Ryan W. Himes Robert J. Shulman
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24 Himes Shulman
Test (specimen) Normal range1 Function/description Deficiency Pitfalls to avoid
Albumin (serum)
Infant: 29–55 g/l Child: 37–55 g/l [2]
Most abundant serum protein, half-life 20 days
Negative acute-phase reactant
↓ with hepatic synthetic dysfunction
Changes with hydration status and fluid shifts
Alkaline phosphatase (serum)
Infant: 150–420 U/l 2–10 years: 100–320 U/l Adolescent boy: 100–390 U/l Adolescent girl: 100–320 U/l Adult: 30–120 U/l
Zinc-dependent metallo- enzyme found in liver, bone, biliary epithelium, kidney and intestine
Low alkaline phosphatase warrants consideration of zinc deficiency
α1-Antitrypsin (stool)
<6 months: <4.5 mg/g of stool
>6 months: <3 mg/g of stool [3]
Measure of protein loss from the gut
Unstable at pH <3, unsuitable to assess gastric protein loss [4]
Biotin (serum)
214–246 pmol/l [5] Water-soluble vitamin, cofactor for carboxylases
Dermatitis, glossitis, alopecia, poor growth, ataxia, weakness, depression and seizures
Anticonvulsants, hemodialysis and parenteral nutrition may give rise to deficiency Calcium
(serum)
Preterm: 1.6–2.8 mmol/l Term to 10 days: 1.9–2.6 mmol/l 10 days to 2 years: 2.3–2.8 mmol/l 2–12 years: 2.2–2.7 mmol/l Adult: 2.2–2.5 mmol/l
Skeletal integrity, cofactor in clotting cascade and neuromuscular function
Fatigue, muscular irritability, tetany and seizures
Factitious hypocalcemia caused by low albumin (50% is bound to albumin)
Ceruloplasmin (serum)
Birth to 3 months: 40–160 mg/l 3–12 months: 290–380 mg/l 1–15 years: 230–490 mg/l [3]
Carries 90% of serum copper Positive acute-phase reactant
Copper (serum)
11–22 μmol/l [2] Mineral cofactor for superoxide dismutase and enzymes of connective tissue synthesis
Anemia, neutropenia, depigmentation, characteristic hair changes, weakened bone and connective tissue [5]
Supraphysiologic doses of iron or zinc may impair absorption of copper [5]
Creatinine (serum)
Neonate: 27–88 μmol/l Infant: 18–35 μmol/l Child: 27–62 μmol/l Adolescent: 44–88 μmol/l Adult male: 80–115 μmol/l Adult female: 53–97 μmol/l
Product of muscle creatinine- phosphate metabolism; level parallels muscle mass
Diminished glomerular filtration rate, cimetidine, cephalosporins and trimethoprim may increase serum creatinine [6]
Elastase (stool)
>200 μg/g of stool Indicator of exocrine pancreas sufficiency
Sensitivity and specificity in mild insufficiency unclear [8]
Fat (stool)
<3 years: >85%
>3 years: >95%
(expressed as coefficient of absorption)
Indicator of fat malabsorption Classically, a 72-hour stool
collection with diet diary and adequate fat intake
Ferritin (serum)
Neonate: 25–200 μg/l 1 months: 200–600 μg/l 2–5 months: 50–200 μg/l 6 months to 15 years: 7–140 μg/l Adult male: 20–250 μg/l Adult female: 10–120 μg/l
Major storage form of iron;
levels mirror body reserves Early and sensitive indicator of iron deficiency anemia
Positive acute-phase reactant
Folate (serum) Neonate: 16–72 nmol/l Child: 4–20 nmol/l Adult: 10–63 nmol/l
Water-soluble vitamin, role in DNA/RNA synthesis and amino acid metabolism
Macrocytic anemia, hypersegmented neutrophils, glossitis, stomatitis, poor growth and fetal neural tube defects
Deficiency may be clinically indistinguishable from that of B12, but the latter has neurological signs
Methotrexate, phenytoin and sulfasalazine antagonize folate utilization
Table 1. Frequently used laboratory tests in the assessment of childhood nutrition
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 23–28 DOI: 10.1159/000360314
