Effect of patient-related factors on clinical laboratory test results

C H A P T E R

4 Effect of patient-related factors on clinical laboratory test results Octavia M. Peck Palmera,b,c a

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; bDepartment of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; cDepartment of Clinical and Translational Science, University of Pittsburgh School, Pittsburgh, PA, United States

INTRODUCTION

gender specific reference ranges, in some cases, can account for the influence of pre-analytical factors. Understanding how pre-analytical factors influence the accurate measurement of test results will aid in the interpretation of individual patient results within the context of the clinical setting. This chapter discusses patient-related factors: age, gender, dietary intake, and exercise, and their influence on analytes measured in the clinical laboratory. Furthermore, the contribution of ethnicity/race, a social construct that is used as a surrogate marker for environmental, socio-economic/demographic, and/or genetic factors, on test results is reviewed. Only a few tests have widely used ethnic/race-specific reference intervals, with the exception of the estimated glomerular filtration rate calculation used in the United States. Lastly, other less known influences of fasting, special diets, nutraceuticals, genetic factors in the response to food and nutraceuticals, and cross-sex hormone regimens for transgender patients on laboratory tests are discussed.

In the United States, more than 7 billion clinical laboratory tests are performed annually [1]. Clinical laboratory test results are an important part of the decision-making process by clinicians for effective diagnosis, prognosis, treatment, and management. It is imperative that the in vitro diagnostic testing results accurately reflect the in vivo physiological processes of the patient. Inaccurate test results may lead to unnecessary invasive testing, postponement of critical therapies, increased patient anxiety, and expensive healthcare costs (both for the patient and the healthcare system). Clinical laboratories are required to develop procedures to minimize the effect of pre-analytical, analytical, and post-analytical factors on clinical laboratory analysis. Pre-analytical (steps prior to analysis), analytical (sample analysis), and post-analytical (steps after analysis) factors can affect the accuracy of serum/plasma analytes measured in the laboratory. The pre-analytical phase refers to the processes that occur prior to blood/ body fluid testing. These processes include the phlebotomy collection techniques (sample labeling, tourniquet, posture), blood/body fluid tube types (anti-coagulants, gel-separators, clot activators, preservatives), and sample handling (mixing/clotting protocol, temperature, storage, transport). However, in the pre-analytical process, biological factors, such as age (related variables with age e.g., pregnancy, menopause) are not modifiable. Patient-related factors such as gender (to an extent), dietary intake, and exercise regimens can be modified. Standardized patient preparation prior to blood collection can minimize the effects of pre-analytical factors. Age, and

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EFFECT OF AGE RELATED CHANGES ON CLINICAL LABORATORY TEST RESULTS Aging is a complex metabolic process that is not fully understood [2]. A myriad of complex physiological changes occur that also significantly affect clinical laboratory test results as an individual transitions through different phases: prenatal, infancy, childhood/puberty, adulthood and elder hood [3]. Understanding the effects of age on laboratory findings can increase diagnostic accuracy. The recognition of age-related changes allows clinicians to distinguish clinically significant changes in

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4. PATIENT-RELATED FACTORS THAT AFFECT LABORATORY RESULTS

laboratory test results that are attributed to disease from changes that are associated with healthy aging. Reference ranges for a majority of serum/plasma analytes measured in the laboratory have been established for the healthy adult population [4]. Yet, standardized age-specific reference ranges that distinguish pathologic from non-pathologic processes in the newborn, childhood to puberty, and elderly adult populations are not complete. Understanding the effects of age on laboratory results is crucial. In 2000, following the passage of the National Children’s Act, the U.S. Congress authorized the National Children’s Health Study (NCS). NCS is a longitudinal study of 100,000 healthy individuals aged 0e21 years led by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. As a collaborator of the NCS, the American Association of Clinical Chemistry (AACC) has funded several pilot studies to determine age-specific reference ranges [5]. Although the NCS was canceled in 2014, several collaborative studies have emerged under a new project known as Environmental Influences on Child Health Outcomes (ECHOs) program that encompasses multiple longitudinal studies of mothers and their children. ECHO has four key focus areas: upper and lower airway, neurodevelopment, obesity, pre-, peri-, and postnatal outcomes [6].

Prenatal/newborn population Newborn babies demonstrate different normal values than adults for various analytes. Following birth, arterial blood PO2 rises to about 80e90 mmHg. Oxygen consumption is significantly higher in the neonates compared to adults. A significant reduction in uric acid concentrations occurs between birth and six days of age. Healthy newborns rapidly metabolize glucose as a result of their high red blood cell count which is not evident in healthy adults [7]. Newborns have increased circulating bilirubin concentrations owing to their immature liver that is unable to convert bilirubin to bilirubin di-glucuronide. Hyperbilirubinemia due to physiologic jaundice is a common condition in newborns and usually resolves within in 5e7 days following birth but after birth it may be difficult to distinguish this normal physiological phenomenon from hemolytic disease of the newborn [8,9]. In newborns, immature kidney function is evidenced by high vascular resistance, low blood flow with preferential blood flow away from the outer cortex, and a low glomerular filtration rate (GFR). Several important physiological functions of the kidney are compromised in newborns: (i) concentrating and diluting functions, (ii) acid base regulation, (iii) sodium reabsorption, excretion and retention, (iv) natriuretic response to sodium, and (v) hydrogen ion secretion [10].

Newborns experience an expanded extracellular fluid volume state. Hypocalcaemia in this population usually resolves within the first two days of life if not associated with a disease processes [11].

