red blood cells, and kidney).
Gamma-GT is a very sensitive test for liver damage, and unexpected, unexplained mild elevations are common. Alcohol consumption is a common culprit.
Decreased gamma-GT is not clinically significant.
Drugs known to cause cholestasis include the following:
|estrogens||penicillin||gold Na thiomalate||imipramine|
Drugs known to cause hepatocellular damage include the following:
|iron salts||isoniazid||MAO inhibitors||mercaptopurine|
|nicotinic acid||nitrofurantoin||oral contraceptives||papaverine|
Disproportionate elevation of direct (conjugated) bilirubin is seen in cholestasis and late in the course of chronic liver disease. Indirect (unconjugated) bilirubin tends to predominate in hemolysis and Gilbert's disease.
Decreased serum total bilirubin is probably not of clinical significance but has been observed in iron deficiency anemia.
Decrease in serum total protein reflects decreases in albumin, globulin or both [see "Albumin" and "Globulin, A/G ratio," below].
Decreased serum albumin is seen in states of decreased synthesis (malnutrition, malabsorption, liver disease, and other chronic diseases), increased loss (nephrotic syndrome, many GI conditions, thermal burns, etc.), and increased catabolism (thyrotoxicosis, cancer chemotherapy, Cushing's disease, familial hypoproteinemia).
Decreased globulin may be seen in congenital or acquired hypogammaglobulinemic states. Serum and urine protein electrophoresis may help to better define the clinical problem.
Increased T3 uptake (decreased TBG) in euthyroid patients is seen in chronic liver disease, protein-losing states, and with use of the following drugs: androgens, barbiturates, bishydroxycourmarin, chlorpropamide, corticosteroids, danazol, d-thyroxine, penicillin, phenylbutazone, valproic acid, and androgens. It is also seen in hyperthyroidism.
Decreased T3 uptake (increased TBG) may occur due to the effects of exogenous estrogens (including oral contraceptives), pregnancy, acute hepatitis, and in genetically-determined elevations of TBG. Drugs producing increased TBG include clofibrate, lithium, methimazole, phenothiazines, and propylthiouracil. Decreased T3 uptake may occur in hypothyroidism.
T4 is decreased in hypothyroidism and in euthyroid states characterized by decreased TBG. A separate test for "T4" is available, but it is not usually necessary for the diagnosis of functional thyroid disorders.
ASSESSMENT OF ATHEROSCLEROSIS RISK: Triglycerides, Cholesterol, HDL-Cholesterol, LDL-Cholesterol, Chol/HDL ratio
All of these studies find greatest utility in assessing the risk of atherosclerosis in the patient. Increased risks based on lipid studies are independent of other risk factors, such as cigarette smoking.
Total cholesterol has been found to correlate with total and cardiovascular mortality in the 30-50 year age group. Cardiovascular mortality increases 9% for each 10 mg/dL increase in total cholesterol over the baseline value of 180 mg/dL. Approximately 80% of the adult male population has values greater than this, so the use of the median 95% of the population to establish a normal range (as is traditional in lab medicine in general) has no utility for this test. Excess mortality has been shown not to correlate with cholesterol levels in the >50 years age group, probably because of the depressive effects on cholesterol levels expressed by various chronic diseases to which older individuals are prone.
HDL-cholesterol is "good" cholesterol, in that risk of cardiovascular disease decreases with increase of HDL. An HDL-cholesterol level of <35 mg/dL is considered a coronary heart disease risk factor independent of the level of total cholesterol. One way to assess risk is to use the total cholesterol/HDL-cholesterol ratio, with lower values indicating lower risk. The following chart has been developed from ideas advanced by Castelli and Levitas, Current Prescribing, June, 1977. It is not commonly cited in current literature, but I have never seen a specific refutation of its validity either.
Total cholesterol (mg/dL) 150 185 200 210 220 225 244 260 300 ------------------------------------------------------ 25 | #### 1.34 1.50 1.60 1.80 2.00 3.00 4.00 6.00 30 | #### 1.22 1.37 1.46 1.64 1.82 2.73 3.64 5.46 35 | #### 1.00 1.12 1.19 1.34 1.49 2.24 2.98 4.47 HDL-chol 40 | #### 0.82 0.92 0.98 1.10 1.22 1.83 2.44 3.66 (mg/dL) 45 | #### 0.67 0.75 0.80 0.90 1.00 1.50 2.00 3.00 50 | #### 0.55 0.62 0.66 0.74 0.82 1.23 1.64 2.46 55 | #### 0.45 0.50 0.54 0.60 0.67 1.01 1.34 2.01 60 | #### 0.37 0.41 0.44 0.50 0.55 0.83 1.10 1.65 65 | #### 0.30 0.34 0.36 0.41 0.45 0.68 0.90 1.35 over 70 | #### #### #### #### #### #### #### #### ####
The numbers with two-decimal format represent the relative risk of atherosclerosis vis-à-vis the general population. Cells marked "####" indicate very low risk or undefined risk situations. Some authors have warned against putting too much emphasis on the total-chol/HDL-chol ratio at the expense of the total cholesterol level.