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Table 1 (continued)
Test (specimen) Normal range1 Function/description Deficiency Pitfalls to avoid
Hemoglobin (whole blood)
0–8 days: 2.06–3.79 mmol/l 9 days: 1.66–3.33 mmol/l 3 months: 1.53–2.25 mmol/l 1 year: 1.38–2.14 mmol/l 3 years: 1.58–2.31 mmol/l 11 years: 1.72–2.43 mmol/l Adult male: 1.86–2.48 mmol/l Adult female: 2.17–2.79 mmol/l
Oxygen-carrying moiety in RBC
Microcytic
Iron deficiency, chronic disease
Normocytic
Chronic disease, acute bleeding
Macrocytic B12, folate deficiency
Influenced by hydration status, nutrition and pregnancy
Iron (serum) Neonate: 17.9–44.8 μmol/l Infant: 7.2–17.9 μmol/l Child: 9–21.5 μmol/l Adult male: 11.6–31.3 μmol/l Adult female: 9–30.4 μmol/l
Component in heme and cytochrome proteins
Microcytic anemia, pallor, weakness and dyspnea
Transferrin is a sensitive measure of body iron stores;
however, it is a negative acute-phase protein
Lymphocytes (whole blood)
>1,500/mm3 Total lymphocyte count is
inversely correlated to degree of malnutrition [6]
Magnesium (serum)
0.63–1.00 mmol/l Important for neuromuscular conduction; enzyme cofactor
Arrhythmia, tetany, hypocalcemia and hypokalemia
↓ by low serum albumin
↑ by hemolyzed specimens
pH (stool) >5.5 [7] Low fecal pH usually implies
carbohydrate malabsorption
Improper specimen processing may lead to falsely low values Phosphorus
(serum)
Neonate: 1.45–2.91 mmol/l 10 days to 2 years: 1.29-2.1 mmol/l 3–9 years: 1.03–1.87 mmol/l 10–15 years: 1.07–1.74 mmol/l
>15 years: 0.78–1.42 mmol/l
Vital for energy transfer at cellular level
Confusion, respiratory distress, tissue hypoxia, bone abnormalities and ↑ alkaline phosphatase
‘Refeeding syndrome’ is hypophosphatemia and hypokalemia complicating nutritional rehabilitation of the severely malnourished patient Prealbumin
(serum)
Neonate: 70–390 mg/l 1–6 months: 80–340 mg/l 6 months to 4 years: 120–360 mg/l 4–6 years: 120–300 mg/l 6–19 years: 120–420 mg/l
Gauge of visceral protein stores; half-life of 2 days
Negative acute-phase reactant
Prothrombin time (plasma)
11–15 s [2] Used to assess vitamin K
sufficiency, although better assessed with undercarboxylated prothrombin (PIVKA-II)
Also prolonged in liver dysfunction, malabsorption syndromes, prolonged antibiotic use and warfarin therapy
Reducing substances (stool)
Negative Presence suggests carbo-
hydrate malabsorption
Improper specimen processing may lead to falsely normal values
Retinol-binding protein (serum)
<9 years: 10–78 mg/l
>9 years: 13–99 mg/l [2]
Gauge of visceral protein stores; half-life of 12 h
Negative acute-phase reactant
↓ in vitamin A deficiency, hepatic dysfunction
↑ in renal failure Selenium
(serum)
Preterm: 0.6–1 μmol/l Term: 0.8–1.1 μmol/l 1–5 years: 1.4–1.7 μmol/l 6–9 years: 1.4–1.8 μmol/l
>10 years: 1.6–2.1 μmol/l [5]
Trace mineral essential for glutathione peroxidase
Cardiomyopathy (Keshan disease), myositis and nail dystrophy
Urea nitrogen (serum)
Preterm (1st week): 1.1–8.9 mmol/l Neonate: 0.7–6.7 mmol/l Infant/child: 1.8–6.4 mmol/l Adult: 2.1–7.1 mmol/l
Produced in liver from protein degradation and excreted renally
↓ in low-protein-intake states
↑ in high-protein diets, but also kidney disease
26 Himes Shulman
total protein is predicated on normal globulin levels, limiting its clinical usefulness. Generally, se- rial measurements of protein status are more meaningful than single values and an understand- ing of their biological half-lives will dictate the
frequency of assessment ( table 2 ). A framework for the investigation of hypoalbuminemia is shown in figure 1 .