Childhood to puberty stages Growth and development markedly influence laboratory test results. The Pituitary-Gonadal Axis also undergoes changes that contribute to the luteinizing hormone (LH) and follicle stimulating hormone (FSH) fluctuations. In boys and girls, two weeks following birth LH concentrations increase but decline to pre-pubertal concentrations by their first birthday. Similarly, FSH concentrations follow the same trend as LH concentrations after birth but decline to pre-pubertal concentrations in boys by the first year of life and in girls by the second year of life. Reduced LH and FSH concentrations in the early to mid-teen years are not sensitive enough to distinguish between pubertal delay and hypogonadotropic hypogonadism. Gonadal failure indicated by an upward trajectory of LH and FSH concentrations cannot be expected until 10 years of age. Estradiol concentrations are markedly elevated at birth but rapidly decline during the first week to pre-pubertal concentrations (0.5e5.0 ng/dL for girls, 1.0e3.2 ng/dL for boys), and decline to pre-pubertal concentrations again by the sixth month in boys and by the first year of life in girls [12,13]. Skeletal growth and muscle mass development accounts, in part, for the increased alkaline phosphatase (ALP), gamma-glutamyl transferase (g-GGT), creatinine, and human growth hormone concentrations seen in the childhood to puberty developmental period. ALP concentrations in girls decline after the age of 12 whereas the decline is after the age of 14 in boys [14]. Notably, appreciable alkaline phosphatase concentrations are present during growth spurts but can also be associated with bone diseases (osteoblastic bone cancers, osteomalacia, Paget’s disease and rickets). Alkaline phosphatase concentrations are approximately 3-fold higher in adolescents compared to adults [15]. Creatinine increases with age from 12 to 19 years whereas cystatin C concentrations decrease during the same age range, particularly in females. Uric acid concentrations continue to decline up to 10 years of age [16].

Adulthood In both sexes, total cholesterol increases with advancing age (men age 60 and women age 55). In the second decade of life men have peak uric acid concentrations which are not evident in women until the fifth decade of life [8].

I. SOURCES OF ERRORS IN CLINICAL LABORATORIES: AN OVERVIEW

EFFECT OF AGE RELATED CHANGES ON CLINICAL LABORATORY TEST RESULTS

Menopausal pre- and post- period Post-menopausal women have increased total cholesterol concentrations, which are thought to be due to decreased concentrations of the estrogen. High density lipoprotein (HDL) cholesterol also declines up to 30% [8]. The transition from the peri-to the post-menopausal stage is associated with dramatic endocrine changes. A strong correlation between age and human chorionic gonadotropin (hCG) is observed [17]. Clinical confusion surrounds how to appropriately interpret hCG laboratory results since hCG synthesis is appreciable during healthy pregnancy, cancer or trophoblastic disease. Notably, the pituitary gland produces hCG in addition to LH, FSH and thyroid stimulating hormones, which are all structurally similar glycoprotein [18]. Routine measurements of serum hCG concentrations (reference limit hCG <0.5 mIU/mL) in women are performed to either identify pregnancy or to rule out pregnancy prior to performing invasive medical procedures or administering medications that may be harmful to a developing fetus [19]. Slight increases in serum hCG concentrations (>/ ¼ 0.5 mIU/mL) occur in women between the ages of 41 and 55 years. Thus, it is critical to distinguish the origin of the hCG (placental origin vs. pituitary origin). Misinterpretation of the slightly elevated hCG concentrations in peri- and postmenopausal women may postpone critical clinical treatments. In peri- and postmenopausal women (41e55 years of age), it has been suggested to use serum FSH concentrations to rule out hCG of placental origin and pregnancy. In peri- and postmenopausal women (41e55 years of age) with serum hCG concentrations ranging between 5.0 and 14.0 IU/L, a FSH cutoff of 45.0 IU/L was associated with hCG of placental origin with 100% sensitivity and 75% specificity. Importantly, FSH concentrations >45 IU/L are not present in females with hCG of placental origin. FSH reflex testing should only be used in the setting of pregnancy evaluation in the peri- and postmenopausal population when serum hCG concentrations range between 5.0 and 14.0 IU/L [20]. However, hCG >14.0 IU/L in this age group are indicative of pregnancy unless the clinical setting dictates otherwise. However, hCG concentration related to pituitary origin rarely exceeds 14 IU/L in postmenopausal women [17].

Elderly The aging population is rapidly increasing in the United States. Between the year 2000 (35 million persons) and the year 2010 (40 million persons), the U.S. experienced a 15% increase in the aged population (65 years and older) [21]. In 2014, there were 46 million Americans over the age of 65 years and this populations