Readers outside the US may find the following version of the table more useful. This uses SI units for total and HDL cholesterol:
Total cholesterol (mmol/L) 3.9 4.8 5.2 5.4 5.7 5.8 6.3 6.7 7.8 ------------------------------------------------------ 0.65 | #### 1.34 1.50 1.60 1.80 2.00 3.00 4.00 6.00 0.78 | #### 1.22 1.37 1.46 1.64 1.82 2.73 3.64 5.46 0.91 | #### 1.00 1.12 1.19 1.34 1.49 2.24 2.98 4.47 HDL-chol 1.04 | #### 0.82 0.92 0.98 1.10 1.22 1.83 2.44 3.66 (mmol/L) 1.16 | #### 0.67 0.75 0.80 0.90 1.00 1.50 2.00 3.00 1.30 | #### 0.55 0.62 0.66 0.74 0.82 1.23 1.64 2.46 1.42 | #### 0.45 0.50 0.54 0.60 0.67 1.01 1.34 2.01 1.55 | #### 0.37 0.41 0.44 0.50 0.55 0.83 1.10 1.65 1.68 | #### 0.30 0.34 0.36 0.41 0.45 0.68 0.90 1.35 over 1.81 | #### #### #### #### #### #### #### #### ####
Triglyceride level is risk factor independent of the cholesterol levels. Triglycerides are important as risk factors only if they are not part of the chylomicron fraction. To make this determination in a hypertriglyceridemic patient, it is necessary to either perform lipoprotein electrophoresis or visually examine an overnight- refrigerated serum sample for the presence of a chylomicron layer. The use of lipoprotein electrophoresis for routine assessment of atherosclerosis risk is probably overkill in terms of expense to the patient.
LDL-cholesterol (the amount of cholesterol associated with low-density, or beta, lipoprotein) is not an independently measured parameter but is mathematically derived from the parameters detailed above. Some risk- reduction programs use LDL-cholesterol as the primary target parameter for monitoring the success of the program. The "desirable" level for LDL-cholesterol is less than 100 mg/dL.
A detailed statement on this subject is "Primary Prevention of Coronary Heart Disease: Guidance From Framingham", Circulation 97:1876-1887, 1998. The full text is available online, courtesy of the American Heart Association.
HEMOGLOBIN, HEMATOCRIT, MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), MCHC (mean corpuscular hemoglobin concentration)
Strictly speaking, anemia is defined as a decrease in total body red cell mass. For practical purposes, however, anemia is typically defined as hemoglobin <12.0 g/dL and direct determination of total body RBC mass is almost never used to establish this diagnosis. Anemias are then classed by MCV and MCHC (MCH is usually not helpful) into one of the following categories:
*Drugs and other substances that have caused aplastic anemia include the following:
amphotericin sulfonamides phenacetin trimethadione silver chlordiazepoxide tolbutamide thiouracil carbamazepine chloramphenicol tetracycline oxyphenbutazone arsenicals chlorpromazine pyrimethamine carbimazole acetazolamide colchicine penicillin aspirin mephenytoin bismuth promazine quinacrine methimazole chlorothiazide dinitrophenol ristocetin indomethacin phenytoin gold trifluoperazine carbutamide perchlorate chlorpheniramine streptomycin phenylbutazone primidone mercury meprobamate chlorpropamide thiocyanate tripelennamine benzene
The drugs listed above produce marrow aplasia via an unpredictable, idiosyncratic host response in a small minority of patients. In addition, many antineoplastic drugs produce predictable, dose-related marrow suppression; these are not detailed here.