The most important limitation to interpreting serum protein levels is their function in the acute-
Table 1 (continued)
Test (specimen) Normal range1 Function/description Deficiency Pitfalls to avoid
Vitamin A (serum)
Preterm: 0.46–1.6 μmol/l Term: 0.63–1.75 μmol/l 1–6 years: 0.7–1.5 μmol/l 7–12 years: 0.9–1.7 μmol/l 13–19 years: 0.9–2.5 μmol/l
Fat-soluble vitamin that functions in vision, maintenance of epithelial tissue and immunity; 90%
stored in liver
Reversible night blindness (1st clinical manifestation), which, uncorrected, can progress to corneal scarring
↓ in liver disease, zinc deficiency [5]
↑ with oral contraceptive pill use
Vitamin B1 – thiamine (whole blood)
Measure RBC transketolase activity
<15% [2]
Water-soluble vitamin with role in oxidative
phosphorylation and pentose phosphate pathway
Beriberi: cardiac failure, peripheral neuropathy ± edema
Wernicke encephalopathy, Korsakoff syndrome Vitamin B2
– riboflavin (whole blood)
Measure RBC glutathione reductase activity
<20% [2]
Water-soluble vitamin that facilitates redox reactions
Dermatitis, cheilitis, glossitis and visual impairment
Vitamin B6 – pyridoxine (plasma)
Measure pyridoxal 5′-phosphate concentration
14.6–72.8 nmol/l [3]
Cofactor for enzymes in aminotransferase reactions including δ-aminolevulinic acid and the manufacture of serotonin [5]
Microcytic, hypochromic anemia, dermatitis, cheilosis, stomatitis, peripheral neuropathy, seizures and ↓ AST and ALT
↓ level with isoniazid treatment
Vitamin B12 – cobalamin (serum)
Neonate: 118–959 pmol/l Infant/child: 148–616 pmol/l
Water-soluble vitamin active in DNA synthesis and branched-chain amino acid metabolism
Megaloblastic anemia, hypersegmented neutrophils and glossitis, stomatitis, weakness, elevated homocysteine and methylmalonic acid
↓ by phenytoin, proton-pump inhibitors, neomycin and folate deficiency
Vitamin C – ascorbate (plasma)
23–114 μmol/l Water-soluble antioxidant
vitamin important in collagen synthesis
Scurvy: petechial and gingival hemorrhage, gingivitis and poor wound healing Vitamin D
– 25-hydroxy (plasma)
Summer: 15–80 μg/l Winter: 14–42 μg/l [3]
Fat-soluble vitamin involved in calcium and phosphorus homeostasis
Deficiency primarily affects bone and is called ‘rickets’;
↓ serum calcium and phosphate,
↑ alkaline phosphatase
↓ with anticonvulsant therapy and cholestyramine
Vitamin E (serum)
Preterm: 1–8 μmol/l Term: 2–8 μmol/l 1–12 years: 7–21 μmol/l 13–19 years: 14–23 μmol/l
Fat-soluble antioxidant that protects cell membranes
Diminished deep tendon reflexes, impaired balance and gait
Carried in serum bound to lipid;
therefore, hyperlipidemia may mask deficiency; vitamin E/lipid ratio useful in these
circumstances Zinc (plasma) 10.7–18.4 μmol/l Cofactor for >200 enzymes,
notably alkaline phosphatase, RNA/DNA polymerase and superoxide dismutase [5]
Acrodermatitis enteropathica, also delayed wound healing, impaired taste, growth failure, delayed puberty and diarrhea
↑ in hemolyzed specimens
↓ in sickle cell patients, hypoalbuminemia
1 All reference ranges from Tschudy and Arcara [1] unless otherwise noted.
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 23–28 DOI: 10.1159/000360314
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phase response ( table 3 ). Appreciating the posi- tive and negative acute-phase reactants will help avoid misinterpretation of data. Another limita- tion of measuring serum proteins is that their manufacture is tied to hepatic synthetic function.