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growth is expected to be >98 million by 2060 [22]. Aging-related diseases are diagnosed, treated and monitored using various in vitro diagnostic testing. However, interpretation of laboratory findings in the elderly adult population is challenging due to multiple confounding factors: (i) physiologic changes that naturally occur with healthy aging, (ii) acute and chronic conditions (kidney disease, diabetes and cardiovascular disease), (iii) diets, (iv) lifestyles, and (v) medication regimens [23]. Age-related changes in serum proteins are evident in elderly adults including albumin, an indicator of malnutrition and disease, which is more significantly affected. After the age of 60, albumin concentrations decline each decade, with significant decreases noted in individuals >90 years old [24]. The majority of circulating calcium is bound to protein. Low serum calcium concentration in the elderly adult population is most commonly caused by low serum albumin concentrations [25]. Protein concentration changes may be entirely due to compromised liver function or poor dietary regimens. Iron-related changes occur during aging and are noted as decreased iron storage, serum iron, and total iron-binding capacity. Depletion of iron stores may be followed by increases in serum ferritin and decreases in serum transferrin. Dysregulated liver synthesis during aging may account for the reduced transferrin concentrations [4]. In general, decreased iron storage and iron deficiency anemia in the elderly adult population reflect poor dietary iron intake or substantial loss of iron through occult bleeding from the intestinal tract, both of which should be fully investigated prior to interpretation the changes as age-related. It is hypothesized that the anemia in this age group, may, in part, be explained by the age-related decreases in stomach hydrochloric acid (HCl), a key acid responsible for iron absorption in the intestines. Vitamin B12 deficiency is also prevalent in elderly adults due to age-related decreases in serum vitamin B12 concentrations. The underlying cause for vitamin B12 deficiency may be decreased HCI concentrations or chronic atrophic gastritis, which subsequently accounts for insufficient intrinsic factor and vitamin B12 absorption [23]. Age-associated organ function decline is correlated with changes in laboratory findings (e.g., reduced creatinine clearance, glucose tolerance, and hypothalamicpituitary adrenal axis regulation) that may represent disease or non-disease processes. In 10% or more of the healthy elderly population, physiologic changes in partial pressure of oxygen in arterial blood (between the 3rd and 8th decade decreases by 25%), serum alkaline phosphatase (increases by 20% between the 3rd and 8th decade), 2-h postprandial glucose (after age 40 increases 30e40 mg/dL per decade), cholesterol (by age 60 increases by 30e40 mg/dL), erythrocyte sedimentation

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4. PATIENT-RELATED FACTORS THAT AFFECT LABORATORY RESULTS

rate (values as high as 40 can be non-pathogenic), and magnesium (decreases by 15%), are apparent in the elderly but may not be associated with disease processes [8,23]. A 30%e40% decline in functioning kidney and the glomerular filtration rate (GFR) is associated with reduced creatinine clearance. Creatinine and blood urea nitrogen (BUN) concentrations can overestimate the kidney functioning capacity, as measured by GFR or creatinine clearance, due to reduced muscle mass [26]. The decline in muscle mass results in reduced creatinine production; thus serum creatinine concentrations remain within normal limits despite the underlying diminished renal clearance capacity [23]. Mean creatinine clearance decreases by 10 mL/min/1.73 m2 per decade and is significantly different between the adult and geriatric populations. The mean creatinine clearance for a 30-year old is 140 mL/min (2.33 mL/s) per 1.73 m2 of body surface area, whereas in an 80-year old the creatinine clearance concentration is 97 mL/min (1.62 mL/s) per 1.73 m2 of body surface area [27]. Small increases in serum aspartate aminotransferase (AST) (18 U/L to 30 U/L) are noted between 60 and 90 years of age whereas serum alanine aminotransferase (ALT) peaks in the fifth decade of life and by the sixth decade gradually declines to concentrations well below those noted in young adults [23]. Gamma-glutamyl transferase (GGT) concentrations rise during aging. A steady increase in serum glucose concentrations and a decrease in glucose tolerance are prevalent in elderly adults. Lower glucose concentrations in elderly adults may be due to poor diet and reduced body mass. Higher serum insulin concentrations are prevalent in elderly adults and may be associated with insulin resistance [23]. In persons older than 75 years, insulin resistance is reportedly responsible for impaired glucose tolerance. These changes may be explained by the fact that the response capacity of insulin receptors is significantly lower in elderly adults compared to young adults. Regarding serum immunoglobulin concentrations, IgA concentration increases slightly in elderly men but overall IgG and IgM concentrations gradually decline. The hypothalamic-pituitary-adrenal axis is compromised during aging and changes include decreases in free thyroxine (FT4), triiodothyronine (T3), corticotropin, and corticosteroid concentrations [28]. Specific to men, free testosterone decreases with age, without significant changes in total testosterone [29,30]. Prostate specific antigen (PSA) concentrations increase up to 6.5 ng/mL in men over the age of 70 without clinical evidence of prostate cancer [23]. Serum electrolytes, such as potassium and calcium, increase during aging. Calcium concentration increase in individuals aged 60 to 90 in the presence of normal albumin concentrations. However, after the age of 90, calcium concentrations

gradually decline. Hypercalcemia may be due to a simultaneous drop in serum pH and an increase in parathyroid hormone concentrations. Age significantly impacts lung elastic architecture, alveoli function and diaphragm strength and significantly alters respiratory function. Consequently, the partial pressure of arterial oxygen is decreased while carbon dioxide pressure and bicarbonate-ion concentration are increased [23]. Although age can significantly account for altered clinical laboratory test results, one must consider the overlapping effects caused by disease, such as obesity and hypertension, and/or inadequate dietary intake when interpreting laboratory results that are outside of the reference limits [31]. The abnormal results may highlight age associated disease processes that require clinical intervention. Experimental investigations focused on systematic effects of aging on laboratory analytes are warranted and may provide data useful for the development of effective age-specific diagnostic cutoffs.