Polycythemia is defined as an increase in total body erythrocyte mass. As opposed to the situation with anemias, the physician may directly measure rbc mass using radiolabeling by 51Cr, so as to differentiate polycythemia (absolute erythrocytosis, as seen in polycythemia vera, chronic hypoxia, smoker's polycythemia, ectopic erythropoietin production, methemoglobinemia, and high O2 affinity hemoglobins) from relative erythrocytosis (as seen in stress polycythemia and dehydration). Further details of the work-up of polycythemias are beyond the scope of this monograph.
|Further online reading on hematology and red cell disease|
Cells and the CBC is an introduction to the
morphology and function of the red cells, white cells,
and platelets. Photomicrographs are included. The
complete blood count (CBC) is also covered.|
Anemia: Pathophysiologic Consequences, Classification, and Clinical Investigation is an introduction to anemia.
Nutritional Anemias and Anemia of Chronic Disease deals with anemias caused by iron, folate, and vitamin B12 deficiencies.
Hemolytic Anemias is concerned with anemias caused by red cells being destroyed faster than a healthy marrow can replace them.
Hemoglobinopathies and Thalassemias covers sickle cell disease, hemoglobins C and E, and alpha- and beta-thalassemias.
Understanding Anemia, my first book, is now available in hardback and paper. The publisher has kindly allowed me to post the full text of Chapter 1 online. You can access it through the book outline at this link. There is also a link to buy the book from online bookstores at a substantial discount. This book is aimed at general readers and presumes a knowledge of biology at the high school level, then builds from there.
Thrombocytopenia is divided pathophysiologically into production defects and consumption defects based on examination of the bone marrow aspirate or biopsy for the presence of megakaryocytes. Production defects are seen in Wiskott-Aldritch syndrome, May-Hegglin anomaly, Bernard-Soulier syndrome, Chediak-Higashi anomaly, Fanconi's syndrome, aplastic anemia (see list of drugs, above), marrow replacement, megaloblastic and severe iron deficiency anemias, uremia, etc. Consumption defects are seen in autoimmune thrombocytopenias (including ITP and systemic lupus), DIC, TTP, congenital hemangiomas, hypersplenism, following massive hemorrhage, and in many severe infections.
Smokers tend to have higher granulocyte counts than nonsmokers. The usual increment in total wbc count is 1000/µL for each pack per day smoked.
Repeated excess of "bands" in a differential count of a healthy patient should alert the physician to the possibility of Pelger-Huët anomaly, the diagnosis of which can be established by expert review of the peripheral smear. The manual band count is so poorly reproducible among observers that it is widely considered a worthless test. A more reproducible hematologic criterion for acute phase reaction is the presence in the smear of any younger forms of the neutrophilic line (metamyelocyte or younger).
Neutropenia may be paradoxically seen in certain infections, including typhoid fever, brucellosis, viral illnesses, rickettsioses, and malaria. Other causes include aplastic anemia (see list of drugs above), aleukemic acute leukemias, thyroid disorders, hypopitituitarism, cirrhosis, and Chediak-Higashi syndrome.
Eosinopenia is seen in the early phase of acute insults, such as shock, major pyogenic infections, trauma, surgery, etc. Drugs producing eosinopenia include corticosteroids, epinephrine, methysergide, niacin, niacinamide, and procainamide.
Basopenia is not generally a clinical problem.
Lymphopenia is characteristic of AIDS. It is also seen in acute infections, Hodgkin's disease, systemic lupus, renal failure, carcinomatosis, and with administration of corticosteroids, lithium, mechlorethamine, methysergide, niacin, and ionizing irradiation. Of all hematopoietic cells lymphocytes are the most sensitive to whole-body irradiation, and their count is the first to fall in radiation sickness.
Monocytopenia is generally not a clinical problem.
Many thanks to Michael Gayler, FIBMS, DMS, CertHSm (MLSO2, Department of Chemical Pathology, Leicester Royal Infirmary) <email@example.com> for the excellent review and comments, and for the labor of translating American to SI units.
Please send all constructive comments regarding this FAQ to Ed Uthman, MD (firstname.lastname@example.org). I am especially interested in correcting any errors of commission or omission.
This article is provided "as is" without any express or implied warranties. While reasonable effort has been made to ensure the accuracy of the information, the author assumes no responsibility for errors or omissions, or for damages resulting from use of the information herein.
Copyright © 1994-98, Edward O. Uthman. This material may be reformatted and/or freely distributed via online services or other media, as long as it is not substantively altered. Authors, educators, and others are welcome to use any ideas presented herein, but I would ask for acknowledgment in any published work derived therefrom. Commercial use is not allowed without the prior written consent of the author.