Therefore, in a child with advanced liver disease, low serum protein may not necessarily reflect a lack of substrate but rather a lack of synthetic function. Finally, their concentrations are also susceptible to changes in hydration status and fluid shifts, and these changes may occur rapidly (e.g. increased vascular permeability associated with sepsis or trauma).
Vitamins and Minerals
The decision to evaluate vitamin and mineral stores should take into account the suspected underlying pathophysiology (e.g. measurement of fat-soluble vitamins in conditions associated with fat malabsorption, such as celiac disease or cystic fibrosis). Frequently, signs and symptoms of nutrient deficiency overlap with one another, underscoring the importance of an informed ap- proach to laboratory investigation. An often overlooked class of patients prone to malnutri- tion are those with absent (surgically resected) or diseased (Crohn’s disease, small-bowel bacterial
overgrowth syndrome) terminal ilea. Deficiencies of vitamin B 12 , vitamin K and zinc are prevalent in these patients.
Finally, the potential effects of therapeutic drugs are important considerations. An exhaus- tive list of these interactions is beyond the scope of this text; however, some important nutrient- specific examples are shown in table 1 .
Table 2. Serum proteins used in the assessment of vis- ceral protein stores
Protein Half-life
Albumin 20 days
Prealbumin (transthyretin) 2 days Retinol-binding protein 12 h
Table 3. Serum proteins in the acute-phase response Positive acute-phase
reactants
Negative acute-phase reactants
α1-Antitrypsin Albumin
C3 complement Prealbumin (transthyretin) C-reactive protein Retinol-binding protein Ceruloplasmin Transferrin
Fibrinogen Thyroxin-binding globulin Low serum albumin
? Intake ? Factitious ? Losses
Diet history
• Food security
• Restrictive diets
• Formula preparation
Assess volume status
Consider inflammatory state Urine (urinalysis) Gastrointestinal (stool į1-antitrypsin) Burns
Fig. 1. A suggested framework for investigating hypoalbuminemia in children.
28 Himes Shulman
Tests of Maldigestion/Malabsorption/Enteric Protein Loss
Analysis of the stool is a logical starting point for the investigation of malabsorption.
(1) Fat malabsorption: fecal fat as assessed by 72-hour collection with diet record is an accurate, albeit cumbersome tool (for pa- tients and laboratory technicians) to quan- titate fat malabsorption. A fecal smear with Sudan staining gives a rough qualitative es- timate of steatorrhea and may be useful for screening purposes
(2) Pancreatic insufficiency: in addition to fe- cal fat measurement, determination of fecal elastase can be used as a measure of exo- crine pancreas sufficiency. Its level is not af- fected by pancreatic enzyme supplementa- tion. Although reliable for detecting severe pancreatic insufficiency, it is less so for mild-to-moderate pancreatic insufficiency;
it will not identify other isolated enzyme deficiencies (e.g. lipase) and gives falsely low values in the presence of watery stools unless they are lyophilized [8]
(3) Carbohydrate malabsorption: a low fecal pH and the presence of reducing substanc- es are indicators of unabsorbed carbohy-
drate in stool. Testing should be done on the most liquid portion of the stool and can be done at the bedside using the same test strips used to measure pH and glucose in urine
(4) Hydrogen breath testing: this test detects the passage of carbohydrate into the colon.
Breath hydrogen is measured at baseline and after the child is given an oral load of the carbohydrate of interest (e.g. lactose); a rise in hydrogen above baseline (dependent on the sugar of interest) is diagnostic. False- negative tests may be seen in patients re- cently administered antibiotics. Addition- ally, a positive test does not always correlate with symptoms of intolerance
(5) Small-bowel bacterial overgrowth syn- drome may be assessed in an analogous manner using lactulose or glucose. A breath hydrogen peak that occurs within 15–30 min of ingestion is suggestive of over- growth
(6) Stool α 1 -antitrypsin: unlike albumin, α 1 - antitrypsin passes into the stool undegrad- ed and reflects enteric protein loss but does not define etiology (can be increased in gut graft-versus-host disease, lymphangiecta- sia, severe heart failure, etc.)