GENDER RELATED CHANGES ON CLINICAL LABORATORY VALUES Gender encompasses a myriad of complex endocrine and metabolic responses. Gender differences in laboratory analytes can be explained by differential endocrine organ related functions and skeletal muscle mass [32]. On average, albumin, calcium, magnesium, hemoglobin, ferritin and iron concentrations are lower in females [8]. Reduced iron concentrations are attributed to blood loss during monthly menses. Mean serum creatinine and cystatin C concentrations are commonly lower in adolescent females compared to adolescent males [16]. Aldolase concentrations are higher in males following the start of puberty. ALP concentrations are higher in girls ages 10e11 and in boys ages 12e13, 14e15, and 16e17 had higher ALP concentrations. A decline in ALP concentrations begins after age 12 for girls and 14 for boys [14]. Menopausal women have higher ALP concentrations than males. Serum bilirubin concentrations are lower in women owing to the decreased hemoglobin concentrations. Gender differences in mean creatinine and creatine kinase concentrations are attenuated when comparing athletic females and males. Females have higher albumin concentrations compared to males of the same age [33]. Lipid profiles are heavily influence by gender. Total cholesterol concentrations vary not only with age but with gender. Females, under the age of 20 years, have higher total cholesterol concentrations compared to males in the corresponding age span. However, between the ages of 20 and 45 males commonly have higher total cholesterol concentrations than females. Males experience a peak in lipid concentrations generally between the ages of 40 and 60 whereas

I. SOURCES OF ERRORS IN CLINICAL LABORATORIES: AN OVERVIEW

DIETARY RELATED CHANGES ON CLINICAL LABORATORY VALUES

females peak lipid concentrations occur between the ages of 60 and 80 [34]. Individuals over 90 years of age may have significantly decreased total cholesterol concentrations. Between the ages of 30 and 80, mean high density lipoprotein cholesterol (HDL) decreases by approximately 30% in females but increases by 30% in males [23,35]. These lipid increases may be due to the stimulatory effect of estrogen in the women. In contrast, low-density lipoprotein cholesterol (LDL-C) is higher in men. Men also have higher 24-h urinary excretions of epinephrine, norepinephrine, cortisol, and creatinine excretion compared to women [36]. Women have higher serum GGT and copper, and reticulocyte count (due to increased erythrocyte turnover) compared to their male counterparts.

DIETARY RELATED CHANGES ON CLINICAL LABORATORY VALUES Diet may affect test results while starvation also has profound effect on clinical laboratory test results. Various dietary factors that affect clinical laboratory test results are discussed in this section.

Food ingestion-related changes on clinical laboratory values Food ingestion activates in vivo metabolic signaling pathways that significantly influence laboratory test results [37]. First, the stomach secretes HCl in response to food consumption which causes a decrease in plasma chloride concentrations. This mild metabolic alkalotic state (alkaline tide phenomenon) results from exaggerated circulating bicarbonate concentrations in the stomach’s venous blood and is accompanied by decreased ionized calcium by 0.05 mmol/L (0.2 mg/dL) [38]. Secondly, postprandial-associated impairment in the liver leads to increased bilirubin, and enzyme activities. Depending upon the content of the meal ingested the effects on commonly measured analytes may be short or long lasting. Thus, an overnight fasting for at least 12 h is necessary to obtain an accurate representation of in vivo glucose, lipids, iron, phosphorus, urate, urea, and ALP concentrations. Interestingly, ALP activity rises in response to the ingestion of a high-fat meal in Lewis a secretors of the blood groups B and O. Lipemia can also interfere with a variety of analytical methods, such as indirect potentiometry. Prior to analysis, lipids can be removed from lipemic samples via ultracentrifugation or by the use of lipid clearing reagents [39]. Carbohydrate (increases glucose and insulin, decreases phosphorus) and protein meals (increases cholesterol and growth hormone within 1 h of food consumption, increases glucagon and insulin) have differential effects on serum

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analytes. High protein diet can significantly affect various analytes measured in 24-h urine. A standard 700 calories meal markedly increases triglycerides (w50%), AST (w20%), bilirubin and glucose (w15%) and AST concentrations (w10%) [3]. Rapid changes in lipid concentrations are consistent with dietary changes, medications, or disease. Caffeine intake has significant effects on the human body. It is contained in a variety of foods (coffee, tea, chocolate, soft drinks, and energy drinks) in varying concentrations. The short half-life of caffeine (3e7 h) also varies among individuals. Caffeine induces catecholamine excretion from the adrenal medulla and increases gluconeogenesis, resulting in subsequently increases in glucose concentrations and impaired glucose tolerance following caffeine intake. The adrenal cortex is also vulnerable to caffeine’s stimulatory effects as evidenced by increased cortisol, free cortisol, 11-hydroxycorticoids and 5-hydroxindoleaceatic acid concentrations. Caffeine is responsible for a 3-fold increase in non-esterified fatty acids, which interfere with the accurate quantification of albumin-bound drugs and hormones. Spuriously high ionized calcium concentrations can occur following caffeine ingestion since caffeine-induced elevations in free fatty acids can cause a rapid decrease in pH that facilitates the removal of calcium from protein. Noni juice contains significant amounts of potassium (approximately 56 mEq/L). Ingestion of noni juice can led to hyperkalemia in vulnerable populations such as individuals with renal dysfunction and/or populations receiving potassium increasing regimens such as spironolactone or angiotensin converting enzyme inhibitors. Bran stimulates bile acid synthesis within 8 h of ingestion [38]. However, bran inhibits gastrointestinal absorption of important nutrients including calcium (decreased by 0.3 mg/dL/0.08 mmol/L), cholesterol, and triglycerides (decreased by 20 mg/dL/0.23 mmol/L) [3]. Serotonin (5-hydroxytryptamine) is contained in a myriad of fruits and vegetables such as bananas, black walnuts, kiwis, pineapples, and plantains. Bananas markedly increase 24-h urinary excretion of 5-hydroxyindoleacetic acid in the absence of disease. Avocados suppress insulin secretion causing impaired glucose tolerance.

