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This article is a revised English version of a paper originally published in
the Journal of the Japan Medical Association (Vol. 129, No. 5, 2003, pages 607–612).
What are Trace Elements?
The human body is composed of elements
which can be roughly divided into abundant
elements and trace elements. Abundant ele-
ments consist of the major elements that are
involved in the formation of covalent bonds
What are Trace Elements?
—Their deficiency and excess states—
JMAJ 47(8): 351–358, 2004
Osamu WADA
Professor Emeritus, University of Tokyo
Abstract: Elements which are detected in small but not precisely known amounts in the living body were called “trace elements” in the past. Recent advances in analytical technologies, such as the development of atomic absorption spectrom- etry, have made it possible to measure these elements precisely and to determine their functions and the characteristics of their deficiency and excess states. The so-called vitamin boom has passed, and it now appears to be boom-time for trace elements. Nowadays, cases with trace element deficiencies are often encountered clinically, especially during high-calorie parenteral therapy or enteral nutrition, and congenital abnormalities of trace element metabolism have been clarified successively. Thus, knowledge of the clinical aspects of trace elements is becoming indispensable for front-line clinicians.1)^ Meanwhile, epidemiological surveys and animal studies have suggested the possibility that some trace element deficiencies are associated with a reduced anti-oxidant potential in organisms (which is believed to possibly underlie the onset of cancer and atherosclerosis), accelerated aging, developmental retardation in children, and an increased inci- dence of abnormal pregnancies, immunological abnormalities, and lifestyle-related diseases. Thus, from the viewpoint of prophylactic medicine, study, survey, and prophylaxis of trace elements are also attracting close attention.
Key words: Trace element; Trace element deficiency; Excess of trace elements; Congenital abnormality in trace element metabolism
and are important constituents of tissues (oxygen, carbon, hydrogen, nitrogen, etc.), and semi-major elements, which often exist in the ionic state, and are involved in functions of the living body through maintenance of osmotic pressure and membrane potentials (potassium, sodium, etc.). Major elements account for 96%
Trace Elements
Table 1 Functions of Trace Elements and Symptoms of Their Deficiency and Excess States
Trace Enzymes containing element the elements andactive forms^ Physiological functions^ Symptoms of deficiency state^ Symptoms of excess state
Carbonic anhydrase Protein metabolism Major symptoms: Acute: Peptidase Lipid metabolism Gradually exacerbating Relative Fe-Cu deficiency, Alcohol dehydrogenase Carbohydrate metabolism eruptions, first affecting nausea, vomiting, Alkaline phosphatase Bone metabolism the face and perineum abdominal pain, melena, Polymerase Associated symptoms: hyperamylasemia, Zinc finger Stomatitis, glossitis, alopecia, somnolence, hypotension, Zinc etc. nail changes, abdominal lung edema, diarrhea, symptoms (diarrhea, vomiting), jaundice, oliguria fever Chronic: Delayed wound healing, dwarfism Reduced reproductive Growth retardation, negative function, dwarfism, N balance, taste disorder, hyposmia, Immunosuppression, anemia Mental symptoms (depression), Taste disorder, anorexia
Ceruloplasmin Hemopoiesis Anemia Nausea, vomiting, Monoamine oxidase Bone metabolism Leukopenia heartburn, diarrhea, Cytochrome oxidase Connective tissue Neutropenia jaundice, hemoglobinuria, Ascorbic acid oxidase metabolism Disturbed maturation of hematuria, oliguria, Copper DopamineSuperoxide dismutase^ -hydroxylase Bone changes (children):myeloleukocytes^ anuria, hypotension, coma,melena etc. Reduced osseous age, irregular/spurring metaphysis, bone radiolucency, bone cortex thinning