6 Ravel R: Clinical Laboratory Medicine, ed 6. St Louis, Mosby, 1995, pp 655, 433.
7 Guandalini S: Essential Pediatric Gastro- enterology, Hepatology, and Nutrition.
New York, McGraw-Hill, 2005, pp 133–
134.
8 Leeds JS, Oppong K, Sanders DS: The role of fecal elastase-1 in detecting exo- crine pancreatic disease. Nat Rev Gas- troenterol Hepatol 2011; 8: 405–415.
References
1 Tschudy M, Arcara K (ed): The Harriet Lane Handbook, ed 19. Philadelphia, Mosby, 2012, pp 639–647.
2 Kleinman R (ed): Pediatric Nutrition Handbook, ed 6. Elk Grove Village, American Academy of Pediatrics, 2009, pp 573–575.
3 Benedict A, Gilger M, Klish W, Motil K, Phillips S, Shulman R, Terrazas N, Thomas J: The Baylor Pediatric Nutri-
tion Handbook, ed 4. Houston, Baylor College of Medicine, 2004, pp 34–43.
4 Walker A, Goulet O, Kleinman R, Sherman P, Shneider B, Sanderson I (ed): Pediatric Gastrointestinal Dis- ease, ed 4. Hamilton, BC Decker, 2004, p 195.
5 Sauberlich H: Laboratory Tests for the Assessment of Nutritional Status, ed 2.
Boca Raton, CRC Press, 1999.
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 23–28 DOI: 10.1159/000360314
1 Specific Aspects of Childhood Nutrition
Key Words
Nutrient recommendations ã Nutrient requirements ã Upper safe levels of intake ã Extrapolation ã Interpolation
Key Messages
• Nutrient intake values (NIV) provide estimates on appropriate dietary substrate supply for popula- tions of healthy people
• The average nutrient requirement is the estimated median requirement for a particular age- and sex- specific group
• The population reference intake is the intake that meets the nutrient needs of practically all healthy individuals in a particular population
• Major uncertainties exist in the establishment of NIV for infants, children and adolescents due to lim- ited scientific data. Deriving NIV from observed nutrient intakes (e.g. the nutrient supply provided by human milk) or extrapolation from other age groups has considerable limitations
© 2015 S. Karger AG, Basel
Introduction
Nutrient intake values (NIV) comprise a set of recommendations on dietary substrate supply for populations of healthy people. NIV are used to
assess intake data from dietary surveys and food statistics; to provide guidance on appropriate di- etary composition, meal provision and food- based dietary guidelines, they serve as the basis for national or regional nutrition policies, nutri- tional education programmes and food regula- tions and provide reference points for the label- ling of food products if nutrient contents are ex- pressed as a percentage of an NIV [1, 2] . The term NIV has been agreed upon by an expert consulta- tion convened by the United Nations University’s Food and Nutrition Programme in collaboration with the FAO, WHO and UNICEF [3] , rather than the terms ‘nutrient reference values’ (previ- ously used in Australia and New Zealand), ‘refer- ence values for nutrient supply’ (in Germany/
Austria/Switzerland), ‘dietary reference values’
(in the UK), ‘dietary reference intakes’ or, previ- ously, ‘recommended dietary allowances’ (RDA;
in the USA and Canada) [3] .
Conceptually, NIV are based on physiological requirements, which are defined as the amounts and chemical forms of nutrients needed system- atically to maintain normal health and develop- ment without disturbance of the metabolism of any other nutrient and without extreme homoeo- static processes, excessive depletion and/or sur- plus in bodily depots [1, 4–6] . The dietary re-
Koletzko B, et al. (eds): Pediatric Nutrition in Practice. World Rev Nutr Diet. Basel, Karger, 2015, vol 113, pp 29–33 DOI: 10.1159/000369234