Special diet-related changes on clinical laboratory values The ketogenic diet is a low carbohydrate (<40 g/d), moderate-protein, high-fat diet. In the absence of sufficient carbohydrates, the liver is forced to convert fat into fatty acids and ketones. Adherence to a ketogenic diet results in elevated blood and urine ketones within several days and diuresis within 2 weeks. Reportedly, a decline in serum triglycerides and an increase in HDL-C occur over several weeks [40]. The non-vegetarian diet

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is associated with higher plasma ammonia, uric acid and urea concentrations compared to a vegetarian diet. The ketogenic diet commonly includes saturated fatty acids, which in the case of palmitic acid can significantly increase plasma cholesterol concentrations. The substitution of saturated fatty acids with polyunsaturated fats and complex carbohydrates can lower LDL-C (low density lipoprotein cholesterol) concentrations. Intake of omega-3 oils may lower triglycerides and very lowdensity lipoprotein (VLDL) concentrations. Vegetarians have lower LDL-C (approximately 37% lower) and HDL-C (approximately 12%) concentrations compared to non-vegetarians. In contrast, lactovegetarians (vegetarians that consume dairy products) have higher LDL-C (approximately 24% higher) and HDL-C (approximately 7% higher) concentrations compared to vegetarians. Within 20 weeks, a lactovegetarian diet regimen accompanied by low protein and high dietary fiber intake can reduce adrenocortical activity. Lactovegetarians have higher plasma concentrations of dehydroepiandrosterone sulfate (DHEAS) compared to non-vegetarians (individuals who adhere to a moderately protein-rich with diet). Moreover, lactovegetarians have reduced urinary 24-h excretion rates for C-peptide, free cortisol, DHEAS, and total 17-ketosteroid [41]. In middle-aged North American black individuals, urinary 24-h excretion rates of adrenal and gonadal androgen metabolites were reduced after changing from a meat-containing Western diet to a vegetarian diet. The fecal fat test, which measures the amount of fat content in stool to diagnose absorption or digestion abnormalities, is susceptible to dietary influences. It is critical that individuals refrain from significant dietary changes during before and during sample collection. The hCG diet consists of hCG sublingual drops or injections paired with a low 500-calorie diet. As previously discussed, hCG can be of placental or non-placental origin. hCG is evident in placental trophoblastic (hydatidiform mole, choriocarcinoma), gonadal (ovarian, testicular or extragonadal teratoma), ectopic or nontrophoblastic tumors. Although, exogenous hCG is normally excreted from the body within 10 days, hCG may linger in the body. Individuals on the hCG diet that received injections of hCG have markedly elevated serum hCG concentrations in the absence of pregnancy or malignancy [42]. It is evident that individuals on the hCG diet may have unreliable hCG test results. However, the effects of hCG sublingual drops on other laboratory tests are currently unknown. In healthy males, hCG injections (purified urinary and recombinant hCG) cause a consistent dose-dependent and sustained rise in serum testosterone concentrations through stimulation of Leydig cell testosterone secretion [43].

Fasting/starvation-related changes on clinical laboratory values Fasting (decreased caloric intake) and starvation (no caloric intake) initiate complex metabolic derangements. Many individuals fast in accordance with culture and religious traditions so understanding the effects of fasting on laboratory results is important. Within 3 days of fasting, glucose concentrations decrease by as much as 18 mg/dL despite the body’s coordinated efforts to conserve proteins. Subsequently, insulin rapidly declines while glucagon secretion increases to restore blood glucose to pre-fasting concentrations. The fasting individual undergoes both lipolysis and hepatic ketogenesis, and the metabolic acidosis state is noted by elevated serum acetoacetic acid, beta-hydroxybutyrate, and fatty acids as well as reduced pH, pCO2 and bicarbonate concentrations. The resultant focal necrosis of the liver is characterized by reduced hepatic blood flow, impaired glomerular filtration and creatinine clearance, and elevated serum ALT, AST, bilirubin, creatinine and lactate concentrations are observed [3]. The body’s reduced energy stores mainly account for significant declines up to 50% in both total and free triiodothyronine concentrations. Fasting differentially affects lipid concentrations: within 6 days, cholesterol and triglycerides increase and HDL decreases. Sharp increases up to 15 times the pre-fast plasma in growth hormone concentrations occur early in fasting. Within 3 days of completing a fast, the plasma growth hormone concentration returns to pre-fast concentrations. Albumin, prealbumin and complement 3 (C3) decline during an extended fast but the analytes are rapidly restored to pre-fasting concentrations following protein supplementation. Starvation triggers the release of aldosterone and excessive urinary ammonia, calcium, magnesium and potassium excretion. In contrast, urinary excretion of phosphorus over time declines. Following a short term, 14-h fast, acetoacetate, beta-hydroxybutyrate, lactate, and pyruvate blood concentrations begin to rise. Long term starvation lasting for 40e48 h causes up to a 30-fold increase in beta-hydroxybutyrate. Reportedly, starvation for four weeks significantly increased AST, creatinine, and uric acid (20e40%) and decreased GGT, triglycerides, and urea (20e50%). Upon adequate caloric intake, the body begins to restore blood constituents to pre-fasting concentrations and retains sodium as a result of decreased urinary excretion of both sodium and chloride. Subsequently, aldosterone exceeds fasting concentrations and urinary excretion potassium slowly returns to normal.