Glucose tolerance factor Carbohydrate metabolism Abnormal glucose tolerance Nausea, vomiting, Cholesterol metabolism Reduced respiratory quotient peptic ulcer, CNS disorder, Connective tissue Weight loss Liver/kidney dysfunction, Chromium (^) Protein metabolismmetabolism^ Peripheral neuropathyIncreased serum free fatty acids^ growth retardation Abnormal nitrogen balance Metabolic consciousness disturbance
Glutathione peroxidase Antioxidant action Myalgia (lower extremities) Selenosis (alopecia, nail (GSH-Px) T4T3 conversion Cardiomyopathy detachment, CNS disorder) Selenium 5 -deiodinase (type I) Reduced carcinogenicity (myocardial cell collapse, Various selenoproteins action fibrosis) Nail bed whitening
Arginase Bone metabolism Reduced serum cholesterol Parkinsonian syndrome Pyruvate carboxylase Carbohydrate metabolism Reduced coagulation Early chronic: Superoxide dismutase Lipid metabolism Hair reddening Impotence, loss of vigor, Manganese Glycosyltransferase^ ReproductionImmunity Dermatitis (miliaria crystallina)Growth retardation somnolence, anorexia,edema, myalgia, headache, Increased radiolucency at the excitation, fatigue epiphyses of long bones Advanced stage: Extrapyramidal disorder
Xanthine oxidase Amino acid metabolism Tachycardia Hyperuricemia, gout Xanthine dehydrogenase Uric acid metabolism Polypnea Aldehyde oxidase Sulfuric acid/sulfurous Night blindness Molybdenum Nitrous acid oxidase^ acid metabolism^ ScotomaIrritability Somnolence Disorientation Coma
Cobalt Vitamin B^12 Hemopoiesis^ Pernicious anemiaMethylmalonic acidemia^ Cobalt poisoning
Iodine Thyroid hormone Tissue metabolism Goiter, hypothyroidism Goiter, hypothyroidism (Summary of many reports)
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relation to trace elements. It is noteworthy
that the mean daily intake and the RDA are
approximately the same for most trace ele-
ments. This can be interpreted as evidence that
over the long history of humankind, dietary
styles allowing approximately stable supply of
trace elements have become established, and
that the amounts of trace elements ingested via
food represent the appropriate levels. In other
words, trace element deficiencies are unlikely
to occur unless the dietary patterns of indi- viduals change dramatically, or the metabolism of trace elements is disturbed. Table 4 shows the major causes of trace element deficiencies. High-calorie parenteral therapy and enteral nutrition can be viewed as representing dra- matic alterations of the dietary pattern, while extremely low intake and congenital metabolic abnormalities can be viewed as representing disturbed metabolism of trace elements. In recent years, the prevalence of these metabolic abnormalities has been on the increase, and their pathophysiology has been clarified in depth, highlighting the importance of trace elements in clinical practice. It is also important to note that the ratio of the RfD to RDA, i.e., the safety margin, is not very large. Amidst the tendency of people to consume health promotion foods based on their distrust of medicines, preparations of trace elements are available commercially, and inappropriate use of these preparations can cause excess states of these trace elements. It is also noteworthy that the doses at which trace elements exert pharmacologically effec- tive actions are much higher than the RfD.
Table 3 Daily Dietary Requirements of Trace Elements in Adult Japanese Males (body weight: 50 kg)
“No “Lowest Effective Recommended (^) Reference Trace element Mean daily intake effects” leveladverse^ effect” leveladverse^ pharmacologicalreplenishment/^ allowancedietary^ dose RfD/ (NOAEL) (LOAEL) dose (RDA) (RfD)^ RDA
Zinc 7 11 mg 30 mg* 600 mg 200mg 9.6 mg 30 mg 3 (immune functions, etc.) Copper 1 4mg 9 mg* 10 mg — 1.8 mg 9 mg 5 Chromium (III) 28 62 g 1,000 g* — 150 1,000 g 35 g 250 g 7 (diabetes mellitus, etc.) Selenium 41 168 g 400 g 750 g* 200 g 55 g 250 g 4. (cancer prevention, etc.) Manganese 3 4mg 10 mg* — — 4 mg 10 mg 2. Molybdenum 135 215 g 350 g 7 mg* — 30 g 250 g 8 Iodine 200 30,000 g 3,000 g* 23,000 g — 150 g 3,000 g 20 Arsenic 10 34 g 40 g* 700 g — 10–34 g 140 g 4
- Basis for calculation of RfD
- The mean daily intake is approximately equal to the RDA.