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DIETARY RELATED CHANGES ON CLINICAL LABORATORY VALUES

Nutraceutical-related changes on clinical laboratory values

TABLE 4.1

In 1989, Dr. Stephen DeFelice coined the term “Nutraceutical” from “Nutrition” and “Pharmaceutical”. Nutraceuticals, according to the American Nutraceutical Association, includes functional foods with healthpromoting and disease-preventing benefits. Rigorous safety and efficacy studies are lacking and little is known about the pharmacokinetic properties of the commercially available nutraceuticals. An estimated 170 million Americans regularly take dietary supplements to enhance their overall wellbeing. Although, nutraceuticals exhibit pharmacological effects, patients do not consider them ‘drugs’ and often do not disclose usage to their physicians [44]. It is not fully clear how different types of nutraceuticals and conventional drugs interact within the body or the effects of the interaction. Few studies have documented the pharmacokinetic effects of nutraceuticals on laboratory findings [45]. Although it has been known for several decades that biotin is an interfering substance in assays that employ the biotinylated-streptavidin binding, the recent pervasive non-medical ingestion of supraphysiologic doses of biotin, prompted the FDA in 2017 to issue a warning. The warning was directed at consumers, healthcare providers, laboratory personnel, and lab test manufacturers and developers and stated that ‘ingesting high levels of biotin in dietary supplements can cause clinically significant incorrect lab test results’ [46]. Biotin is a cofactor in enzymatic carboxylation reactions. Significant biotin interference has been reported by several studies in which biotin dosages was 10,000 mg and higher. The typical Western diet can fulfill the adult recommended daily intake of biotin, 30 mcg. Medically necessary high dose biotin therapy is common for multiple sclerosis, malabsorption syndrome, genetic biotin deficiency, biotin-thiamin responsive basal ganglia disease, and hemodialysis patients. Awareness of potential high biotin blood levels in the fore-mentioned patient populations is important to ensure appropriate alternative non-biotinylated assays are used for testing. Excessive biotin supplementation can produce falsely low results when using a 2-site “sandwich” assay and falsely elevated test results when using a competitive immunoassay (Table 4.1) [47e49]. High protein supplements are not only associated with intermittent abdominal pain but with laboratory manifestations of hyperalbuminemia and transient increases in AST and ALT. Albumin and liver enzyme activities returned to normal once the patients discontinued using the high protein supplements [50]. Widely used as an anti-depressant, St. John’s Wort (Hypericum perforatum)

Cortisol (competitive)

Falsely high

DHEAS (competitive)

Falsely high

Estradiol (competitive)

Falsely high

Free thyroxine (competitive)

Falsely high

Free triiodothyronine (competitive)

Falsely high

Insulin (2-site “sandwich”)

Falsely low

FSH (2-site “sandwich”)

Falsely low

LH (2-site “sandwich”)

Falsely low

NT-proBNP (2-site “sandwich”)

Falsely low

Parathyroid hormone (2-site “sandwich”)

Falsely low

PSA (2-site “sandwich”)

Falsely low

Prolactin (2-site “sandwich”)

No effect observed

Testosterone (competitive)

Falsely high

Thyroglobulin (2-site “sandwich”)

Falsely low

TSH (2-site “sandwich”)

Falsely low

TSH receptor antibodies (2-site “sandwich”)

Falsely low

Troponin T (2-site “sandwich”)

Falsely low

Vitamin B12 (competitive)

Falsely high

25-hydroxyvitamin D (competitive)

Falsely high

25-hydroxyvitamin D (2-site “sandwich”)

Falsely low

Effects of excessive biotin supplementation on common endocrine tests measured by immunoassays.

markedly interferes with the metabolism of prescribed drugs as it is a potent inducer of P-glycoprotein and cytochrome P450 3A4 (CYP3A4) and to a lesser extent CYP1A2 and CYP2C9 [44]. Co-administration of St. John’s Wort significantly alters concentrations of cyclosporine (transplant rejection) [51], indinavir (HIV inhibitor) [52], and Digoxin (P-glycoprotein transporter) [53]. Royal jelly is a milky secretion produced by glands in the heads of nurse honey bees for the development and nurturing of queen bees. Ingestion of Royal jelly by an 87-year-old man, who was previously stabilized on warfarin, developed hematuria and was found to have a highly elevated international normalized ratio, (INR) of 7.29 after taking a royal jelly supplement for a week. It is not known how Royal jelly might increase the effects of warfarin. Valerian, also used for its anti-depressant properties, has been acute hepatotoxicity (elevated ALT, AST, GGT) however long-term effects on liver function are unclear. See Chapter 7 for more in-depth discussion on the effects of herbal supplements on clinical laboratory test results.

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Cross-sex hormone therapy effects on laboratory test results In many clinical laboratories gender-specific reference intervals are appended to test results. These reference intervals are not appropriate for patients on cross-sex hormone regimens and thus may be challenging for the clinician to interpret. Although limited, there are studies that have examined analyte changes in transgender individuals and may serve as a reference for laboratories establishing reference intervals (Table 4.2) [54]. Interestingly, in male-to-female patients on cross-sex hormone therapy, hematocrit, low-density lipoprotein, and hemoglobin reference ranges were within the cis female reference intervals. Yet, creatinine, alkaline phosphatase, and potassium reference ranges were within the cis male reference ranges. Overall, triglycerides were higher than both the cis female or cis male reference intervals (Fig. 4.2) [55]. To eliminate health disparities in the delivery of care provided to transgender patients, additional studies that examine analyte changes in patients on cross-sex hormone therapy are needed to identify: (i). analytes that should be monitored during the transitioning period; (ii) analytes that have diagnostic and prognostic strength for acute and chronic diseases in this population [56e58]. TABLE 4.2

Differences in routinely measured analytes in male to female trans patients on hormone therapy.

Analyte

Male

Male-to-female

Female

ALP

34.3e83.8a

24.4e90.7a

31.0e98.0

ALT

8.2e37.5

6.3e35.3

9.7e34.1

AST

9.7e37.6

11.7e36.9

11.1e32.6

BUN

7.2e19.9

5.9e18.8

4.9e21.9

Creatinine

0.73e1.3

a

a

0.55e1.3

0.65e1.0 a

Hgb

13.3e16.2

12.6e14.7

11.9e14.6a

HCT

38.4e45.7

34.6e43.7a

34.4e41.9a

Na

134.9e141.7

134.2e141.2

135.7e140.8

K

3.6e4.6a

3.4e4.9a

3.6e5.2

Cholesterol

120.5e246.3

110.2e244.5

104.5e254.3

Triglycerides

5.7e183.3

34.2e242.6b

31.2e110.6

HDL

24.9e63.9

19.5e85.1

32.0e76.2

LDL

73.8e151.2

4.3e161.4a

45.6e166.0a

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; HCT, hematocrit; HDL, high-density lipoprotein; Hgb, hemoglobin; K, potassium; LDL, low-density lipoprotein; Na, sodium. a Indicates consistent changes aligned with either natal or identified gender. b Indicates consistent changes intermediate to natal and identified gender. Source: Roberts TK, Kraft CS, French D, et al. Interpreting laboratory results in transgender patients on hormone therapy. Am J Med 2014;127:159e62, Table 1. ©Elsevier reprinted with permission.

EXERCISE RELATED CHANGES ON CLINICAL LABORATORY VALUES The effects of exercise on laboratory findings varies and is highly correlated with the health status of the person [59], temperature, and dietary intake (food or liquid) that occurs during or following exercise [60]. Fig. 4.1 shows that the frequency distribution of serum creatinine concentrations in athletes and controls (sedentary people) [59]. Thyroid function is markedly affected by the exercise intensity. Anaerobic exercise (characterized by 70% of maximal heart rate and lactate values 4.59 þ 1.75 mmol/L) caused a rise in T4, free T4 and thyroid stimulating hormone (TSH) but a fall in T3 and free T3 [61]. Physical exercise significantly alters plasma volume as a resultant of fluid volume loss due to sweating and fluid shifts between both the intravascular and interstitial bodily compartments [62]. Exercise reduces urinary erythrocyte and leukocyte content and the volume of urine while increasing the urinary protein excretion. Elevated urinary protein will clear within 24e48 h. Following exercising, a transient increase in the white blood cells, hematocrit and platelets occurs in parallel with electrolyte abnormalities (serum potassium decreases by 8%), which are present due to the altered hydration state and usually normalize with rehydration. Dehydration is also associated elevated creatinine and BUN concentrations. In the setting of severe dehydration, a sharp rise in BUN occurs but creatinine is only mildly elevated. Again, rehydration will gradually decrease these concentrations to normal. Regular vigorous exercise raises HDL-C and lowers triglycerides, very low density lipoprotein cholesterol (VLDL-C), and LDL-cholesterol. On the other hand, weightlifting exercise in healthy men (aged 18e45) induced pathological liver function test results [63]. AST, ALT, LD, CK and myoglobin were significantly increased following weightlifting and remained increased for approximately 7 days post exercise. Yet, bilirubin, GGT and ALP were within normal limits. These findings highlight the importance of refraining from weightlifting prior to clinical laboratory testing. Among healthy males, exercise comprised of 30-min cycling at 70e75% of maximal heart rate with a 30-min recovery significantly increased concentrations of hematocrit, red blood cell count, plasma albumin and fibrinogen concentrations, plasma viscosity, and whole blood viscosity from baseline in all three age groups (20e30 years, 40e50 years, and 60e70 years) in male subjects [64]. However, the changes were temporary and returned to baseline after the 30-min recovery period. In endurance runners exercise-associated iron deficiency is common. In moderately trained female long-distance runners, long-term endurance exercise

I. SOURCES OF ERRORS IN CLINICAL LABORATORIES: AN OVERVIEW

53

EXERCISE RELATED CHANGES ON CLINICAL LABORATORY VALUES

(A)

(B)

Creatinine *** ***

Alkaline Phosphatase (ALP) 1.5

150 * U/L 50 0

1.0

mg/dL

100

Male

(C)

MTF

0.0

Female

16 g/dL

%

Female

Hemoglobin (Hgb) *** ***

18

45 40

14 12

35

10

30 Male

MTF

(E)

(F)

mg/dL

150 100 50

Female

Triglycerides ** ***

300

**

MTF

Male

Female

LDL 200

mg/dL

MTF

Male

(D)

Hematocrit (HCT) *** ***

50

0.5

200 100

0

0 Male

MTF

Female

(G)

Male

MTF

Female

Potassium (K) **

6.0

**

mg/dL

5.5 5.0 4.5 4.0 3.5 3.0 Male

MTF

Female

FIG. 4.1 Consistent differences in laboratory measured and routinely monitored in male-to-females on hormone therapy. Values for maleto-female trans patients on hormone therapy for 6 months (n ¼ 55) compared with healthy male (n ¼ 20) and female (n ¼ 20) controls. Data are expressed as the 25th, 50th (median), and 75th percentiles (boxes) and the 2.5th and 97.5th percentiles (whiskers). *P < .05; **P < .01; ***P < .005. LDL, low-density lipoprotein. Source: Roberts TK, Kraft CS, French D, et al. Interpreting laboratory results in transgender patients on hormone therapy. Am J Med 2014; 127:159e62, Fig. 1 ©Elsevier, reprinted with permission.