- RfD/RDA indicates the safety margin between daily requirements and toxic levels, and is not very large. (Quoted from Wada, O.: Usefulness and safety of trace chemicals. Proceedings of Trace Nutrients Research 2001; 18: 1–10.)
Table 4 Major Causes of Trace Element Deficiency
- Inadequate supply
- Congenital metabolic disorders: Acrodermatitis enteropathica (zinc), Menkes disease (copper)
- Inadequate intake: Unbalanced nutrition, excessive purification of crops, ingestion of foods poor in trace elements, undevelopment of the food transportation system
- Iatrogenic: High-calorie parenteral therapy, chelating drugs, surgery, etc.
- Diseases, etc.: Pregnancy, excessive alcohol consump- tion, liver disease, nephropathy
Note: Underlined factors are predominant.
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Figure 1 graphically represents these rela-
tionships for zinc. 3)
Deficiency and Excess States of
Trace Elements
As shown in Table 5, deficiency and excess
of trace elements are either congenital or
acquired. Deficiency states of trace elements
are most frequently seen during high-calorie
parenteral therapy or enteral nutrition. Zinc
deficiency can develop within 2 weeks after
the start of such therapies. 4)^ Therefore, while
administering these therapies, caution must be
exercised to ensure that all trace element defi-
ciencies are prevented.
Congenital abnormalities of trace element
metabolism are rare. Abnormal intestinal absorp-
tion or disturbed transport of absorbed trace
elements more often lead to deficiency of trace elements. Acrodermatitis enteropathica due to disturbed zinc absorption and Menkes disease due to abnormal copper transport through the intestinal mucosa5)^ are some examples of such conditions. If the site of uptake of trace elements into an active form is disturbed, the trace element is pooled there, causing excess of the element. In cases of Wilson disease characterized by dis- turbed uptake of copper into ceruloplasmin,5) tissue damage and fibrosis due to copper occur in the liver and other sites.
Trace Element Deficiencies as Viewed from the Standpoint of Prophylactic Medicine
Many epidemiological surveys and animal
Fig. 1 Toxic levels, recommended daily dietary allowance, effective replenishment dose, and “no adverse effect” level of zinc (amounts of zincabsolute level) The effective replenishment level (pharmacological level) is higher than toxic levels. The amount ordinarily ingested is slightly lower than the recommended daily dietary allowance. (Quoted from Wada, O.: Usefulness and safety of trace chemicals. Proceedings of Trace Nutrients Research 2001; 18: 1–10.)
(Toxic Levels and Recommended Daily Dietary Allowance)
Nauseant level (455 mg)
Elevated serum LDL (300 mg)
Reduced immune functions (300 mg)
Causing gastrointestinal symptoms (100 mg) NOAEL for immunosuppression (100 mg)
LOAEL for serum HDL reduction (75 mg)
NOAEL for serum HDL reduction (50 mg)
Suppressing copper and iron absorption (50 mg)
RfD for adult Japanese (30 mg)
RfD by US EPA (18 20 mg/60 kg/day)
RDA for adult US males (15 mg)
RDA for adult US females (12 mg)
RDA for adult Japanese males (9.6 mg)
RDA for adult Japanese females (7.8 mg)
Minimum balancing level (5.5 mg)
(100)
(10)
(0)
(1,000) amounts of zinc mg/day (Effective Replenishment and “No Adverse Effect”)
LDL-decrease and HDL-increase in patients with ischemic heart disease (240 mg) LDL-decrease in females (150 mg)
No effects on immune functions (100 mg) Improved immune functions (14 200 mg) Treatment of gastric ulcer (48 mg) Treatment of various diseases (30 45 mg) Improved the sense of taste (30 mg) Favorable effects on pregnancy and labor (30 mg) Improved dark adaptation (25 mg)
No antagonism against copper and iron (8 24 mg)
Amounts taken with supplement by the US population (0.