(8 weeks) was evaluated and no differences were apparent in high sensitivity C-reactive protein (CRP) concentrations, suggesting that inflammation is not a normal process of endurance exercise in females. On the other hand, both serum hepcidin and soluble

transferrin receptor (sTfR) were affected and may explain the higher prevalence of iron deficiency in this population. Analytes that are affected by exercise are summarized in Table 4.3.

I. SOURCES OF ERRORS IN CLINICAL LABORATORIES: AN OVERVIEW

54

4. PATIENT-RELATED FACTORS THAT AFFECT LABORATORY RESULTS

FIG. 4.2 Frequency distribution of serum creatinine concentrations in the 2 groups, athletes and controls. Data are divided considering as threshold the median value of the control group [88 mmol/L (1.0 mg/dL)]. Source: Banfi G, Del Fabbro M. Serum creatinine values in elite athletes competing in 8 different sports: comparison with sedentary people. Clin Chem Feb 2006;52(2):330e1. https://doi.org/10.1373/clinchem.2005.061390, Fig. 1. Reproduced with permission from the American Association for Clinical Chemistry.

TABLE 4.3

Analytes that are affected by exercise.

Analyte

Effect of exercise

Urea

Value may increase after exercise

Creatinine

Value may increase after exercise

Aspartate Aminotransferase (AST)

Value may increase after exercise

Lactate Dehydrogenase (LDH)

Value may increase after exercise

Total Creatinine Kinase (CK)

Value may increase after exercise

CK-MB

Value may increase after exercise

Myoglobin

Value may increase after exercise

WBC Count

Value may increase after exercise

Platelet Count

Value may increase after exercise

Prothrombin Time

Value may increase after exercise

D-Dimer

Value may increase after exercise

Packed Cell Volume

Value may decrease after exercise

Activated Partial Thromboplastin Time

Value may decrease after exercise

Fibrinogen

Value may decrease after exercise

DIFFERENCE IN LABORATORY TEST RESULTS AMONG POPULATIONS Several analytes have been reported to exhibit small to large differences among different ethnic populations [65].

The clinical significant of these differences are not always evident and may ‘racialize’ the delivery of patient care [66]. It is imperative that laboratory professionals and clinicians refrain from using ethnicity or race as the ultimate indicator for diagnosis, management, and prognosis as such use can increase the risk of serious medical errors. Self-identification and social categorization of populations continues to evolve as many individuals identify with more than one race. Population differences in total serum protein concentration was reported to be higher in black individuals compared to white individuals and was attributed to gamma-globulin concentrations although serum albumin concentration was lower in black individuals. Along similar lines, creatinine kinase was reportedly higher in a study comparing black and white subjects noting higher muscle mass in the black subjects. However, each patient is different and a white individual’s muscle mass can be equivalent or exceed a black individual’s muscle mass. Healthcare professionals must incorporate ‘personalized medicine’ when evaluating clinical results. One study reported that black children exhibited higher ALP compared to white children. Another study showed that serum cystatin C concentrations were different among non-Hispanic white, non-Hispanic black, and Mexican American adolescents (aged 12 to 19) [16]. Cystatin C concentrations were higher in non-Hispanic white compared to non-Hispanic black and Mexican Americans. In contrast, creatinine was lower in non-Hispanic white and Mexican Americans compared with non-Hispanic black Americans. In an adult population-based sample (aged 50e67), black men had higher 24-h urinary excretion of creatinine and higher concentrations of the stress hormones epinephrine and norepinephrine compared to white men [36]. Hematological differences were reported between African Americans and white subjects in which the hematocrit, hemoglobin, mean corpuscular volume, serum transferring saturation, and white blood cell counts were lower in the African American group. Ferritin was higher in the African American group [67]. Currently, in the United States the Modified Diet of Renal Disease (MDRD) calculation the ethnicity factor of 1.2 is used to estimate the glomerular filtration rate (GFR) in Black/African Americans. However, two large studies conducted in sub-Saharan Africa (Ghana n ¼ 944 and South Africa n ¼ 100) showed the MDRD equation performed better in the absence of the ethnicity factor of 1.2 [68]. In a Saudi population (n ¼ 32), GFR estimated by MDRD strongly correlated with the

I. SOURCES OF ERRORS IN CLINICAL LABORATORIES: AN OVERVIEW

REFERENCES

measured inulin clearance [69]. Yet, in a Japanese population (n ¼ 248), GFR estimated by the 0.881xMDRD equation correlated better with measured inulin clearance than with the 1.0xMDRD equation [70]. Clearly, estimation of GFR by MDRD varies by global region and most likely this variability correlates with genetic/ environmental factors that are associated with body muscle mass. Interpretation of laboratory findings based solely on the presumed effect of ethnicity/race should not occur.

CONCLUSIONS It is important for laboratory professionals to implement age and gender specific reference ranges for certain analytes and such reference range information should be a part of routine reporting of laboratory test results. Nevertheless diet, exercise and other factors may alter expected laboratory test results and proper investigation must be made to interpret such laboratory test results for proper patient management. Especially for pharmacogenetics testing.

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I. SOURCES OF ERRORS IN CLINICAL LABORATORIES: AN OVERVIEW