100
mg)
No effects on lipids
(
^150
mg)
Amounts ingested by
Japanese
(7.
12
mg)
DEFICIENCY AND EXCESS OF TRACE ELEMENTS
studies have demonstrated that health prob-
lems are caused by deficiency of trace elements
(Table 6).6)^ It has been shown that the defi-
ciency of many trace elements, especially zinc,
is associated with accelerated aging,7)^ immuno-
deficiency, 8)^ accelerated progression of HIV in-
fection, 9)^ increased incidence of abnormal
pregnancies,10)^ developmental retardation in
children, 11)^ and taste disorder. 12)^ It has also
been shown that deficiency of chromium13)^ is
related to the development of diabetes mellitus
and atherosclerosis, and that selenium defi-
ciency 14)^ is associated with the increase of
cancer and ischemic heart disease. Clarifying
these abnormalities clinically and establishing
countermeasures against them are important
issues that must be addressed by regional
hospitals engaged in both prophylactic medi-
cine and clinical medicine. Studies in this field
may be expected to advance rapidly from now
on and contribute to improving the dietary
habits of populations in local communities.
Decreased anti-oxidant potential of the liv-
ing body, which is a subject that has recently
attracted close attention, is thought to underlie
the development of numerous lifestyle disease
conditions. Several trace elements have been
shown to be involved in the anti-oxidant effi-
cacy of the body (Fig. 2).13)
Conclusion
In this article, the basic biology of trace elements and features of their deficiency and excess states have been presented to provide an overview of these elements. Clinically, as well as in nutritional evaluations, one of the most difficult problems concerning trace ele- ments is the difficulty of diagnosing trace element deficiencies. Although the currently available methods of diagnosis are listed in Table 7, there are few methods that allow accurate diagnosis, especially in cases with mild to moderate deficiency. The development of more accurate methods is an issue that must be addressed in future.
REFERENCES
1) Wada, O. et al. : Trace elements and their
abnormalities. Integrated Handbook of Inter-
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2) Wada, O.: Usefulness and safety of trace
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3) Wada, O. and Yanagisawa, H.: Trace elements,
with special reference to the usefulness and
safety of zinc. Medicine and Drug Journal
1997; 33(12): 126–134. (in Japanese)
Table 7 Diagnosis of Trace Element Deficiency
- Trace element deficiency is one of the most difficult conditions to diagnose. Few valid methods are available (due to the wide overlap between the normal state and the deficiency state).
- Methods currently used
- Measurement of trace element concentrations in samples: serum, erythrocytes, leukocytes, lymphocytes, hair (for many elements); urine (for iodine)
- Measurement of the activity of enzymes containing trace elements in their core: alkaline phosphatase (zinc), 5-nucleotidase (zinc), ACE ratio (zinc), ceruloplasmin (copper), thyroid hormone (iodine), glutathione peroxidase (selenium), etc.
- Function tests: dark adaptation (zinc), taste test (zinc), electroretinogram (zinc)
- Balance studies: many elements, not practical
- Analysis of daily intake: not practical, large variance (many elements)
- Checking for alleviation of symptoms following replenishment: most reliable method of diagnosing deficiency (many elements)
Note: Underlined methods are the most frequently used. (Quoted from Wada, O. et al .: Trace elements and their abnormalities. Integrated Handbook of Internal Medicine 6, Nakayama-Shoten Co., Ltd., Tokyo, 1995; pp. 253–263.)
DEFICIENCY AND EXCESS OF TRACE ELEMENTS
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Japanese Journal of Clinical Medicine 1996; 54:
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